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Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen

The simultaneous administration of three antiplatelet agents has been proposed as an efficient strategy for the secondary prevention of atherothrombotic events and is included in the European guidelines. However, this strategy presented an increased risk of bleeding; therefore, the identification of...

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Autores principales: Tsiailanis, Antonios D., Tellis, Constantinos C., Papakyriakopoulou, Paraskevi, Kostagianni, Androniki D., Gkalpinos, Vasileios, Chatzigiannis, Christos M., Kostomitsopoulos, Nikolaos, Valsami, Georgia, Tselepis, Alexandros D., Tzakos, Andreas G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005222/
https://www.ncbi.nlm.nih.gov/pubmed/36903557
http://dx.doi.org/10.3390/molecules28052311
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author Tsiailanis, Antonios D.
Tellis, Constantinos C.
Papakyriakopoulou, Paraskevi
Kostagianni, Androniki D.
Gkalpinos, Vasileios
Chatzigiannis, Christos M.
Kostomitsopoulos, Nikolaos
Valsami, Georgia
Tselepis, Alexandros D.
Tzakos, Andreas G.
author_facet Tsiailanis, Antonios D.
Tellis, Constantinos C.
Papakyriakopoulou, Paraskevi
Kostagianni, Androniki D.
Gkalpinos, Vasileios
Chatzigiannis, Christos M.
Kostomitsopoulos, Nikolaos
Valsami, Georgia
Tselepis, Alexandros D.
Tzakos, Andreas G.
author_sort Tsiailanis, Antonios D.
collection PubMed
description The simultaneous administration of three antiplatelet agents has been proposed as an efficient strategy for the secondary prevention of atherothrombotic events and is included in the European guidelines. However, this strategy presented an increased risk of bleeding; therefore, the identification of new antiplatelet agents, with improved efficacy and diminished side effects, is of great importance. In silico studies, UPLC/MS Q-TOF plasma stability, in vitro platelet aggregation experiments, and pharmacokinetic studies were exploited. In the present study, it has been predicted that the flavonoid apigenin could target different platelet activation pathways, including P2Y12, protease-activated receptor-1 (PAR-1), and cyclooxygenase 1 (COX-1). To enhance apigenin’s potency, hybridization with docosahexaenoic acid (DHA) was performed, as fatty acids have illustrated potent efficacy against cardiovascular diseases (CVDs). The new molecular hybrid, termed 4′-DHA-apigenin, demonstrated enhanced inhibitory activity against platelet aggregation induced by thrombin receptor activator peptide-6 (TRAP-6), adenosine diphosphate (ADP), and arachidonic acid (AA), with respect to the parent apigenin. The 4′-DHA-apigenin hybrid illustrated an almost 2-fold enhanced inhibitory activity, with respect to apigenin, and an almost 3-fold enhanced inhibitory activity, with respect to DHA, for the ADP-induced platelet aggregation. Additionally, the hybrid presented a more than 12-fold enhanced inhibitory activity with respect to DHA for the TRAP-6 induced platelet aggregation. Furthermore, a 2-fold enhanced inhibitory activity was recorded for the 4′-DHA-apigenin hybrid for the AA-induced platelet aggregation with respect to apigenin. To surmount the reduced LC-MS based plasma stability, a novel dosage form in olive oil has been developed. The 4′-DHA-apigenin olive oil-based formulation presented an enhanced antiplatelet inhibitory effect in three activation pathways. To further explore the pharmacokinetic profile of 4′-DHA-apigenin in olive oil formulations, a UPLC/MS Q-TOF protocol has been established to quantify the serum levels of apigenin after oral administration to C57BL/6J wild type mice. The olive oil-based formulation of 4′-DHA-apigenin demonstrated an increase in apigenin bioavailability of 262 %. This study may offer a new therapeutic strategy tailored to improve the treatment of CVDs.
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spelling pubmed-100052222023-03-11 Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen Tsiailanis, Antonios D. Tellis, Constantinos C. Papakyriakopoulou, Paraskevi Kostagianni, Androniki D. Gkalpinos, Vasileios Chatzigiannis, Christos M. Kostomitsopoulos, Nikolaos Valsami, Georgia Tselepis, Alexandros D. Tzakos, Andreas G. Molecules Article The simultaneous administration of three antiplatelet agents has been proposed as an efficient strategy for the secondary prevention of atherothrombotic events and is included in the European guidelines. However, this strategy presented an increased risk of bleeding; therefore, the identification of new antiplatelet agents, with improved efficacy and diminished side effects, is of great importance. In silico studies, UPLC/MS Q-TOF plasma stability, in vitro platelet aggregation experiments, and pharmacokinetic studies were exploited. In the present study, it has been predicted that the flavonoid apigenin could target different platelet activation pathways, including P2Y12, protease-activated receptor-1 (PAR-1), and cyclooxygenase 1 (COX-1). To enhance apigenin’s potency, hybridization with docosahexaenoic acid (DHA) was performed, as fatty acids have illustrated potent efficacy against cardiovascular diseases (CVDs). The new molecular hybrid, termed 4′-DHA-apigenin, demonstrated enhanced inhibitory activity against platelet aggregation induced by thrombin receptor activator peptide-6 (TRAP-6), adenosine diphosphate (ADP), and arachidonic acid (AA), with respect to the parent apigenin. The 4′-DHA-apigenin hybrid illustrated an almost 2-fold enhanced inhibitory activity, with respect to apigenin, and an almost 3-fold enhanced inhibitory activity, with respect to DHA, for the ADP-induced platelet aggregation. Additionally, the hybrid presented a more than 12-fold enhanced inhibitory activity with respect to DHA for the TRAP-6 induced platelet aggregation. Furthermore, a 2-fold enhanced inhibitory activity was recorded for the 4′-DHA-apigenin hybrid for the AA-induced platelet aggregation with respect to apigenin. To surmount the reduced LC-MS based plasma stability, a novel dosage form in olive oil has been developed. The 4′-DHA-apigenin olive oil-based formulation presented an enhanced antiplatelet inhibitory effect in three activation pathways. To further explore the pharmacokinetic profile of 4′-DHA-apigenin in olive oil formulations, a UPLC/MS Q-TOF protocol has been established to quantify the serum levels of apigenin after oral administration to C57BL/6J wild type mice. The olive oil-based formulation of 4′-DHA-apigenin demonstrated an increase in apigenin bioavailability of 262 %. This study may offer a new therapeutic strategy tailored to improve the treatment of CVDs. MDPI 2023-03-02 /pmc/articles/PMC10005222/ /pubmed/36903557 http://dx.doi.org/10.3390/molecules28052311 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsiailanis, Antonios D.
Tellis, Constantinos C.
Papakyriakopoulou, Paraskevi
Kostagianni, Androniki D.
Gkalpinos, Vasileios
Chatzigiannis, Christos M.
Kostomitsopoulos, Nikolaos
Valsami, Georgia
Tselepis, Alexandros D.
Tzakos, Andreas G.
Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title_full Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title_fullStr Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title_full_unstemmed Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title_short Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen
title_sort development of a novel apigenin dosage form as a substitute for the modern triple antithrombotic regimen
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005222/
https://www.ncbi.nlm.nih.gov/pubmed/36903557
http://dx.doi.org/10.3390/molecules28052311
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