Development of a DHA-Losartan hybrid as a potent inhibitor of multiple pathway-induced platelet aggregation

References

• Adili, R., Hawley, M., & Holinstat, M. (2018). Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids. Prostaglandins & Other Lipid Mediators, 139, 10–18. https://doi.org/10.1016/j.prostaglandins.2018.09.005
   PubMed Web of Science ®Google Scholar
• Agarwal, N., Jain, A., Mahmoud, A. N., Bishnoi, R., Golwala, H., Karimi, A., Mojadidi, M. K., Garg, J., Gupta, T., Patel, N. K., Wayangankar, S., & Anderson, R. D. (2017). Safety and efficacy of dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention. The American Journal of Medicine, 130(11), 1280–1289. https://doi.org/10.1016/j.amjmed.2017.03.057
   PubMed Web of Science ®Google Scholar
• Allayee, H., Roth, N., & Hodis, H. N. (2009). Polyunsaturated fatty acids and cardiovascular disease: Implications for nutrigenetics. Journal of Nutrigenetics and Nutrigenomics, 2(3), 140–148. https://doi.org/10.1159/000235562
   PubMedGoogle Scholar
• Altman, R., Rivas, A. J., & Gonzalez, C. D. (2012). Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: Rescue of the template bleeding time in a single-center prospective study. Thrombosis Journal, 10(1), 3. https://doi.org/10.1186/1477-9560-10-3
   PubMedGoogle Scholar
• Andreadelis, I., Chatziathanasiadou, Μ. V., Ntountaniotis, D., Valsami, G., Papaemmanouil, C., Christodoulou, E., Mitropoulou, G., Kourkoutas, Y., Tzakos, A. G., & Mavromoustakos, T. (2021). Charting the structural and thermodynamic determinants in phenolic acid natural product - Cyclodextrin encapsulations. Journal of Biomolecular Structure & Dynamics, 39(7), 2642–2658. https://doi.org/10.1080/07391102.2020.1751716
   PubMed Web of Science ®Google Scholar
• Bagger, H., Hansson, M., Kander, T., & Schött, U. (2020). Synergistic platelet inhibition between Omega-3 and acetylsalicylic acid dose titration; an observational study. BMC Complementary Medicine and Therapies, 20(1), 204. https://doi.org/10.1186/s12906-020-02990-9
   PubMedGoogle Scholar
• Bertolino, F. (1994). Prevention of thromboxane A2 receptor-mediated pulmonary hypertension by a nonpeptide angiotensin II type 1 receptor antagonist. Journal of Pharmacology and Experimental Therapeutics., 268(2), 747–752.
   PubMed Web of Science ®Google Scholar
• Borghi, C., Rossi, F., & SIF Task Force. (2015). Role of the renin-angiotensin-aldosterone system and its pharmacological inhibitors in cardiovascular diseases: Complex and critical issues. High Blood Pressure & Cardiovascular Prevention: The Official Journal of the Italian Society of Hypertension, 22(4), 429–444. https://doi.org/10.1007/s40292-015-0120-5
   PubMedGoogle Scholar
• Calder, P. C. (2012). Mechanisms of action of (n-3) fatty acids. The Journal of Nutrition, 142(3), 592S–599S. https://doi.org/10.3945/jn.111.155259
   PubMed Web of Science ®Google Scholar
• Chlopicki, S. (2000). Antiplatelet action of losartan involves TXA2 receptor antagonism but not TXA2 synthase inhibition. Journal of Physiology and Pharmacology, 51(4 Pt 1), 715–722.
   PubMed Web of Science ®Google Scholar
• Chung, I., & Lip, G. Y. (2006). Platelets and heart failure. European Heart Journal, 27(22), 2623–2631. https://doi.org/10.1093/eurheartj/ehl305
   PubMed Web of Science ®Google Scholar
• Dahlof, B. (2002). Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet, 359(9311), 995–1003.
   PubMed Web of Science ®Google Scholar
• Dasgupta, C., & Zhang, L. (2011). Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discovery Today, 16(1–2), 22–34. https://doi.org/10.1016/j.drudis.2010.11.016
   PubMed Web of Science ®Google Scholar
• Diamantis, D. A., Ramesova, S., Chatzigiannis, C. M., Degano, I., Gerogianni, P. S., Karadima, K. E., Perikleous, S., Rekkas, D., Gerothanassis, I. P., Galaris, D., Mavromoustakos, T., Valsami, G., Sokolova, R., & Tzakos, A. G. (2018). Exploring the oxidation and iron binding profile of a cyclodextrin encapsulated quercetin complex unveiled a controlled complex dissociation through a chemical stimulus. Biochimica et Biophysica Acta. General Subjects, 1862(9), 1913–1924. https://doi.org/10.1016/j.bbagen.2018.06.006
   PubMed Web of Science ®Google Scholar
• DiNicolantonio, J. J., & OKeefe, J. (2019). Importance of maintaining a low omega-6/omega-3 ratio for reducing platelet aggregation, coagulation and thrombosis. Open Heart, 6(1), e001011. https://doi.org/10.1136/openhrt-2019-001011
   PubMed Web of Science ®Google Scholar
• Farid, R., Day, T., Friesner, R. A., & Pearlstein, R. A. (2006). New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies. Bioorganic & Medicinal Chemistry, 14(9), 3160–3173. https://doi.org/10.1016/j.bmc.2005.12.032
   PubMed Web of Science ®Google Scholar
• Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., Sanschagrin, P. C., & Mainz, D. T. (2006). Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. Journal of Medicinal Chemistry, 49(21), 6177–6196. https://doi.org/10.1021/jm051256o
   PubMed Web of Science ®Google Scholar
• Gajos, G., Rostoff, P., Undas, A., & Piwowarska, W. (2010). Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: The OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study. Journal of the American College of Cardiology, 55(16), 1671–1678. https://doi.org/10.1016/j.jacc.2009.11.080
   PubMed Web of Science ®Google Scholar
• Gasparyan, A. Y. (2010). Aspirin and clopidogrel resistance: Methodological challenges and opportunities. Vascular Health and Risk Management, 6, 109–112. https://doi.org/10.2147/vhrm.s9087
   PubMedGoogle Scholar
• Gremmel, T., Michelson, A. D., Frelinger, A. L., & Bhatt, D. L. (2018). Novel aspects of antiplatelet therapy in cardiovascular disease. Research and Practice in Thrombosis and Haemostasis, 2(3), 439–449. https://doi.org/10.1002/rth2.12115
   PubMed Web of Science ®Google Scholar
• Grothusen, C., Umbreen, S., Konrad, I., Stellos, K., Schulz, C., Schmidt, B., Kremmer, E., Teebken, O., Massberg, S., Luchtefeld, M., Schieffer, B., & Gawaz, M. (2007). EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: Potential impact on atherothrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(5), 1184–1190. https://doi.org/10.1161/ATVBAHA.106.138693
   PubMed Web of Science ®Google Scholar
• Guirgis, M., Thompson, P., & Jansen, S. (2017). Review of aspirin and clopidogrel resistance in peripheral arterial disease. Journal of Vascular Surgery, 66(5), 1576–1586. https://doi.org/10.1016/j.jvs.2017.07.065
   PubMed Web of Science ®Google Scholar
• Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004). Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry, 47(7), 1750–1759. https://doi.org/10.1021/jm030644s
   PubMed Web of Science ®Google Scholar
• Iadecola, C., & Davisson, R. L. (2008). Hypertension and cerebrovascular dysfunction. Cell Metabolism, 7(6), 476–484. https://doi.org/10.1016/j.cmet.2008.03.010
   PubMed Web of Science ®Google Scholar
• Ito, M. K. (2015). A comparative overview of prescription omega-3 fatty acid products. P & T: A Peer-Reviewed Journal for Formulary Management, 40(12), 826–857.
   PubMedGoogle Scholar
• Jiang, P., Loyau, S., Tchitchinadze, M., Ropers, J., Jondeau, G., & Jandrot-Perrus, M. (2015). Inhibition of glycoprotein VI clustering by collagen as a mechanism of inhibiting collagen-induced platelet responses: The example of losartan. PLoS One, 10(6), e0128744. https://doi.org/10.1371/journal.pone.0128744
   PubMed Web of Science ®Google Scholar
• Kalinowski, L., Matys, T., Chabielska, E., Buczko, W., & Malinski, T. (2002). Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release. Hypertension (Dallas, TX: 1979), 40(4), 521–527. https://doi.org/10.1161/01.hyp.0000034745.98129.ec
   PubMed Web of Science ®Google Scholar
• Kellici, T. F., Chatziathanasiadou, M. V., Diamantis, D., Chatzikonstantinou, A. V., Andreadelis, I., Christodoulou, E., Valsami, G., Mavromoustakos, T., & Tzakos, A. G. (2016). Mapping the interactions and bioactivity of quercetin-(2-hydroxypropyl)-β-cyclodextrin complex. International Journal of Pharmaceutics, 511(1), 303–311. https://doi.org/10.1016/j.ijpharm.2016.07.008
   PubMed Web of Science ®Google Scholar
• Kjeldsen, S. E. (2018). Hypertension and cardiovascular risk: General aspects. Pharmacological Research, 129, 95–99. https://doi.org/10.1016/j.phrs.2017.11.003
   PubMed Web of Science ®Google Scholar
• Kontogianni, V. G., Tsoumani, M. E., Kellici, T. F., Mavromoustakos, T., Gerothanassis, I. P., Tselepis, A. D., & Tzakos, A. G. (2016). Deconvoluting the dual antiplatelet activity of a plant extract. Journal of Agricultural and Food Chemistry, 64(22), 4511–4521. https://doi.org/10.1021/acs.jafc.6b00544
   PubMed Web of Science ®Google Scholar
• Lawes, C. M. M., Vander Hoorn, S., Rodgers, A., & International Society of Hypertension. (2008). Global burden of blood-pressure-related disease, 2001. Lancet (London, England), 371(9623), 1513–1518. https://doi.org/10.1016/S0140-6736(08)60655-8
   PubMed Web of Science ®Google Scholar
• Leonis, G., Christodoulou, E., Ntountaniotis, D., Chatziathanasiadou, M. V., Mavromoustakos, T., Naziris, N., Chountoulesi, M., Demetzos, C., Valsami, G., Damalas, D. E., Tzakos, A. G., Thomaidis, N. S., Karageorgos, V., & Liapakis, G. (2020). Antihypertensive activity and molecular interactions of irbesartan in complex with 2-hydroxypropyl-β-cyclodextrin. Chemical Biology & Drug Design, 96(1), 668–683. https://doi.org/10.1111/cbdd.13664
   PubMed Web of Science ®Google Scholar
• Lewington, S., Clarke, R., Qizilbash, N., Peto, R., Collins, R., & Prospective Studies Collaboration. (2002). Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet (London, England), 360(9349), 1903–1913. https://doi.org/10.1016/s0140-6736(02)11911-8
   PubMed Web of Science ®Google Scholar
• Li, P., Ferrario, C. M., & Brosnihan, K. B. (1997). Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries. The Journal of Pharmacology and Experimental Therapeutics, 281(3), 1065–1070.
   PubMed Web of Science ®Google Scholar
• Li, P., Ferrario, C. M., & Brosnihan, K. B. (1998). Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology, 32(2), 198–205.
   PubMed Web of Science ®Google Scholar
• Li, S., Tarlac, V., & Hamilton, J. R. (2019). Using PAR4 inhibition as an anti-thrombotic approach: Why, how, and when? International Journal of Molecular Sciences, 20(22), 5629.
   PubMed Web of Science ®Google Scholar
• Liossi, Α. S., Ntountaniotis, D., Kellici, T. F., Chatziathanasiadou, M. V., Megariotis, G., Mania, M., Becker-Baldus, J., Kriechbaum, M., Krajnc, A., Christodoulou, E., Glaubitz, C., Rappolt, M., Amenitsch, H., Mali, G., Theodorou, D. N., Valsami, G., Pitsikalis, M., Iatrou, H., Tzakos, A. G., & Mavromoustakos, T. (2017). Exploring the interactions of irbesartan and irbesartan-2-hydroxypropyl-β-cyclodextrin complex with model membranes. Biochimica et Biophysica Acta. Biomembranes, 1859(6), 1089–1098. https://doi.org/10.1016/j.bbamem.2017.03.003
   PubMed Web of Science ®Google Scholar
• Lopez-Farre, A. (2001). Angiotensin II AT(1) receptor antagonists and platelet activation. Nephrology Dialysis Transplantation, 16(Suppl 1), 45–49.
   PubMedGoogle Scholar
• Manta, K., Papakyriakopoulou, P., Chountoulesi, M., Diamantis, D. A., Spaneas, D., Vakali, V., Naziris, N., Chatziathanasiadou, M. V., Andreadelis, I., Moschovou, K., Athanasiadou, I., Dallas, P., Rekkas, D. M., Demetzos, C., Colombo, G., Banella, S., Javornik, U., Plavec, J., Mavromoustakos, T., Tzakos, A. G., & Valsami, G. (2020). Preparation and biophysical characterization of quercetin inclusion complexes with β-cyclodextrin derivatives to be formulated as possible nose-to-brain quercetin delivery systems. Molecular Pharmaceutics, 17(11), 4241–4255. https://doi.org/10.1021/acs.molpharmaceut.0c00672
   PubMed Web of Science ®Google Scholar
• Martinez-Quinones, P., McCarthy, C. G., Watts, S. W., Klee, N. S., Komic, A., Calmasini, F. B., Priviero, F., Warner, A., Chenghao, Y., & Wenceslau, C. F. (2018). Hypertension induced morphological and physiological changes in cells of the arterial wall. American Journal of Hypertension, 31(10), 1067–1078. https://doi.org/10.1093/ajh/hpy083
   PubMed Web of Science ®Google Scholar
• Matys, T. (2000). Losartan inhibits the adhesion of rat platelets to fibrillar collagen–A potential role of nitric oxide and prostanoids. Journal of Physiology and Pharmacology, 51(4 Pt 1), 705–713.
   PubMed Web of Science ®Google Scholar
• Matys, T. (2003). Nitric oxide-dependent antiplatelet action of AT1-receptor antagonists in a pulmonary thromboembolism in mice. Journal of Cardiovascular Pharmacology, 42(6), 710–713.
   PubMed Web of Science ®Google Scholar
• Mensah, G. A., Roth, G. A., & Fuster, V. (2019). The global burden of cardiovascular diseases and risk factors: 2020 and beyond. Journal of the American College of Cardiology, 74(20), 2529–2532. https://doi.org/10.1016/j.jacc.2019.10.009
   PubMed Web of Science ®Google Scholar
• Monton, M. (2000). Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation. Journal of Cardiovascular Pharmacology, 35(6), 906–913.
   PubMed Web of Science ®Google Scholar
• Moschonas, I. C., Kellici, T. F., Mavromoustakos, T., Stathopoulos, P., Tsikaris, V., Magafa, V., Tzakos, A. G., & Tselepis, A. D. (2017). Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand. Platelets, 28(8), 812–821. https://doi.org/10.1080/09537104.2017.1282607
   PubMed Web of Science ®Google Scholar
• Munger, M. A. (2011). Use of angiotensin receptor blockers in cardiovascular protection: Current evidence and future directions. P & T: A Peer-Reviewed Journal for Formulary Management, 36(1), 22–40.
   PubMedGoogle Scholar
• Nehme, A., & Zibara, K. (2017). Cellular distribution and interaction between extended renin-angiotensin-aldosterone system pathways in atheroma. Atherosclerosis, 263, 334–342. https://doi.org/10.1016/j.atherosclerosis.2017.05.029
   PubMed Web of Science ®Google Scholar
• Nehme, A., & Zibara, K. (2017). Efficiency and specificity of RAAS inhibitors in cardiovascular diseases: How to achieve better end-organ protection? Hypertension Research: Official Journal of the Japanese Society of Hypertension, 40(11), 903–909. https://doi.org/10.1038/hr.2017.65
   PubMed Web of Science ®Google Scholar
• Ntountaniotis, D., Andreadelis, I., Kellici, T. F., Karageorgos, V., Leonis, G., Christodoulou, E., Kiriakidi, S., Becker-Baldus, J., Stylos, E. K., Chatziathanasiadou, M. V., Chatzigiannis, C. M., Damalas, D. E., Aksoydan, B., Javornik, U., Valsami, G., Glaubitz, C., Durdagi, S., Thomaidis, N. S., Kolocouris, A., … Mavromoustakos, T. (2019). Host-guest interactions between candesartan and its prodrug candesartan cilexetil in complex with 2-hydroxypropyl-β-cyclodextrin: on the biological potency for angiotensin ii antagonism. Molecular Pharmaceutics, 16(3), 1255–1271. https://doi.org/10.1021/acs.molpharmaceut.8b01212
   PubMed Web of Science ®Google Scholar
• ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group & The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. (2002). Coordinators for the, and T. lipid-lowering treatment to prevent heart attack, major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 288(23), 2981–2997.
   PubMed Web of Science ®Google Scholar
• Palomo, I., Toro, C., & Alarcon, M. (2008). The role of platelets in the pathophysiology of atherosclerosis (Review). Molecular Medicine Reports, 1(2), 179–184.
   PubMed Web of Science ®Google Scholar
• Pryce, R., Bernaitis, N., Davey, A., Badrick, T., & Anoopkumar-Dukie, S. (2016). The use of fish oil with warfarin does not significantly affect either the international normalised ratio or incidence of adverse events in patients with atrial fibrillation and deep vein thrombosis: A retrospective study. Nutrients, 8(9), 578. https://doi.org/10.3390/nu8090578
   PubMed Web of Science ®Google Scholar
• Remkova, A., & Remko, M. (2010). The role of renin-angiotensin system in prothrombotic state in essential hypertension. Physiological Research, 59(1), 13–23. https://doi.org/10.33549/physiolres.931525
   PubMed Web of Science ®Google Scholar
• Renziehausen, A., Tsiailanis, A. D., Perryman, R., Stylos, E. K., Chatzigiannis, C., O'Neill, K., Crook, T., Tzakos, A. G., & Syed, N. (2019). Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma. Molecular Cancer Therapeutics, 18(9), 1497–1505. https://doi.org/10.1158/1535-7163.MCT-18-1250
   PubMed Web of Science ®Google Scholar
• Rincon-Choles, H. (2019). ACE inhibitor and ARB therapy: Practical recommendations. Cleveland Clinic Journal of Medicine, 86(9), 608–611. https://doi.org/10.3949/ccjm.86a.19016
   PubMed Web of Science ®Google Scholar
• Roberto, G., Simonetti, M., Cricelli, C., Cricelli, I., Giustini, S. E., Parretti, D., & Lapi, F. (2016). Concurrent use of low-dose aspirin and omega-3 fatty acids and risk of upper gastrointestinal complications: A cohort study with nested case-control analysis. Basic & Clinical Pharmacology & Toxicology, 118(2), 136–142. https://doi.org/10.1111/bcpt.12454
   PubMed Web of Science ®Google Scholar
• Sakamoto, T., Kudoh, T., Sakamoto, K., Matsui, K., & Ogawa, H. (2014). Antithrombotic effects of losartan in patients with hypertension complicated by atrial fibrillation: 4A (Angiotensin II Antagonist of platelet Aggregation in patients with Atrial fibrillation), A pilot study. Hypertension Research, 37(6), 513–518. https://doi.org/10.1038/hr.2014.22
   PubMed Web of Science ®Google Scholar
• Sayyad, N., Vrettos, E. I., Karampelas, T., Chatzigiannis, C. M., Spyridaki, K., Liapakis, G., Tamvakopoulos, C., & Tzakos, A. G. (2019). Development of bioactive gemcitabine-D-Lys6-GnRH prodrugs with linker-controllable drug release rate and enhanced biopharmaceutical profile. European Journal of Medicinal Chemistry, 166, 256–266. https://doi.org/10.1016/j.ejmech.2019.01.041
   PubMed Web of Science ®Google Scholar
• Sherman, W., Day, T., Jacobson, M. P., Friesner, R. A., & Farid, R. (2006). Novel procedure for modeling ligand/receptor induced fit effects. Journal of Medicinal Chemistry, 49(2), 534–553. https://doi.org/10.1021/jm050540c
   PubMed Web of Science ®Google Scholar
• Shmyr, D., Van der Merwe, V., Yakiwchuk, E., Barry, A., & Kosar, L. (2017). Triple antithrombotic therapy for atrial fibrillation and coronary stents. Canadian Family Physician Medecin de Famille Canadien, 63(5), 375–381.
   PubMed Web of Science ®Google Scholar
• Singh, K. D., Unal, H., Desnoyer, R., & Karnik, S. S. (2019). Mechanism of hormone peptide activation of a GPCR: Angiotensin II activated state of AT1R initiated by van der Waals attraction. Journal of Chemical Information and Modeling, 59(1), 373–385. https://doi.org/10.1021/acs.jcim.8b00583
   PubMed Web of Science ®Google Scholar
• Stupin, M., Kibel, A., Stupin, A., Selthofer-Relatić, K., Matić, A., Mihalj, M., Mihaljević, Z., Jukić, I., & Drenjančević, I. (2019). The physiological effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) intake and exercise on hemorheology, microvascular function, and physical performance in health and cardiovascular diseases; is there an interaction of exercise and dietary n-3 PUFA intake? Frontiers in Physiology, 10, 1129.
   PubMed Web of Science ®Google Scholar
• Stylos, E., Chatziathanasiadou, M. V., Tsiailanis, A., Kellici, T. F., Tsoumani, M., Kostagianni, A. D., Deligianni, M., Tselepis, A. D., & Tzakos, A. G. (2017). Tailoring naringenin conjugates with amplified and triple antiplatelet activity profile: Rational design, synthesis, human plasma stability and in vitro evaluation. Biochimica et Biophysica Acta. General Subjects, 1861(11 Pt A), 2609–2618. https://doi.org/10.1016/j.bbagen.2017.08.018
   PubMed Web of Science ®Google Scholar
• Suresh, A. (2016). A pilot study on the effect of angiotensin receptor blockers on platelet aggregation in hypertensive patients- A prospective observational study. Journal of Clinical and Diagnostic Research, 10(11), FC14–FC16.
   PubMedGoogle Scholar
• Tamaki, T., Nishiyama, A., Kimura, S., Aki, Y., Yoshizumi, M., Houchi, H., Morita, K., & Abe, Y. (1997). EXP3174: The major active metabolite of losartan. Cardiovascular Drug Reviews, 15(2), 122–136. https://doi.org/10.1111/j.1527-3466.1997.tb00327.x
   Google Scholar
• Tamura, T., Sakaeda, T., Kadoyama, K., & Okuno, Y. (2012). Aspirin- and clopidogrel-associated bleeding complications: Data mining of the public version of the FDA adverse event reporting system, AERS. International Journal of Medical Sciences, 9(6), 441–446. https://doi.org/10.7150/ijms.4549
   PubMed Web of Science ®Google Scholar
• Toto, R. (2001). Angiotensin II subtype 1 receptor blockers and renal function. Archives of Internal Medicine, 161(12), 1492–1499. https://doi.org/10.1001/archinte.161.12.1492
   PubMedGoogle Scholar
• Touyz, R. M., & Schiffrin, E. L. (1993). Effects of angiotensin II and endothelin-1 on platelet aggregation and cytosolic pH and free Ca2+ concentrations in essential hypertension. Hypertension, 22(6), 853–862. https://doi.org/10.1161/01.HYP.22.6.853
   PubMed Web of Science ®Google Scholar
• Tsiailanis, A. D., Renziehausen, A., Kiriakidi, S., Vrettos, E. I., Markopoulos, G. S., Sayyad, N., Hirmiz, B., Aguilar, M.-I., Del Borgo, M. P., Kolettas, E., Widdop, R. E., Mavromoustakos, T., Crook, T., Syed, N., & Tzakos, A. G. (2020). Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid. Free Radical Biology & Medicine, 160, 391–402. https://doi.org/10.1016/j.freeradbiomed.2020.08.007
   PubMed Web of Science ®Google Scholar
• Tsiailanis, A. D., Tzakos, A. G., & Mavromoustakos, T. (2021). Advancing the therapeutic efficacy of bioactive molecules by delivery vehicle platforms. Current Medicinal Chemistry, 28(14), 2697–2706. https://doi.org/10.2174/0929867327666200605154506
   PubMed Web of Science ®Google Scholar
• Tsiailanis, A., Tsoumani, M., Stylos, E. K., Chatziathanasiadou, M. V., Kellici, T. F., Mavromoustakos, T., Tselepis, A. D., & Tzakos, A. G. (2018). Designing natural product hybrids bearing triple antiplatelet profile and evaluating their human plasma stability. Methods in Molecular Biology (Clifton, NJ), 1824, 371–385.
   PubMedGoogle Scholar
• Tzakos, A. G., Kontogianni, V. G., Tsoumani, M., Kyriakou, E., Hwa, J., Rodrigues, F. A., & Tselepis, A. D. (2012). Exploration of the antiplatelet activity profile of betulinic acid on human platelets. Journal of Agricultural and Food Chemistry, 60(28), 6977–6983. https://doi.org/10.1021/jf3006728
   PubMed Web of Science ®Google Scholar
• Vrettos, E. I., Sayyad, N., Mavrogiannaki, E. M., Stylos, E., Kostagianni, A. D., Papas, S., Mavromoustakos, T., Theodorou, V., & Tzakos, A. G. (2017). Unveiling and tackling guanidinium peptide coupling reagent side reactions towards the development of peptide-drug conjugates. RSC Advances, 7(80), 50519–50526. https://doi.org/10.1039/C7RA06655D
   Web of Science ®Google Scholar
• Wing, L. M. H., Reid, C. M., Ryan, P., Beilin, L. J., Brown, M. A., Jennings, G. L. R., Johnston, C. I., McNeil, J. J., Macdonald, G. J., Marley, J. E., Morgan, T. O., West, M. J., & Second Australian National Blood Pressure Study Group. (2003). A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. The New England Journal of Medicine, 348(7), 583–592. https://doi.org/10.1056/NEJMoa021716
   PubMed Web of Science ®Google Scholar
• World Health Organization (WHO). (2020). Cardiovascular diseases. https://www.who.int/health-topics/cardiovascular-diseases
   Google Scholar
• Yang, S.-H., Cho, Y.-A., & Choi, J.-S. (2011). Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats. Acta Pharmacologica Sinica, 32(7), 967–972. https://doi.org/10.1038/aps.2011.32
   PubMed Web of Science ®Google Scholar
• Yeung, J., & Holinstat, M. (2012). Newer agents in antiplatelet therapy: A review. Journal of Blood Medicine, 3, 33–42.
   PubMedGoogle Scholar