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PRECLINICAL STUDY: APO: A-I_MILANO

Dose-Related Effects of Repeated ETC-216 (Recombinant Apolipoprotein A-I_Milano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine Complexes) Administrations on Rabbit Lipid-Rich Soft Plaques

In Vivo Assessment by Intravascular Ultrasound and Magnetic Resonance Imaging

Cinzia Parolini, PhD^_*, Marta Marchesi, PhD^_*, Paolo Lorenzon^_*, Mauro Castano, PhD, Elena Balconi, BS^_*, Luigi Miragoli, Linda Chaabane, PhD, Alberto Morisetti, BS, Vito Lorusso, BS, Bradley J. Martin, PhD, Charles L. Bisgaier, PhD, Brian Krause, PhD, Roger S. Newton, PhD, Cesare R. Sirtori, MD, PhD^_* and Giulia Chiesa, PhD^_*,_*

^_* Department of Pharmacological Sciences, University of Milan, Milan, Italy
Bracco Imaging SpA, Colleretto Giacosa, Turin, Italy
Esperion Therapeutics, Pfizer Inc., Plymouth, Michigan.

Manuscript received June 28, 2008; revised manuscript received November 8, 2008, accepted December 2, 2008.

^_* Reprint requests and correspondence: Dr. Giulia Chiesa, Department of Pharmacological Sciences, via Balzaretti, 9, 20133 Milan, Italy. (Email: giulia.chiesa{at}unimi.it).

Objectives: This study sought to evaluate in vivo the minimal dose of apolipoprotein (apo) A-I_Milano phospholipid complex (recombinant apoA-I_Milano and 1-palmitoyl-2-oleoyl phosphatidylcholine complexes [ETC-216]) able to induce atherosclerosis regression in a rabbit model of lipid-rich plaques.

Background: A single high dose of recombinant apoA-I_Milano has promoted atherosclerosis regression in animal models. More recently, regression of atherosclerosis was achieved in coronary patients by repeated infusions of ETC-216.

Methods: Thirty-six rabbits underwent perivascular injury at both carotid arteries, followed by a 1.5% cholesterol diet. After 90 days, rabbits were randomly divided into 6 groups and treated 5 times with vehicle or ETC-216 at 5, 10, 20, 40, or 150 mg/kg dose every 4 days. Carotid plaque changes were evaluated in vivo by intravascular ultrasound (IVUS) and magnetic resonance imaging (MRI), performed before and at the end of treatments. Magnetic resonance imaging scans were also recorded after administration of the second dose for rabbits infused with vehicle 40 or 150 mg/kg.

Results: Atheroma volume in vehicle-treated rabbits increased dramatically between the first and the second IVUS analyses (+26.53%), whereas in ETC-216–treated animals, a reduced progression at the lower doses and a significant regression at the higher doses, up to –6.83%, was detected. Results obtained by MRI analysis correlated significantly with those at IVUS (r = 0.706; p < 0.0001). The MRI evaluations after the second infusion established that a significant regression was achieved with only 2 administrations of the highest dose.

Conclusions: These results confirm the efficacy of ETC-216 for atherosclerosis treatment and provide guidance for dose selection and frequency to obtain a significant reduction of plaque volume.

Abbreviations and Acronyms   apo = apolipoprotein   ETC-216 = recombinant apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complexes   HDL = high-density lipoprotein   IVUS = intravascular ultrasound   MRI = magnetic resonance imaging

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Xue-Qiao Zhao and B. Greg Brown
J. Am. Coll. Cardiol. 2008 51: 1110-1111. [Full Text] [PDF]

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