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DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists

The novel clopidogrel conjugate, DT‐678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT‐678 and currently approved P2Y(12) antagonists has yet to be determined. The objective of this study was to evaluate the bleeding...

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Autores principales: Lauver, Dale A., Kuszynski, Dawn S., Christian, Barbara D., Bernard, Matthew P., Teuber, James P., Markham, Bruce E., Chen, Yuqing E., Zhang, Haoming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658415/
https://www.ncbi.nlm.nih.gov/pubmed/31372229
http://dx.doi.org/10.1002/prp2.509
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author Lauver, Dale A.
Kuszynski, Dawn S.
Christian, Barbara D.
Bernard, Matthew P.
Teuber, James P.
Markham, Bruce E.
Chen, Yuqing E.
Zhang, Haoming
author_facet Lauver, Dale A.
Kuszynski, Dawn S.
Christian, Barbara D.
Bernard, Matthew P.
Teuber, James P.
Markham, Bruce E.
Chen, Yuqing E.
Zhang, Haoming
author_sort Lauver, Dale A.
collection PubMed
description The novel clopidogrel conjugate, DT‐678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT‐678 and currently approved P2Y(12) antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT‐678. Ninety‐one New Zealand white rabbits were randomized to one of 13 treatment groups (n = 7). Platelet activation was assessed by flow cytometry and light transmission aggregometry before and after the administration of various doses of DT‐678, clopidogrel, and ticagrelor. Tongue template bleeding times were also measured before and after drug treatment. Treatment with P2Y(12) receptor antagonists caused a dose‐dependent reduction in markers of platelet activation (P‐selectin and integrin α(IIb)β(3)) and aggregation in response to adenosine diphosphate stimulation. At the same doses required for platelet inhibition, clopidogrel and ticagrelor significantly prolonged bleeding times, while DT‐678 did not. DT‐678 and the FDA‐approved P2Y(12) antagonists clopidogrel and ticagrelor are effective inhibitors of platelet activation and aggregation. However, unlike clopidogrel and ticagrelor, DT‐678 did not prolong bleeding times at equally effective antiplatelet doses. The results suggest a more favorable benefit/risk ratio for DT‐678 and potential utility as part of a dual antiplatelet therapy regimen.
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spelling pubmed-66584152019-08-01 DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists Lauver, Dale A. Kuszynski, Dawn S. Christian, Barbara D. Bernard, Matthew P. Teuber, James P. Markham, Bruce E. Chen, Yuqing E. Zhang, Haoming Pharmacol Res Perspect Original Articles The novel clopidogrel conjugate, DT‐678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT‐678 and currently approved P2Y(12) antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT‐678. Ninety‐one New Zealand white rabbits were randomized to one of 13 treatment groups (n = 7). Platelet activation was assessed by flow cytometry and light transmission aggregometry before and after the administration of various doses of DT‐678, clopidogrel, and ticagrelor. Tongue template bleeding times were also measured before and after drug treatment. Treatment with P2Y(12) receptor antagonists caused a dose‐dependent reduction in markers of platelet activation (P‐selectin and integrin α(IIb)β(3)) and aggregation in response to adenosine diphosphate stimulation. At the same doses required for platelet inhibition, clopidogrel and ticagrelor significantly prolonged bleeding times, while DT‐678 did not. DT‐678 and the FDA‐approved P2Y(12) antagonists clopidogrel and ticagrelor are effective inhibitors of platelet activation and aggregation. However, unlike clopidogrel and ticagrelor, DT‐678 did not prolong bleeding times at equally effective antiplatelet doses. The results suggest a more favorable benefit/risk ratio for DT‐678 and potential utility as part of a dual antiplatelet therapy regimen. John Wiley and Sons Inc. 2019-07-25 /pmc/articles/PMC6658415/ /pubmed/31372229 http://dx.doi.org/10.1002/prp2.509 Text en © 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Lauver, Dale A.
Kuszynski, Dawn S.
Christian, Barbara D.
Bernard, Matthew P.
Teuber, James P.
Markham, Bruce E.
Chen, Yuqing E.
Zhang, Haoming
DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title_full DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title_fullStr DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title_full_unstemmed DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title_short DT‐678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y(12) antagonists
title_sort dt‐678 inhibits platelet activation with lower tendency for bleeding compared to existing p2y(12) antagonists
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658415/
https://www.ncbi.nlm.nih.gov/pubmed/31372229
http://dx.doi.org/10.1002/prp2.509
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