title: Vascular response to zotarolimus-coated balloons in injured superficial femoral arteries of the familial hypercholesterolemic Swine.
abstract: BACKGROUND
  Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine.
  
  
  RESULTS
  A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 μg/cm(2)) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 μg/cm(2), n=16), low-dose (300 μg/cm(2), n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P=0.007; low-dose ZCB 22% reduction, P=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups.
  
  
  CONCLUSIONS
  The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.
authors.affiliation: Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, 8 Corporate Drive, Orangeburg, NY, USA. jgranada@crf.org
authors.forename: Juan F
authors.initials: JF
authors.lastname: Granada
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Milewski
authors.forename: Hugh
authors.initials: H
authors.lastname: Zhao
authors.forename: John J
authors.initials: JJ
authors.lastname: Stankus
authors.forename: Armando
authors.initials: A
authors.lastname: Tellez
authors.forename: Michael S
authors.initials: MS
authors.lastname: Aboodi
authors.forename: Greg L
authors.initials: GL
authors.lastname: Kaluza
authors.forename: Christian G
authors.initials: CG
authors.lastname: Krueger
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Schwartz
authors.forename: Alexander
authors.initials: A
authors.lastname: Nikanorov
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D002404:Catheterization; D002985:Clinical Protocols; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015918:Infusion Pumps, Implantable / Q000706:statistics & numerical data; D023421:Models, Animal; D058426:Neointima / Q000209:etiology* / Q000517:prevention & control; D011183:Postoperative Complications; D011859:Radiography; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C489443:zotarolimus; D020123:Sirolimus