Oral everolimus inhibits in-stent neointimal growth.
BACKGROUND
Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries.


RESULTS
New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits.


CONCLUSIONS
Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.
Farb
Andrew
A
Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
John
Michael
M
Acampado
Eduardo
E
Kolodgie
Frank D
FD
Prescott
Margaret Forney
MF
Virmani
Renu
R
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D000068338:Everolimus; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007083:Iliac Artery / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011817:Rabbits; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015607:Stents / Q000009:adverse effects*; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D014654:Vascular Patency / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D000068338:Everolimus; D001241:Aspirin; D020123:Sirolimus