High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients.

Autor:	Kempen HJ; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.). herman.kempen@themedco.com., Asztalos BF; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Moerland M; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Jeyarajah E; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Otvos J; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Kallend DG; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Bellibas SE; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.)., Wijngaard PL; From The Medicines Company (Schweiz) GmbH, Zürich, Switzerland (H.J.K., D.G.K., P.L.J.W.); Lipid Metabolism Laboratory, Tufts University, Boston, MA (B.F.A.); Center of Human Drug Research, Leiden, The Netherlands (M.M.); Liposcience, Laboratory Corporation of America Holdings, Raleigh, NC (E.J., J.O.); and The Medicines Company Inc, Parsippany, NJ (S.E.B.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2016 Apr; Vol. 36 (4), pp. 736-42. Date of Electronic Publication: 2016 Feb 25.
DOI:	10.1161/ATVBAHA.115.307052
Abstrakt:	Objective: To determine effects of single ascending doses of MDCO-216 on high-density lipoprotein (HDL) subfractions in relation to changes in cholesterol efflux capacity in healthy volunteers and in patients with stable angina pectoris. Approach and Results: Doses of 5- (in volunteers only), 10-, 20-, 30-, and 40-mg/kg MDCO-216 were infused during 2 hours, and plasma and serum were collected during 30 days. Plasma levels of HDL subfractions were assessed by 2-dimensional gel electrophoresis, immunoblotting, and image analysis. Lipoprotein particle concentrations and sizes were also assessed by proton nuclear magnetic resonance ((1)H-NMR). There was a rapid dose-dependent increase of total apolipoprotein A-I (apoA-I) in pre-β1, α-1, and α-2 HDL levels and decrease in α-3 and α-4 HDL. Using a selective antibody apoA-IMilano was detected in the large α-1 and α-2 HDL on all doses and at each time point. ApoA-IMilano was also detected at the α-4 position but only at high doses. (1)H-NMR analysis similarly showed a rapid and dose-dependent shift from small- to large-sized HDL particles. The increase of basal and ATP-binding cassette transporter A1-mediated efflux capacities reported previously correlated strongly and independently with the increase in pre-β1-HDL and α-1 HDL, but not with that in α-2 HDL. Conclusions: On infusion, MDCO-216 rapidly eliminates small HDL and leads to formation of α-1 and α-2 HDL containing both wild-type apoA-I and apoA-IMilano. In this process, endogenous apoA-I is liberated appearing as pre-β1-HDL. In addition to pre-β1-HDL, the newly formed α-1 HDL particle containing apoA-I Milano may have a direct effect on cholesterol efflux capacity. (© 2016 American Heart Association, Inc.)
Databáze:	MEDLINE
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