Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease

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 percuta...

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Veröffentlicht in:Arteriosclerosis, thrombosis, and vascular biology Jg. 36; H. 1; S. 189
Hauptverfasser: Gurbel, Paul A, Bliden, Kevin P, Turner, Susan E, Tantry, Udaya S, Gesheff, Martin G, Barr, Travis P, Covic, Lidija, Kuliopulos, Athan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.01.2016
Schlagworte:
Adult
Aged
Blood Platelets - drug effects
Blood Platelets - metabolism
Cell-Penetrating Peptides - administration & dosage
Cell-Penetrating Peptides - adverse effects
Cell-Penetrating Peptides - pharmacokinetics
Coronary Artery Disease - blood
Coronary Artery Disease - diagnosis
Coronary Artery Disease - therapy
Dose-Response Relationship, Drug
Female
Half-Life
Humans
Infusions, Intravenous
Lipopeptides - administration & dosage
Lipopeptides - adverse effects
Lipopeptides - pharmacokinetics
Male
Middle Aged
Percutaneous Coronary Intervention - adverse effects
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - administration & dosage
Platelet Aggregation Inhibitors - adverse effects
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Function Tests
Receptor, PAR-1 - antagonists & inhibitors
Receptor, PAR-1 - metabolism
Treatment Outcome
coronary artery disease
collagen
aspirin
risk factors
lipopeptides
ISSN:1524-4636, 1524-4636
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Zusammenfassung: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. 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. 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1524-4636
1524-4636
DOI:10.1161/ATVBAHA.115.306777