title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Herman J
authors.initials: HJ
authors.lastname: Kempen
authors.affiliation: 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.).
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.affiliation: 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.).
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moerland
authors.affiliation: 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.).
authors.forename: Elias
authors.initials: E
authors.lastname: Jeyarajah
authors.affiliation: 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.).
authors.forename: James
authors.initials: J
authors.lastname: Otvos
authors.affiliation: 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.).
authors.forename: David G
authors.initials: DG
authors.lastname: Kallend
authors.affiliation: 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.).
authors.forename: S Eralp
authors.initials: SE
authors.lastname: Bellibas
authors.affiliation: 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.).
authors.forename: Peter L J
authors.initials: PL
authors.lastname: Wijngaard
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000097:blood; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015180:Electrophoresis, Gel, Two-Dimensional; D064368:Healthy Volunteers; D053442:High-Density Lipoproteins, Pre-beta / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D008075:Lipoproteins, HDL / Q000097:blood*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009426:Netherlands; D010316:Particle Size; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000097:blood; D066244:Proton Magnetic Resonance Spectroscopy; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D015415:Biomarkers; D004338:Drug Combinations; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; C000609591:MDCO-216; D010713:Phosphatidylcholines; D002784:Cholesterol
keywords: apolipoprotein A-I; cholesterol; healthy volunteers; immunoblotting; stable angina