Optimal dosing and duration of oral everolimus to inhibit in-stent neointimal growth in rabbit iliac arteries.
BACKGROUND
Everolimus is an orally active derivative of sirolimus. Oral administration of rapamycin is efficacious in the reduction of neointima formation and clinical restenosis; however, its optimal dose and duration have not been determined.


METHODS
New Zealand White rabbits were divided into three groups. The first (low-dose) group received 1.5 mg/kg everolimus 1 day before stenting, followed by 0.75 mg/kg/day everolimus for 28 days. The second (high-dose) group received 6 mg/kg everolimus 1 day before, on the day of, and on the day after stenting, followed by 2 mg/kg/day for 4 days. The third (placebo) group received a matching volume of vehicle similar to that of Group 2. Twenty-eight days after stenting, animals were euthanized and morphometry was performed.


RESULTS
In the high-dose group, circulating everolimus levels corresponded with administrated dose levels; by Day 12, no circulating everolimus could be detected. In the low-dose everolimus group, levels remained constant up to 28 days. When compared with placebo, low-dose everolimus was associated with a significant reduction in medial thickness (32%), neointimal area (60%), and percent stent stenosis (33%); however, high-dose everolimus had no significant effect.


CONCLUSIONS
In conclusion, oral everolimus suppresses in-stent neointimal growth in rabbit iliac arteries. Four weeks of low-dose everolimus is more effective than 7 days of high-dose everolimus.
Waksman
Ron
R
Cardiovascular Research Institute, Washington Hospital Center, Washington, DC 20010, USA. ron.waksman@medstar.net
Pakala
Rajbabu
R
Baffour
Richard
R
Hellinga
David
D
Seabron
Rufus
R
Kolodgie
Frank
F
Virmani
Renu
R
D000284:Administration, Oral; D000818:Animals; D019917:Blood Vessel Prosthesis Implantation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006083:Graft Occlusion, Vascular / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D015607:Stents; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017540:Tunica Media / Q000187:drug effects / Q000601:surgery; D014654:Vascular Patency / Q000187:drug effects
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus