title: Optimal dosing and duration of oral everolimus to inhibit in-stent neointimal growth in rabbit iliac arteries.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute, Washington Hospital Center, Washington, DC 20010, USA. ron.waksman@medstar.net
authors.forename: Ron
authors.initials: R
authors.lastname: Waksman
authors.forename: Rajbabu
authors.initials: R
authors.lastname: Pakala
authors.forename: Richard
authors.initials: R
authors.lastname: Baffour
authors.forename: David
authors.initials: D
authors.lastname: Hellinga
authors.forename: Rufus
authors.initials: R
authors.lastname: Seabron
authors.forename: Frank
authors.initials: F
authors.lastname: Kolodgie
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus