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Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans
BACKGROUND: Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therape...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603266/ https://www.ncbi.nlm.nih.gov/pubmed/23525448 http://dx.doi.org/10.1161/JAHA.112.006007 |
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author | Japp, Alan G. Chelliah, Raj Tattersall, Laura Lang, Ninian N. Meng, Xu Weisel, Kathleen Katz, Arie Burt, David Fox, Keith A. A. Feuerstein, Giora Z. Connolly, Thomas M. Newby, David E. |
author_facet | Japp, Alan G. Chelliah, Raj Tattersall, Laura Lang, Ninian N. Meng, Xu Weisel, Kathleen Katz, Arie Burt, David Fox, Keith A. A. Feuerstein, Giora Z. Connolly, Thomas M. Newby, David E. |
author_sort | Japp, Alan G. |
collection | PubMed |
description | BACKGROUND: Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P‐selectin antagonist PSI‐697 on platelet–monocyte aggregate formation in humans. METHODS AND RESULTS: In a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral PSI‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI‐697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (P>0.05). P‐selectin‐blocking antibody (CLB‐Thromb6), but not PSI‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (P<0.001). CONCLUSIONS: The novel small‐molecule P‐selectin antagonist PSI‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. CLINICAL TRIAL REGISTRATION: URL: http://EudraCT.ema.europa.eu Unique identifier: 2007‐005695‐14. |
format | Online Article Text |
id | pubmed-3603266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-36032662013-03-27 Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans Japp, Alan G. Chelliah, Raj Tattersall, Laura Lang, Ninian N. Meng, Xu Weisel, Kathleen Katz, Arie Burt, David Fox, Keith A. A. Feuerstein, Giora Z. Connolly, Thomas M. Newby, David E. J Am Heart Assoc Original Research BACKGROUND: Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P‐selectin antagonist PSI‐697 on platelet–monocyte aggregate formation in humans. METHODS AND RESULTS: In a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral PSI‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI‐697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (P>0.05). P‐selectin‐blocking antibody (CLB‐Thromb6), but not PSI‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (P<0.001). CONCLUSIONS: The novel small‐molecule P‐selectin antagonist PSI‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. CLINICAL TRIAL REGISTRATION: URL: http://EudraCT.ema.europa.eu Unique identifier: 2007‐005695‐14. Blackwell Publishing Ltd 2013-02-22 /pmc/articles/PMC3603266/ /pubmed/23525448 http://dx.doi.org/10.1161/JAHA.112.006007 Text en © 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by/2.5/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Japp, Alan G. Chelliah, Raj Tattersall, Laura Lang, Ninian N. Meng, Xu Weisel, Kathleen Katz, Arie Burt, David Fox, Keith A. A. Feuerstein, Giora Z. Connolly, Thomas M. Newby, David E. Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title | Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title_full | Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title_fullStr | Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title_full_unstemmed | Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title_short | Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans |
title_sort | effect of psi‐697, a novel p‐selectin inhibitor, on platelet–monocyte aggregate formation in humans |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603266/ https://www.ncbi.nlm.nih.gov/pubmed/23525448 http://dx.doi.org/10.1161/JAHA.112.006007 |
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