Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel?

BACKGROUND: The purpose of this study was to investigate the elimination of paclitaxel from the arterial wall after a single short administration with a coated balloon. METHODS AND RESULTS: Slightly oversized paclitaxel-coated balloons (dose 3 or 9 µg/mm(2)) without or with premounted stents were inflated in nonatherosclerotic coronary arteries of either young domestic pigs or adult Goettingen minipigs. The paclitaxel content of plasma, arterial segments, and residual hearts (without treated arteries) was measured for up to 180 days using high-performance liquid chromatography/ultraviolet detection or mass spectrometry. Angiograms were evaluated for lumen narrowing. The paclitaxel concentration in plasma remained <10 ng/mL. In arteries of domestic pigs and minipigs treated with paclitaxel-coated balloons with premounted stents, 10%±5% or 21%±8% of dose, respectively, was initially detected and decreased to 3.5%±3.1% of dose (domestic pig) by Day 7. Within 6 months it fell with a half-life of 1.9 months to 0.40%±0.35%. After 3 months the concentration in the arterial wall was 17±11 µmol/L. Without a stent, drug transfer to the vessel wall was somewhat reduced and elimination faster. Immediately after treatment up to 26%±4% of dose was detected in the residual whole hearts. It dropped with a half-life of 45 days to 1.5%±0.6% of dose (0.3 µmol/L) within 6 months. CONCLUSIONS: After a single local administration with coated balloons, paclitaxel stays in the vessel wall of pigs long enough to explain persistent inhibition of neointimal proliferation. The pharmacokinetics of paclitaxel does, however, not exclude other reasons for sustained efficacy such as early blocking of processes initiating excessive and prolonged neointimal proliferation.

Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model.

OBJECTIVE: There is little published information regarding the efficacy of paclitaxel-coated balloon catheters except for the iopromide-containing formulation, and less is known about the kind of toxicity at overdose. The aim of our study was to assess 2 different paclitaxel matrix formulations on angioplasty balloon catheters in vitro, with respect to pharmacokinetics, and efficacy and tolerance to determine the minimum effective dose and local toxicity at extremely high dose which is only achieved in experimental studies. METHODS AND MATERIALS: Adherence of coatings was tested in vitro in dry state and during passage through hemostatic valves, guiding catheters, and blood. Drug release, transfer to the vessel wall during coronary angioplasty, inhibition of neointimal proliferation, and tolerance were investigated in swine. Efficacy and tolerance of balloons were examined for doses ranging from 1 to 9 µg/mm2 and 3 overlapping applications of balloons coated with 3 times the regular dose of 3 µg/mm2. Paclitaxel concentrations were determined by high performance liquid chromatography, efficacy and tolerance by vital signs, clinical observation, quantitative coronary angiography, and histomorphometry 4 weeks after implanting premounted bare stents in coronary arteries applying 1:1.2 overstretch. RESULTS: Under worst-case conditions, drug loss on the way through the guiding catheter and blood was in the range of 30%. After inflation of balloons coated with the clinically tested dose of 3 µg/mm2 in a coronary artery about 10% of drug remained on balloons, 20% to 30% was taken up into the vessel wall (∼200 µg). Neointimal area on cross sections was 6.8 ± 2.2 mm2 (uncoated control); 3.1 ± 1.1 mm2 (iopromide-matrix) and 3.0 ± 0.5 mm2 (urea-matrix) at 1 µg/mm2; 2.0 ± 0.4 mm2 versus 1.7 ± 1.1 mm2 at 3 µg/mm2 with no further decrease at higher doses. Thrombotic occlusions were observed in 3 of 15 vessel segments treated with overlapping inflations of 3 high-dose balloons but without any signs of aneurysms. CONCLUSION: In the animal model, 2 paclitaxel matrix formulations were similar in respect of uptake in the vessel wall, and effective already at a dose of 1 µg/mm2. Except thrombotic events for the intentionally excessive dose, paclitaxel-coated balloons were well tolerated in the animal model.

Comparison of carotid stents: an in-vitro experiment focusing on stent design.

PURPOSE: To examine and compare different carotid stent designs with regard to flexibility, adaptability (adjustability), conformability (compliance) to the vessel, and scaffolding to reduce plaque prolapse and embolization. METHODS: Six stents of different design were compared (Precise, Acculink, Protégé, Xact, Wallstent, and Cristallo Ideale). Optical microscopy was used to determine exact dimensions and scaffolding of each stent. Radial force was tested using a parallel plate setup, and flexibility (torsion and bending) was measured in water at body temperature. Particle penetration simulation was performed using plastic spheres from 1.5- to 6.0-mm outer diameter. RESULTS: Stent dimensions met the manufacturers' data; none of the products showed any failure during the test program. Cell sizes in the middle part of the stents ranged from 1.36 mm(2) (Wallstent) to 15.10 mm(2) (Acculink). Bending forces at 20 degrees /30 degrees ranged from 0.063 N / 0.074 N (Cristallo Ideale) to 0.890 N / 0.616 N (Xact); forces to achieve torsion at 10 degrees /15 degrees ranged from 0.032 N / 0.043 N (Acculink) to 0.905 N / 1.071 N (Xact). According to the parallel plate method, mean lowest force was measured for Xact (0.765 N), while the Wallstent had the highest force (2.136 N). Mean radial force measurements were lowest for Cristallo Ideale (9.06 N at mid part) and highest for Protégé (24.09 N). The Cristallo Ideale stent at mid part resisted penetration by all but the smallest plastic spheres (1.5-mm spheres penetrated only at 0.65 N); the Precise and Protégé stent had the highest variation in sphere penetration (1.5- to 4.0-mm spheres). Only the Acculink let 6-mm spheres penetrate. CONCLUSION: Despite comparable stent sizes, these carotid stents showed differences in behavior due to stent design. The open-cell design displayed the greatest flexibility and adaptability to the vessel but easily allowed particle penetration due to the open structure. Closed-cell designs had low flexibility and thus low adaptability to the vessel but high resistance to particle penetration due to the closed-cell design and high scaffolding. The hybrid stent design (Cristallo Ideale) was able to combine both the flexibility of an open-cell structure and the resistance to particle penetration of closed-cell structures.

Stent-protected carotid angioplasty using a membrane stent: a comparative cadaver study.

PURPOSE: To evaluate the performance of a prototype membrane stent, MembraX, in the prevention of acute and late embolization and to quantify particle embolization during carotid stent placement in human carotid explants in a proof of concept study. METHODS: Thirty human carotid cadaveric explants (mild stenoses 0-29%, n = 23; moderate stenoses 30-69%, n = 3; severe stenoses 70-99%, n = 2) that included the common, internal and external carotid arteries were integrated into a pulsatile-flow model. Three groups were formed according to the age of the donors (mean 58.8 years; sample SD 15.99 years) and randomized to three test groups: (I) MembraX, n = 9; (II) Xpert bare stent, n = 10; (III) Xpert bare stent with Emboshield protection device, n = 9. Emboli liberated during stent deployment (step A), post-dilatation (step B), and late embolization (step C) were measured in 100 microm effluent filters. When the Emboshield was used, embolus penetration was measured during placement (step D) and retrieval (step E). Late embolization was simulated by compressing the area of the stented vessel five times. RESULTS: Absolute numbers of particles (median; >100 microm) caught in the effluent filter were: (I) MembraX: A = 7, B = 9, C = 3; (II) bare stent: A = 6.5, B = 6, C = 4.5; (III) bare stent and Emboshield: A = 7, B = 7, C.=.5, D = 8, E = 10. The data showed no statistical differences according to whether embolic load was analyzed by weight or mean particle size. When summing all procedural steps, the Emboshield caused the greatest load by weight (p = 0.011) and the largest number (p = 0.054) of particles. CONCLUSIONS: On the basis of these limited data neither a membrane stent nor a protection device showed significant advantages during ex vivo carotid angioplasty. However, the membrane stent seems to have the potential for reducing the emboli responsible for supposed late embolization, whereas more emboli were observed when using a protection device. Further studies are necessary and warranted.

Flow velocities after carotid artery stenting: impact of stent design. A fluid dynamics study in a carotid artery model with laser Doppler anemometry.

PURPOSE: To study the influence of a newly developed membrane stent design on flow patterns in a physiologic carotid artery model. METHODS: Three different stents were positioned in silicone models of the carotid artery: a stainless steel stent (Wall-stent), a nitinol stent (SelfX), and a nitinol stent with a semipermeable membrane (MembraX). To increase the contact area of the membrane with the vessel wall, another MembranX model was modified at the outflow tract. The membrane consists of a biocompatible silicone-polyurethane copolymer (Elast-Eon) with a pore size of 100 mum. All stents were deployed across the bifurcation and the external carotid artery origin. Flow velocity measurements were performed with laser Doppler anemometry (LDA), using pulsatile flow conditions (Re = 220; flow 0.39 l/min; flow rate ratio ICA:ECA = 70:30) in hemodynamically relevant cross-sections. The hemodynamic changes were analyzed by comparing velocity fluctuations of corresponding flow profiles. RESULTS: The flow rate ratio ICA:ECA shifted significantly from 70/30 to 73.9/26.1 in the MembraX and remained nearly unchanged in the SelfX and Wallstent. There were no changes in the flow patterns at the inflow proximal to the stents. In the stent no relevant changes were found in the SelfX. In the Wallstent the separation zone shifted from the orifice of the ICA to the distal end of the stent. Four millimeters distal to the SelfX and the Wallstent the flow profile returned to normal. In the MembraX an increase in the central slipstreams was found with creation of a flow separation distal to the stent. With a modification of the membrane this flow separation vanished. In the ECA flow disturbances were seen at the inner wall distal to the stent struts in the SelfX and the Wallstent. With the MembraX a calming of flow could be observed in the ECA with a slight loss of flow volume. CONCLUSIONS: Stent placement across the carotid artery bifurcation induces alterations of the physiologic flow behavior. Depending on the stent design the flow alterations are located in different regions. All the stents tested were suitable for the carotid bifurcation. The MembraX prototype has shown promising hemodynamic properties ex vivo.

An in vitro analysis of a carotid artery stent with a protective porous membrane.

PURPOSE: To prove the effectiveness of a new stent concept with integrated protection (MembraX [MX]) by comparing it with five cerebral protection devices designed for carotid angioplasty in an in vitro model. MATERIALS AND METHODS: Two simulation series of embolization from carotid angioplasty have been performed. In the first series, polyvinyl-alcohol particles (150-250 microm [small], 355-500 microm [medium], 710-1000 microm [large]; 5 mg each) were injected into a silicone flow model simulating the aortic arch with a carotid bifurcation. The particles were injected proximally to the partially deployed MX stent or one of the following protection devices: Angioguard (AG), FilterWire EX (EX), Trap, Neuroshield (NS), or GuardWire Plus (GW). Particles evading the protection device were caught in a filter at the end of the flow model and weighed. In the second series, human plaque material (8-12 particles; total weight 6.09 +/- 0.01 mg; 500-1500 microm) was injected into the model with the respective devices. MX was compared with the AG, EX, Trap, and NS devices. RESULTS: MX had the most effective overall filtration performance for polyvinyl alcohol particles in the effluent of the internal carotid artery (ICA; 0.43 mg, 2.9%), compared with NS (0.53 mg, 3.5%), GW (1.10 mg, 7.0%), EX and AG (1.18 and 1.21 mg, respectively; 7.8% and 8.0%), and Trap (1.24 mg, 8.2%). MX performed best for the small particles (2.0% passed particles into ICA; P < .05 compared with all). Human plaque material was retained best in the in vitro model by MX (0.0%), followed by NS (0.8%), EX (1.3%), Trap (2.6%), and AG (4.4%). CONCLUSIONS: In vitro, none of the tested devices had the ability to prevent embolization completely. Comparing current designs, the MX device captured the highest percentage of the three different particle groups. Tested with human plaque emboli, MX performed effectively in filtering the particles in the ICA.