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.
OBJECTIVE
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.
Parolini
Cinzia
C
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Marchesi
Marta
M
Lorenzon
Paolo
P
Castano
Mauro
M
Balconi
Elena
E
Miragoli
Luigi
L
Chaabane
Linda
L
Morisetti
Alberto
A
Lorusso
Vito
V
Martin
Bradley J
BJ
Bisgaier
Charles L
CL
Krause
Brian
B
Newton
Roger S
RS
Sirtori
Cesare R
CR
Chiesa
Giulia
G
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D016632:Apolipoprotein A-I / Q000008:administration & dosage*; D050197:Atherosclerosis / Q000175:diagnosis* / Q000188:drug therapy*; D017536:Carotid Artery, Common / Q000187:drug effects*; D016893:Carotid Stenosis / Q000175:diagnosis / Q000188:drug therapy*; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008279:Magnetic Resonance Imaging; D008297:Male; D010713:Phosphatidylcholines / Q000008:administration & dosage*; D011817:Rabbits; D011897:Random Allocation; D014463:Ultrasonography
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; C474616:ETC216; D010713:Phosphatidylcholines