Zusammenfassung
Hintergrund
In-vitro-Untersuchungen zeigen für Tacrolimus einen antiproliferativen Effekt auf glatte Gefäßmuskelzellen bei geringer Wirkung auf Endothelzellen. Ziel der vorliegenden Untersuchung war der Vergleich einer Stentbeschichtung auf Polymerbasis mit Paclitaxel und Tacrolimus.
Methoden und Ergebnisse
Bei 40 Haus- und 10 Minischweinen wurden Stents in LAD und CX implantiert mit einer Nachbeobachtungsdauer zwischen 6 Stunden und 3 Monaten.
Nach 3 Tagen führte eine Stentbeschichtung mit 1.73 μg Tacrolimus/mm2 zu Gewebespiegeln von 20 μmol/l in der Koronararterienwand. Antiproliferativ wirksame Gewebespiegel fanden sich bis zu 28 Tagen nach Stentimplantation. Die Tacrolimus beschichteten Stents führten zu einer signifikanten Reduktion der Neointimabildung um 51% nach 28 Tagen im Vergleich zur Kontrollgruppe. Eine hohe Dosis von Paclitaxel auf dem Stent (1.44 μg/mm2) führte gehäuft zu unerwarteten Todesfällen und angiographisch dokumentierten thrombotischen Stentverschlüssen. Nach 3 Monaten zeigte sich weder mit Tacrolimus noch mit Paclitaxel eine persistierende Hemmung der Neointimabildung.
Schlussfolgerung
Tacrolimus führt ähnlich wie Paclitaxel zu einer verminderten Neointimabildung im porcinen Modell der experimentellen Koronarläsion. Dosierung des antiproliferativen Wirkstoffes und Langzeiteffektivität stellen kritische Parameter der Stent-basierten lokalen Medikamentenapplikation dar.
Summary
Background
Tacrolimus is a potent antiproliferative and immunosuppressive agent allowing for improved endothelial regeneration. The aim of our study was the preclinical evaluation of tacrolimus in a drug eluting nonerodable polymer stent system and its comparison with paclitaxel.
Methods and results
A total of 40 domestic pigs and 10 mini-pigs underwent coronary stenting with a follow-up time between 6 hours and 3 months. Stents were implanted in coronary arteries with an overstretch ratio of 1.2. After 3 days, a 1.73 μg/mm2 coating produced tacrolimus tissue levels of 20 μmol/l in the coronary artery wall. Effective tissue concentrations were sustained for 28 days. Based on histomorphometric analysis, tacrolimus stent treated vessels had a reduced extent of neointima formation compared with controls at 28 days (–51% compared to control) but not at 3 months. High dose paclitaxel stent coating (1.44 μg/mm2) was complicated by unexpected deaths of pigs and thrombotic stent occlusion at control angiography. Long-term porcine data showed no persistent inhibition of neointimal growth by paclitaxel and tacrolimus stent coating.
Conclusions
Similar to paclitaxel, tacrolimus stent coating reduces neointimal proliferation in the porcine coronary model. However, dosing and long-term efficacy remains a critical issue in stent-based local drug delivery.
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Scheller, B., Grandt, A., Wnendt, S. et al. Comparative study of tacrolimus and paclitaxel stent coating in the porcine coronary model. ZS Kardiologie 94, 445–452 (2005). https://doi.org/10.1007/s00392-005-0237-y
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DOI: https://doi.org/10.1007/s00392-005-0237-y