Stephen Schröder

Local Paclitaxel Delivery for the Prevention of Restenosis: Biological Effects and Efficacy In Vivo

OBJECTIVE The aim of this study was to evaluate the potential of paclitaxel to prevent restenosis in vivo. BACKGROUND Paclitaxel (Taxol) is a microtubule-stabilizing compound with potent antitumor activity. It influences the cytoskeleton equilibrium by increasing the assembly of altered microtubules, thereby inducing cellular modifications that result in reduced proliferation, migration and signal transduction. METHODS Before the in vivo study, delivery efficiency was determined with radiolabeled paclitaxel in porcine hearts. After induction of a defined plaque in the right carotid arteries of 76 New Zealand rabbits by electrical stimulation, 27 animals underwent balloon dilation and subsequent local paclitaxel delivery (10 ml, 10 micromol/liter) with a double-balloon catheter. Twenty-nine animals served as control with angioplasty only, 10 animals underwent local delivery of vehicle only (0.9% NaCl solution) and 10 animals were solely electrostimulated. Vessels were excised one, four, and eight weeks after intervention. RESULTS The extent of stenosis in paclitaxel-treated animals was significantly reduced compared with balloon-dilated control animals (p = 0.0012, one, four and eight weeks after intervention: 14.6%, 24.6% and 20.5%, vs. 24.9%, 33.8% and 43.1%, respectively). Marked vessel enlargement compared with balloon-dilated control animals could be observed (p = 0.0001, total vessel area after one, four and eight weeks: paclitaxel group: 1.983, 1.700 and 1.602 mm2, control: 1.071, 1.338 and 1.206 mm2, respectively). Tubulin staining and electron microscopy revealed changes in microtubule assembly, which were limited to the intimal area. Vasocontractile function after paclitaxel treatment showed major impairment. CONCLUSIONS Local delivery of paclitaxel resulted in reduced neointimal stenosis and enlargement in vessel size. Both these effects contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton.

Safety, Efficacy, and Indications of β-Adrenergic Receptor Blockade to Reduce Heart Rate prior to Coronary CT Angiography

For selected indications, coronary computed tomographic (CT) angiography is an established clinical technology for evaluation in patients suspected of having or known to have coronary artery disease. In coronary CT angiography, image quality is highly dependent on heart rate, with heart rate reduction to less than 60 beats per minute being important for both image quality and radiation dose reduction, especially when single-source CT scanners are used. β-Blockers are the first-line option for short-term reduction of heart rate prior to coronary CT angiography. In recent years, multiple β-blocker administration protocols with oral and/or intravenous application have been proposed. This review article provides an overview of the indications, efficacy, and safety of β-blockade protocols prior to coronary CT angiography with respect to different scanner techniques. Moreover, implications for radiation exposure and left ventricular function analysis are discussed.

Local drug delivery: Impact of pressure, substance characteristics, and stenting on drug transfer into the arterial wall

Injection parameters for local drug delivery are frequently determined by studies with marker substances. However, the pharmacologic properties of the actual drug may influence delivery efficiency and lead to different results. Aim of this study was to assess the delivery capacities of two device‐drug combinations in order to verify this approach for further in vivo studies. Tritiated (3H) preparations (5 ml) of the hydrophylic low‐molecular‐weight heparin reviparin and the lipophilic taxane paclitaxel were injected into the left anterior descending artery of freshly explanted porcine hearts with the Infusasleeve II catheter system. A balloon support pressure of 6 atm and infusion pressures of 40, 60, 80, or 100 psi were used. In three additional groups, reviparin was injected following stent implantation and paclitaxel was injected prior to or following stent implantation. Arteries along with surrounding myocardium were harvested. The artery was carefully dissected, and artery and myocardium were separately homogenized, and activity was measured. Of the totally delivered activity, 0.09% ± 0.03% (40 psi) to 0.17% ± 0.13% (100 psi) of reviparin and 2.03% ± 0.67% (60 psi) to 2.68% ± 1.57% (100 psi) of paclitaxel were found in the vessel wall. The results for different injection pressures were not significantly different for either drug. The percentage activity delivered to the vessel wall was substantially larger in the paclitaxel group as compared to reviparin delivery (P < 0.01 at 60, 80, and 100 psi). The mean concentration of reviparin in the artery was 20 to 33 times higher than in the myocardium. For paclitaxel the factors were 110 to 243. Stent implantation prior to or following local delivery did not result in a different delivery efficiency. The results demonstrate that the characteristics of the delivered drug contribute largely to the delivery efficiency. Using identical injection parameters, drug concentrations in the arterial wall were significantly higher for the lipophilic paclitaxel as compared to the hydrophilic reviparin. Stenting of the artery did not influence delivery efficiency. Cathet. Cardiovasc. Intervent. 47:102–106, 1999.

MDCT: cardiology indications.

In the past 2 years mechanical multidetector-row CT (MDCT) systems with simultaneous acquisition of four slices and half-second scanner rotation have become widely available. Data acquisition with these scanners allows for considerably faster coverage of the heart volume compared with single-slice scanning. This increased scan speed can be used for retrospective gating together with 1-mm collimated slice widths and allows coverage of the entire cardiac volume in one breath hold. Initial results from studies in correlation with intracoronary ultrasound suggest that MDTC technology not only offers the possibility to visualize intracoronary stenoses non-invasively but also to differentiate plaque morphology. This is especially the case with the next generation of 16-row multidetector CT. An increased number of simultaneously acquired slices and sub-millimeter collimation for cardiac applications allows true isotropic scanning with high temporal resolution. Contrast-enhanced MDTC is a promising non-invasive technique for the detection, visualization, and characterization of stenotic artery disease. It could act as a gate keeper prior to cardiac catherization and finally replace conventional diagnostic modalities.

Paclitaxel: Ein Chemotherapeutikum zur Restenoseprophylaxe? Experimentelle Untersuchungen in vitro und in vivo

Paclitaxel, a potent anti-tumor agent, shifts the cytoskeleton equilibrium towards assembly of altered and extraordinarily stable microtubules. These cellular modifications lead to reduced proliferation, migration, and signal transduction. It is highly lipophilic, which promotes a rapid cellular uptake, and has a long-lasting effect in the cell due to the structural alteration of the cytoskeleton. This makes paclitaxel a promising candidate for local drug delivery intended to address the proliferative and migratory processes involved in restenosis. In this article, results of our in vitro and in vivo studies with paclitaxel are presented. Cell culture experiments with monocultures of human arterial smooth muscle cells as well as cocultures with human endothelial cells showed that paclitaxel leads to an almost complete growth inhibition within a dose range of 1.0–10.0μmol/l, even after a short (20 min) single dose application. The comparison of an active, semi-active, and passive delivery system (porous balloon, microporous balloon, and double balloon) favored the double balloon for the following in vivo experiments. Tubulin staining and electron microscopy enabled visualization of paclitaxel-induced vessel wall alterations. In the rabbit model, locally delivered paclitaxel resulted in reduced neointima formation and enlargement in vessel size; in the pig model, however, after stenting, this inhibition was not significant. Both reduced proliferation and enlargement in vessel size contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton, which is also supported by vascular contraction force experiments. Paclitaxel, eine sehr potente antiproliferative Substanz, fördert die Bildung ungewöhnlich stabiler und funktionsgestörter Mikrotubuli und verändert dadurch zelluläre Mechanismen, die letztlich zu verminderter Proliferation, Migration und Signaltransduktion führen. Paclitaxel ist lipophil, was eine rasche Aufnahme in die Zelle fördert, und hat einen langanhaltenden Effekt in der Zelle aufgrund der strukturellen Veränderung des Zytoskelettes. Diese Eigenschaften machen Paclitaxel zu einem vielversprechenden Kandidaten für die lokale Medikamentenapplikation zur Restenoseprophylaxe. In dieser Arbeit werden die in-vitro und in-vivo Ergebnisse aus unseren Forschungsarbeiten zu Paclitaxel vorgestellt. Zellkulturexperimente mit Monokulturen von humanen glatten Gefäßmuskelzellen sowie mit Co-Kulturen mit humanen Endothelzellen zeigten, daß Paclitaxel in einem Dosisbereich zwischen 1,0 und 10,0μmol/l zu einer beinahe vollständigen Wachstumshemmung, selbst nach kurzer (20 min.) Einmalapplikation führt. Nach Vergleich von 3 verschiedenen Kathetersystemen (poröser Ballon, mikroporöser Ballon und Doppelballon) wurde der Doppelballon für die in-vivo Anwendung favorisiert. Anhand von Anfärbungen des Zytoskelettes sowie elektronenoptisch gelang der Nachweis der Paclitaxelwirkung in den glatten Muskelzellen der Gefäßwand. Im Kaninchen führte lokal appliziertes Paclitaxel zu einer signifikanten Hemmung der neointimalen Proliferation und Erweiterung des Gefäßdurchmessers im Vergleich zu ballondilatierten Kontrolltieren. In Zusatzexperimenten konnte eine drastische Verringerung der vaskulären Kontraktionskraft nach Paclitaxelgabe gezeigt werden. Ähnlich eindeutige Ergebnisse fanden sich nach Stentimplantation im Schweinemodell nicht.

Visualization and comparison of drug effects after local paclitaxel delivery with different catheter types

AbstractBackground: The microtubule stabilizing compound paclitaxel has proved to have potent antiproliferative effects on smooth muscle cells both in vitro and in vivo. It induces cellular modifications that result in reduced proliferation, migration and signal transduction by shifting the cellular microtubule equilibrium towards assembly. We therefore reasoned that a visualization of the altered cytoskeleton could enable an evaluation of the drug effects following local drug delivery. Methods and results: 3 catheters – the porous balloon, the microporous balloon and the double balloon catheter – were chosen for this study representing the spectrum from passive to active, pressure-driven delivery. After the induction of a defined plaque in the right carotid arteries of 40 New Zealand rabbits by electrical stimulation, 32 animals underwent balloon dilatation and 8 animals served as pre-interventional control group with electrostimulation only. In 24 animals (n = 8 in each group) subsequent local paclitaxel delivery (10 μmol/L) was performed. 8 animals served as control with angioplasty only. Vessels were excised 1 week following intervention. Immunohistochemistry with antibodies against bromodeoxyuridine, alpha-actin, macrophages, von Willebrand factor and α-tubulin was performed. Cytoskeletal changes were analyzed by electron microscopy. Tubulin staining and electron microscopy revealed changes with distinct staining patterns for the different catheters. Specific catheter-induced injuries could be identified for the porous and double balloon catheter. Intimal proliferation, percentage of macrophages and extent of injury favor the double balloon catheter for local paclitaxel delivery. Conclusions: The alterations of the cytoskeleton induced by paclitaxel allowed for the detection of drug action by staining of tubulin and electron microscopy. This enables an evaluation of transfer, distribution and drug effects directly in the vasculature without marker substances. The double balloon catheter appears to be best suited for local paclitaxel therapy.

Contrast-enhanced MDCT of the thorax.

The introduction of multidetector-row computed tomography (MDCT) into clinical radiology has revolutionized the spectrum of thoracic imaging. The current generation of MDCT scanners with simultaneous acquisition of up to 16 slices enables scan speeds which are 45 times faster than single-slice CT. The most important difference compared with conventional spiral CT is the conceptual change of acquiring a volume of data rather than individual sections [1]. This has also affected the techniques and protocols of contrast injection for various applications. After some technical remarks, we concentrate in this article on various applications of contrast-enhanced thoracic imaging. The main focus is on imaging of the thoracic aorta, the pulmonary arteries, and the pulmonary veins.

Cardiac and vascular MDCT: thoracic imaging

The current generation of multi-detector row CT (MDCT) with simultaneous acquisition of up to 16 slices enables scan speeds which are 45 times faster compared with single-slice CT [1, 2]. The scan speed translates into the ability to scan the entire thorax in just one breath hold of not more than 10 s [3, 4]. Despite submillimeter resolution, this scan speed allows motion-free images even in the most critically ill patients; however, the most important difference compared with conventional spiral CT is the conceptual change of acquiring a volume of data rather than individual sections [5]. This has also affected the techniques and protocols for contrast injection for various applications. After some technical remarks, we concentrate, in this article, on various applications of contrast-enhanced thoracic imaging. The main focus is on imaging of the thoracic aorta, the pulmonary arteries, and the pulmonary veins. Examination techniques

Local delivery of a low molecular weight heparin following stent implantation in the pig coronary artery

Background: The low molecular weight heparin Reviparin reduces smooth muscle cell proliferation in cell culture experiments. Clinical studies with systemic application of the substance did not show a reduction of the incidence of restenosis following balloon angioplasty. Local delivery, by achieving higher local concentrations of the drug, may have the potential to decrease smooth muscle cell proliferation in the treated arterial segment. Objectives: The aim of this study was to investigate the effects of local delivery of reviparin following stent implantation in the pig coronary artery. Methods: A coronary stent was implanted in the LAD of 34 pigs. In the treatment group 5 ml reviparin was injected with the Infusasleeve catheter at a proximal pressure of 80 psi. After 28 days the animals were sacrificed. Quantitative morphometric analysis comprised the intimal area, medial area and the lumen. The extent of vessel injury and the intimal thickness were assessed separately for each stent strut region. The correlation of injury and neointimal thickness was analysed using linear regression. Results: There was no relevant difference in the extent of vessel injury (1.9 ± 0.7 vs. 1.6 ± 0.6), the neointimal areas (2.4 ± 0.9 vs. 2.4 ± 1.0 mm2) and the resulting stenosis (46 ± 18 vs. 47 ± 17%). The medial area was larger in the animals treated with local delivery (2.2 ± 0.4 vs. 1.6 ± 0.4 mm2; p < 0,01). The correlation of injury and neointimal thickness was comparable in both groups. In two animals the passage of the stent area with the delivery system resulted in stent dislocation and fatal subacute thrombosis. Conclusion: In this animal model, local delivery of reviparin with the Infusasleeve catheter did not result in a reduction of neointimal proliferation following stent implantation. Local delivery after stent implantation carries the risk of stent dislocation as a result of the passage with the delivery system.

Detection of plaque rupture using 64-slice multidetector row computed tomography

The present case report describes a 37-year-old man who presented to the emergency room with symptoms of a myocardial infarction but no high-grade stenosis on conventional catheter angiography. Consecutive multidetector row computed tomography of the coronary arteries showed an intimal flap along a fibrous plaque formation in the left anterior descending artery. This finding was found to represent a plaque rupture, and the lesion was treated with an 18 mm stent. Multidetector row computed tomography helped to correctly position the stent by identifying the exact location of the rupture along the long plaque formation.