Introducing the first polymer-free leflunomide eluting stent.
BACKGROUND
We here describe the pharmacological characteristic, in vivo efficacy, and in vitro mechanisms of a polymer-free leflunomide eluting stent in comparison to its rapamycin-coated equivalent.


METHODS
Stents were coated with 40 mM solutions of leflunomide (L) or rapamycin (R) or were left uncoated (BM). Neointima formation was assessed 6 weeks after implantation into Sprague Dawley rats by optical coherence tomographies (OCT) and histopathology. In vitro proliferation assays were performed using isolated endothelial and smooth-muscle-cells from Sprague Dawley rats to investigate the cell-specific pharmacokinetic effect of leflunomide and rapamycin.


RESULTS
HPLC-based drug release kinetics revealed a similar profile with 90% of the drug being released after 12.1+/-0.2 (L) and 13.0+/-0.2 days (R). After 6 weeks, OCTs showed that in-stent luminal obliteration was less for the coated stents (L:12.0+/-9.4%, R:13.3+/-13.1%) when compared to identical bare metal stents (BM:26.4+/-4.7%; p<or=0.046). Histology with computer-assisted morphometry was performed and demonstrated reduced in-stent I/M thickness ratios (L:2.5+/-1.2, R:3.7+/-3.3, BM:6.7+/-2.3, p<or=0.049 for L and R vs. BM) and neointimal areas (L:0.6+/-0.3, R:0.7+/-0.2, BM:1.3+/-0.4, p<or=0.039 for L and R vs. BM) with stent coating. No differences were found for injury and inflammation scores (L and R vs. BM; p=NS). In vitro SMC proliferation was dose-dependently and similarly inhibited by L and R at 1-100 nM (p=NS L vs. R). Interestingly, human EC proliferation at 10-100 nM was significantly inhibited only by R (p<0.001), but not by L (p=NS).


CONCLUSIONS
The diminished inhibition of EC proliferation may improve arterial healing and contribute to the safety profile of the leflunomide stent.
Deuse
Tobias
T
Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Dr., CVRB MC 5407, Stanford, CA, USA.
Erben
Reinhold G
RG
Ikeno
Fumiaki
F
Behnisch
Boris
B
Boeger
Rainer
R
Connolly
Andrew J
AJ
Reichenspurner
Hermann
H
Bergow
Claudia
C
Pelletier
Marc P
MP
Robbins
Robert C
RC
Schrepfer
Sonja
S
D000818:Animals; D002478:Cells, Cultured; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077339:Leflunomide; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology; D041623:Tomography, Optical Coherence; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects* / Q000473:pathology
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D000077339:Leflunomide; D020123:Sirolimus