{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:19:04Z","timestamp":1791433144212,"version":"4.3.3"},"reference-count":82,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T00:00:00Z","timestamp":1710374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium\u2013hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.<\/jats:p>","DOI":"10.3390\/v16030450","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T05:43:08Z","timestamp":1710394988000},"page":"450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6753-3528","authenticated-orcid":false,"given":"Francesco","family":"Samarelli","sequence":"first","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5575-3240","authenticated-orcid":false,"given":"Giovanni","family":"Graziano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1965-1519","authenticated-orcid":false,"given":"Nicola","family":"Gambacorta","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Graps","sequence":"additional","affiliation":[{"name":"ARESS Puglia\u2014Agenzia Regionale Strategica per la Salute ed il Sociale, I-70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2043-7464","authenticated-orcid":false,"given":"Francesco","family":"Leonetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6533-5539","authenticated-orcid":false,"given":"Orazio","family":"Nicolotti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5016-5805","authenticated-orcid":false,"given":"Cosimo","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/s41564-020-0695-z","article-title":"The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-nCoV and Naming It SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The Cytokine Storm and COVID-19","volume":"93","author":"Hu","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/ddr.21752","article-title":"CB2 Receptor-Selective Agonists as Candidates for Targeting Infection, Inflammation, and Immunity in SARS-CoV-2 Infections","volume":"82","author":"Sharma","year":"2021","journal-title":"Drug Dev. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109022","DOI":"10.1016\/j.clim.2022.109022","article-title":"Anti-Inflammatory and Immune Therapy in Severe Coronavirus Disease 2019 (COVID-19) Patients: An Update","volume":"239","author":"Zhang","year":"2022","journal-title":"Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115109","DOI":"10.1016\/j.ejmech.2023.115109","article-title":"N-Adamantyl-Anthranil Amide Derivatives: New Selective Ligands for the Cannabinoid Receptor Subtype 2 (CB2R)","volume":"248","author":"Graziano","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.2174\/0929867329666220825161603","article-title":"Recent Advances on Type-2 Cannabinoid (CB2) Receptor Agonists and Their Therapeutic Potential","volume":"30","author":"Gasperi","year":"2023","journal-title":"Curr. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.1021\/acs.jcim.3c00914","article-title":"CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning","volume":"63","author":"Gambacorta","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"115647","DOI":"10.1016\/j.ejmech.2023.115647","article-title":"Exploring the 1,3-Benzoxazine Chemotype for Cannabinoid Receptor 2 as a Promising Anti-Cancer Therapeutic","volume":"259","author":"Gambacorta","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eabo5795","DOI":"10.1126\/scitranslmed.abo5795","article-title":"A Persistent Neutrophil-Associated Immune Signature Characterizes Post\u2013COVID-19 Pulmonary Sequelae","volume":"14","author":"George","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-de-las-Pe\u00f1as, C., Palacios-Ce\u00f1a, D., G\u00f3mez-Mayordomo, V., Cuadrado, M.L., and Florencio, L.L. (2021). Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18052621"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gambacorta, N., Caputo, L., Quintieri, L., Monaci, L., Ciriaco, F., and Nicolotti, O. (2022). Rational Discovery of Antiviral Whey Protein-Derived Small Peptides Targeting the SARS-CoV-2 Main Protease. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051067"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115311","DOI":"10.1016\/j.ejmech.2023.115311","article-title":"Broad-Spectrum Coronavirus 3C-like Protease Peptidomimetic Inhibitors Effectively Block SARS-CoV-2 Replication in Cells: Design, Synthesis, Biological Evaluation, and X-Ray Structure Determination","volume":"253","author":"Stefanelli","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/s41586-023-06651-y","article-title":"Distinguishing Features of Long COVID Identified through Immune Profiling","volume":"623","author":"Klein","year":"2023","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e161167","DOI":"10.1172\/JCI161167","article-title":"Long COVID Endotheliopathy: Hypothesized Mechanisms and Potential Therapeutic Approaches","volume":"132","author":"Ahamed","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.dsx.2021.04.007","article-title":"Long COVID: An Overview","volume":"15","author":"Raveendran","year":"2021","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Proal, A.D., and VanElzakker, M.B. (2021). Long COVID or Post-Acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.698169"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1186\/s13054-020-03267-w","article-title":"COVID-19: More than a Cytokine Storm","volume":"24","author":"Riva","year":"2020","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1111\/jth.14975","article-title":"Coagulopathy in COVID-19","volume":"18","author":"Iba","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1055\/s-0042-1749441","article-title":"Platelet Activation and Thrombosis in COVID-19","volume":"49","author":"Iba","year":"2023","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1080\/09537104.2020.1810224","article-title":"A Proof of Evidence Supporting Abnormal Immunothrombosis in Severe COVID-19: Naked Megakaryocyte Nuclei Increase in the Bone Marrow and Lungs of Critically Ill Patients","volume":"31","author":"Roncati","year":"2020","journal-title":"Platelets"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.thromres.2023.03.009","article-title":"Defibrotide Mitigates Endothelial Cell Injury Induced by Plasmas from Patients with COVID-19 and Related Vasculopathies","volume":"225","author":"Elhadad","year":"2023","journal-title":"Thromb. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1016\/j.cell.2023.09.013","article-title":"Serotonin Reduction in Post-Acute Sequelae of Viral Infection","volume":"186","author":"Wong","year":"2023","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tcm.2020.10.005","article-title":"COVID-19\u2014A Vascular Disease","volume":"31","author":"Siddiqi","year":"2021","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_24","unstructured":"(2023, December 01). Espacenet. Available online: https:\/\/worldwide.espacenet.com\/."},{"key":"ref_25","unstructured":"(2023, December 01). Clinical Trials, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41591-022-01689-3","article-title":"Long-Term Cardiovascular Outcomes of COVID-19","volume":"28","author":"Xie","year":"2022","journal-title":"Nat. Med."},{"key":"ref_27","first-page":"e102","article-title":"Cardiovascular Disease, Drug Therapy, and Mortality in COVID-19","volume":"382","author":"Mehra","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eadg7942","DOI":"10.1126\/science.adg7942","article-title":"Persistent Complement Dysregulation with Signs of Thromboinflammation in Active Long Covid","volume":"383","author":"Hoch","year":"2024","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108487","DOI":"10.1016\/j.clim.2020.108487","article-title":"Type 3 Hypersensitivity in COVID-19 Vasculitis","volume":"217","author":"Roncati","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s11239-020-02230-4","article-title":"COVID-19-Associated Vasculitis and Vasculopathy","volume":"50","author":"Becker","year":"2020","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41569-021-00552-1","article-title":"Interplay between Inflammation and Thrombosis in Cardiovascular Pathology","volume":"18","author":"Stark","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Theofilis, P., Sagris, M., Oikonomou, E., Antonopoulos, A.S., Siasos, G., Tsioufis, C., and Tousoulis, D. (2021). Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070781"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Purgatorio, R., Gambacorta, N., de Candia, M., Catto, M., Rullo, M., Pisani, L., Nicolotti, O., and Altomare, C.D. (2021). First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease. Molecules, 26.","DOI":"10.3390\/molecules26175208"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"ATTACC, ACTIV-4a, and REMAP-CAP Investigators (2021). Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with COVID-19. N. Engl. J. Med., 385, 790\u2013802.","DOI":"10.1056\/NEJMoa2105911"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12600","DOI":"10.1039\/D1SC01494C","article-title":"Synergistic Inhibition of SARS-CoV-2 Cell Entry by Otamixaban and Covalent Protease Inhibitors: Pre-Clinical Assessment of Pharmacological and Molecular Properties","volume":"12","author":"Hempel","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"De Maio, F., Rullo, M., de Candia, M., Purgatorio, R., Lopopolo, G., Santarelli, G., Palmieri, V., Papi, M., Elia, G., and De Candia, E. (2022). Evaluation of Novel Guanidino-Containing Isonipecotamide Inhibitors of Blood Coagulation Factors against SARS-CoV-2 Virus Infection. Viruses, 14.","DOI":"10.3390\/v14081730"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s40264-020-00994-5","article-title":"Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Death in Patients Hospitalised with COVID-19: A Retrospective Italian Cohort Study of 43,000 Patients","volume":"43","author":"Massari","year":"2020","journal-title":"Drug Saf."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107710","DOI":"10.1016\/j.jmgm.2020.107710","article-title":"Structural Analysis of Experimental Drugs Binding to the SARS-CoV-2 Target TMPRSS2","volume":"100","author":"Huggins","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.jhep.2019.11.024","article-title":"A Randomized, Placebo-Controlled Trial of Emricasan in Patients with NASH and F1-F3 Fibrosis","volume":"72","author":"Harrison","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41589-022-01059-7","article-title":"Structure and Activity of Human TMPRSS2 Protease Implicated in SARS-CoV-2 Activation","volume":"18","author":"Fraser","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1016\/S0960-894X(02)00213-5","article-title":"Optimization of the \u03b2-Aminoester Class of Factor Xa Inhibitors. Part 2: Identification of FXV673 as a Potent and Selective Inhibitor with Excellent In Vivo Anticoagulant Activity","volume":"12","author":"Guertin","year":"2002","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1021\/acsmedchemlett.3c00035","article-title":"TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform","volume":"14","author":"Peiffer","year":"2023","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/14728222.2022.2031975","article-title":"Ramatroban for Chemoprophylaxis and Treatment of COVID-19: David Takes on Goliath","volume":"26","author":"Chiang","year":"2022","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gupta, A., Kalantar-Zadeh, K., and Reddy, S.T. (2020). Ramatroban as a Novel Immunotherapy for COVID-19. J. Mol. Genet. Med., 14.","DOI":"10.37421\/jmgm.2020.14.457"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1080\/07391102.2020.1823887","article-title":"The Potential Role of Procyanidin as a Therapeutic Agent against SARS-CoV-2: A Text Mining, Molecular Docking and Molecular Dynamics Simulation Approach","volume":"40","author":"Maroli","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1002\/ptr.7436","article-title":"Therapeutic and Prophylactic Effect of Flavonoids in Post-COVID-19 Therapy","volume":"36","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e14649","DOI":"10.14814\/phy2.14649","article-title":"Might Proton Pump or Sodium-Hydrogen Exchanger Inhibitors Be of Value to Ameliorate SARS-CoV-2 Pathophysiology?","volume":"8","author":"Conrad","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/all.14907","article-title":"Caspases and Therapeutic Potential of Caspase Inhibitors in Moderate\u2013Severe SARS-CoV-2 Infection and Long COVID","volume":"77","author":"Plassmeyer","year":"2022","journal-title":"Allergy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"904020","DOI":"10.3389\/fphar.2022.904020","article-title":"Treatment of COVID-19 Pneumonia and Acute Respiratory Distress With Ramatroban, a Thromboxane A2 and Prostaglandin D2 Receptor Antagonist: A Four-Patient Case Series Report","volume":"13","author":"Ogletree","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e21666","DOI":"10.1096\/fj.202100540R","article-title":"High Levels of Eicosanoids and Docosanoids in the Lungs of Intubated COVID-19 Patients","volume":"35","author":"Archambault","year":"2021","journal-title":"FASEB J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1527-3466.2004.tb00132.x","article-title":"Ramatroban (BAY u 3405): A Novel Dual Antagonist of TXA2 Receptor and CRTh2, a Newly Identified Prostaglandin D2 Receptor","volume":"22","author":"Ishizuka","year":"2004","journal-title":"Cardiovasc. Drug Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6812","DOI":"10.1021\/acs.jcim.2c00583","article-title":"An Integrated Machine Learning Model To Spot Peptide Binding Pockets in 3D Protein Screening","volume":"62","author":"Trisciuzzi","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/s40265-020-01367-z","article-title":"Pharmaco-Immunomodulatory Therapy in COVID-19","volume":"80","author":"Rizk","year":"2020","journal-title":"Drugs"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0092-8674(00)81334-3","article-title":"Human ICE\/CED-3 Protease Nomenclature","volume":"87","author":"Alnemri","year":"1996","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nri.2015.7","article-title":"Converging Roles of Caspases in Inflammasome Activation, Cell Death and Innate Immunity","volume":"16","author":"Man","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"109772","DOI":"10.1016\/j.cellsig.2020.109772","article-title":"Cell Death Signalling in Virus Infection","volume":"76","author":"Imre","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Yapasert, R., Khaw-on, P., and Banjerdpongchai, R. (2021). Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets. Molecules, 26.","DOI":"10.3390\/molecules26247459"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10970","DOI":"10.1073\/pnas.2005615117","article-title":"Effective Treatment of Severe COVID-19 Patients with Tocilizumab","volume":"117","author":"Xu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1001\/jama.2020.16349","article-title":"Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial","volume":"324","author":"Spinner","year":"2020","journal-title":"JAMA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"102569","DOI":"10.1016\/j.autrev.2020.102569","article-title":"Immunomodulatory Therapy for the Management of Severe COVID-19. Beyond the Anti-Viral Therapy: A Comprehensive Review","volume":"19","author":"Belizna","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Grobler, C., Maphumulo, S.C., Grobbelaar, L.M., Bredenkamp, J.C., Laubscher, G.J., Lourens, P.J., Steenkamp, J., Kell, D.B., and Pretorius, E. (2020). COVID-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202007.0142.v1"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-020-0944-y","article-title":"A Single-Cell Atlas of the Peripheral Immune Response in Patients with Severe COVID-19","volume":"26","author":"Wilk","year":"2020","journal-title":"Nat. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1021\/jm050307e","article-title":"First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease","volume":"48","author":"Linton","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.4049\/jimmunol.175.4.2630","article-title":"IL-Converting Enzyme\/Caspase-1 Inhibitor VX-765 Blocks the Hypersensitive Response to an Inflammatory Stimulus in Monocytes from Familial Cold Autoinflammatory Syndrome Patients","volume":"175","author":"Stack","year":"2005","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.14336\/AD.2023.0312","article-title":"Complications of COVID-19 on the Central Nervous System: Mechanisms and Potential Treatment for Easing Long COVID","volume":"14","author":"Wei","year":"2023","journal-title":"Aging Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s12967-020-02430-9","article-title":"Advanced Bioinformatics Rapidly Identifies Existing Therapeutics for Patients with Coronavirus Disease-2019 (COVID-19)","volume":"18","author":"Kim","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/j.anai.2021.08.051","article-title":"D020 role of cellular caspases and therapeutic potential of a pan-caspase inhibitor, emricasan, in COVID-19","volume":"127","author":"Alpan","year":"2021","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.jhep.2019.12.010","article-title":"Randomized Placebo-Controlled Trial of Emricasan for Non-Alcoholic Steatohepatitis-Related Cirrhosis with Severe Portal Hypertension","volume":"72","author":"Bosch","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/apt.15030","article-title":"Randomised Clinical Trial: Emricasan versus Placebo Significantly Decreases ALT and Caspase 3\/7 Activation in Subjects with Non-Alcoholic Fatty Liver Disease","volume":"49","author":"Shiffman","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial Cell Infection and Endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/s41401-022-00998-0","article-title":"Endothelial Dysfunction in COVID-19: An Overview of Evidence, Biomarkers, Mechanisms and Potential Therapies","volume":"44","author":"Xu","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e154","DOI":"10.1002\/mco2.154","article-title":"Inflammatory Pathways in COVID-19: Mechanism and Therapeutic Interventions","volume":"3","author":"Jiang","year":"2022","journal-title":"MedComm"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.freeradbiomed.2012.04.013","article-title":"Facilitated Cellular Uptake and Suppression of Inducible Nitric Oxide Synthase by a Metabolite of Maritime Pine Bark Extract (Pycnogenol)","volume":"53","author":"Uhlenhut","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.nutres.2008.03.003","article-title":"Reduction of Cardiovascular Risk Factors in Subjects with Type 2 Diabetes by Pycnogenol Supplementation","volume":"28","author":"Zibadi","year":"2008","journal-title":"Nutr. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"106191","DOI":"10.1016\/j.ijantimicag.2020.106191","article-title":"Projected Supportive Effects of Pycnogenol\u24c7 in Patients Suffering from Multi-Dimensional Health Impairments after a SARS-CoV2 Infection","volume":"56","author":"Weichmann","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1093\/eurheartj\/ehr482","article-title":"Effects of Pycnogenol on Endothelial Function in Patients with Stable Coronary Artery Disease: A Double-Blind, Randomized, Placebo-Controlled, Cross-over Study","volume":"33","author":"Enseleit","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"519","DOI":"10.5507\/bp.2015.060","article-title":"A Minireview on NHE1 Inhibitors. A Rediscovered Hope in Oncohematology","volume":"159","author":"Mihaila","year":"2015","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Gazmuri, R.J., Radhakrishnan, J., and Ayoub, I.M. (2019). Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest. Molecules, 24.","DOI":"10.3390\/molecules24091765"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.hipert.2019.09.002","article-title":"Na+\/H+ Exchanger and Cardiac Hypertrophy","volume":"37","author":"Yeves","year":"2020","journal-title":"Hipertens. Y Riesgo Vasc."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"104999","DOI":"10.1016\/j.phrs.2020.104999","article-title":"Rimeporide as a FIrst- in-Class NHE-1 Inhibitor: Results of a Phase Ib Trial in Young Patients with Duchenne Muscular Dystrophy","volume":"159","author":"Previtali","year":"2020","journal-title":"Pharmacol. Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/3\/450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:13:21Z","timestamp":1760105601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/3\/450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,14]]},"references-count":82,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["v16030450"],"URL":"https:\/\/doi.org\/10.3390\/v16030450","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,14]]}}}