title: Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease.
abstract: OBJECTIVE
  Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report the first human use of a protease-activated receptor-1-based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications of percutaneous coronary interventions.
  
  
  RESULTS
  PZ-128 was administered by 1 to 2 hours continuous intravenous infusion (0.01-2 mg/kg) to 31 subjects with coronary artery disease or multiple coronary artery disease risk factors. Safety, antiplatelet efficacy, and pharmacokinetics were assessed at baseline and 0.5, 1, 2, 6, 24 hours, and 7 to 10 days postdosing. The inhibitory effects of PZ-128 on platelet aggregation stimulated by the protease-activated receptor-1 agonist SFLLRN (8 μmol/L) at 30 minutes to 6 hours were dose dependent with 20% to 40% inhibition at 0.3 mg/kg, 40% to 60% at 0.5 mg/kg, and ≥ 80% to 100% at 1 to 2 mg/kg. The subgroup receiving aspirin in the 0.5 and 1-mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours and 95% to 100% inhibition by 6 hours. The inhibitory effects of 0.5 mg/kg PZ-128 were reversible with 50% recovery of aggregation to SFLLRN by 24 hours. There were no significant effects of PZ-128 on aggregation induced by AYPGKF, ADP, or collagen, indicating that the observed effects were specific to protease-activated receptor-1. The plasma half-life was 1.3 to 1.8 hours, and PZ-128 was nondetectable in urine. There were no effects on bleeding, coagulation, clinical chemistry, or ECG parameters.
  
  
  CONCLUSIONS
  PZ-128 is a promising antiplatelet agent that provides rapid, specific, dose dependent, and reversible inhibition of platelet protease-activated receptor-1 through a novel intracellular mechanism.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bliden
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Susan E
authors.initials: SE
authors.lastname: Turner
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Martin G
authors.initials: MG
authors.lastname: Gesheff
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Travis P
authors.initials: TP
authors.lastname: Barr
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.).
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.affiliation: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T., M.G.G.); and the Center for Hemostasis and Thrombosis Research, MORI, Tufts Medical Center, Boston, MA (S.E.T., T.P.B., L.C., A.K.). athan.kuliopulos@tufts.edu.
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D055666:Lipopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D044463:Receptor, PAR-1 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D057846:Cell-Penetrating Peptides; D055666:Lipopeptides; C000607142:PZ-128 peptide; D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1
keywords: aspirin; collagen; coronary artery disease; lipopeptides; risk factors