{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:50:25Z","timestamp":1791910225065,"version":"4.3.4"},"reference-count":71,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570807"],"award-info":[{"award-number":["81570807"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19AG05537301"],"award-info":[{"award-number":["U19AG05537301"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR069055"],"award-info":[{"award-number":["R01AR069055"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM109036"],"award-info":[{"award-number":["P20GM109036"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH104680"],"award-info":[{"award-number":["R01MH104680"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG061917"],"award-info":[{"award-number":["R01AG061917"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54MD007595"],"award-info":[{"award-number":["U54MD007595"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are urgently needed. Drug repurposing is an efficient and cost-effective strategy with minimum risk for identifying novel potential treatment options by repositioning therapies that were previously approved for other clinical outcomes. Here, we used an integrated network-based pharmacologic and transcriptomic approach to screen drug candidates novel for COVID-19 treatment. Network-based proximity scores were calculated to identify the drug\u2013disease pharmacological effect between drug\u2013target relationship modules and COVID-19 related genes. Gene set enrichment analysis (GSEA) was then performed to determine whether drug candidates influence the expression of COVID-19 related genes and examine the sensitivity of the repurposing drug treatment to peripheral immune cell types. Moreover, we used the complementary exposure model to recommend potential synergistic drug combinations. We identified 18 individual drug candidates including nicardipine, orantinib, tipifarnib and promethazine which have not previously been proposed as possible treatments for COVID-19. Additionally, 30 synergistic drug pairs were ultimately recommended including fostamatinib plus tretinoin and orantinib plus valproic acid. Differential expression genes of most repurposing drugs were enriched significantly in B cells. The findings may potentially accelerate the discovery and establishment of an effective therapeutic treatment plan for COVID-19 patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics13040545","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T22:55:09Z","timestamp":1618354509000},"page":"545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Drug Repurposing for COVID-19 Treatment by Integrating Network Pharmacology and Transcriptomics"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-4103","authenticated-orcid":false,"given":"Dan-Yang","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Liang","sequence":"additional","affiliation":[{"name":"Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-He","family":"Meng","sequence":"additional","affiliation":[{"name":"Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Greenbaum","sequence":"additional","affiliation":[{"name":"Tulane Center of Biomedical Informatics and Genomics, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Mei","family":"Xiao","sequence":"additional","affiliation":[{"name":"Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Jun","family":"Tan","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Wen","family":"Deng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China"},{"name":"Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, Changsha 410013, China"},{"name":"Tulane Center of Biomedical Informatics and Genomics, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jin, Y., Yang, H., Ji, W., Wu, W., Chen, S., Zhang, W., and Duan, G. (2020). Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses, 12.","DOI":"10.3390\/v12040372"},{"key":"ref_2","unstructured":"(2021, January 14). Coronavirus Disease (COVID-19)\u2014World Health Organization. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic Options for the 2019 Novel Coronavirus (2019-NCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: A Descriptive Study","volume":"395","author":"Chen","year":"2020","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/joim.13063","article-title":"Early Antiviral Treatment Contributes to Alleviate the Severity and Improve the Prognosis of Patients with Novel Coronavirus Disease (COVID-19)","volume":"288","author":"Wu","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_7","unstructured":"(2021, March 11). Home\u2014ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nature17180","article-title":"Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys","volume":"531","author":"Warren","year":"2016","journal-title":"Nature"},{"key":"ref_9","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_10","unstructured":"Pan, H., Peto, R., Abdool Karim, Q., Alejandria, M., Henao Restrepo, A.M., Hernandez Garcia, C., Kieny, M.P., Malekzadeh, R., Murthy, S., and Preziosi, M.-P. (2020). Repurposed Antiviral Drugs for COVID-19; Interim WHO SOLIDARITY Trial Results. medRxiv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41467-017-00680-8","article-title":"A Network Integration Approach for Drug-Target Interaction Prediction and Computational Drug Repositioning from Heterogeneous Information","volume":"8","author":"Luo","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1038\/s41467-018-05116-5","article-title":"Network-Based Approach to Prediction and Population-Based Validation of in Silico Drug Repurposing","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tu, Y.-F., Chien, C.-S., Yarmishyn, A.A., Lin, Y.-Y., Luo, Y.-H., Lin, Y.-T., Lai, W.-Y., Yang, D.-M., Chou, S.-J., and Yang, Y.-P. (2020). A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072657"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing","volume":"583","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"ref_15","first-page":"579","article-title":"NGSEA: Network-Based Gene Set Enrichment Analysis for Interpreting Gene Expression Phenotypes with Functional Gene Sets","volume":"42","author":"Han","year":"2019","journal-title":"Mol. Cells"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s12539-016-0194-3","article-title":"A Computational Systems Biology Approach for Identifying Candidate Drugs for Repositioning for Cardiovascular Disease","volume":"10","author":"Yu","year":"2018","journal-title":"Interdiscip. Sci. Comput. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10331","DOI":"10.1038\/ncomms10331","article-title":"Network-Based in Silico Drug Efficacy Screening","volume":"7","author":"Guney","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14621","DOI":"10.1073\/pnas.1000138107","article-title":"Discovery of Drug Mode of Action and Drug Repositioning from Transcriptional Responses","volume":"107","author":"Iorio","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.pharep.2019.02.011","article-title":"Transcriptome-Based Identification of Lovastatin as a Breast Cancer Stem Cell-Targeting Drug","volume":"71","year":"2019","journal-title":"Pharmacol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, M., Luo, H., Xi, Z., and Rogaeva, E. (2015). Drug Repositioning for Diabetes Based on \u201cOmics\u201d Data Mining. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126082"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kinnings, S.L., Liu, N., Buchmeier, N., Tonge, P.J., Xie, L., and Bourne, P.E. (2009). Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000423"},{"key":"ref_22","unstructured":"(2021, January 14). Coronaviridae\u2014NCBI Datasets, Available online: https:\/\/www.ncbi.nlm.nih.gov\/datasets\/coronavirus\/genomes\/."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"ClusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J. Integr. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A Major Update to the DrugBank Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_26","unstructured":"(2021, January 14). SuperTarget. Available online: http:\/\/insilico.charite.de\/supertarget\/index.php?site=drugs."},{"key":"ref_27","first-page":"D489","article-title":"Pathway Commons 2019 Update: Integration, Analysis and Exploration of Pathway Data","volume":"48","author":"Rodchenkov","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1038\/s41467-019-13208-z","article-title":"A Network-Based Approach to Identify Deregulated Pathways and Drug Effects in Metabolic Syndrome","volume":"10","author":"Misselbeck","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Peng, Y., Yuan, M., Xin, J., Liu, X., and Wang, J. (2020). Screening Novel Drug Candidates for Alzheimer\u2019s Disease by an Integrated Network and Transcriptome Analysis. Bioinformatics.","DOI":"10.1093\/bioinformatics\/btaa563"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cca.2020.05.027","article-title":"The Underlying Changes and Predicting Role of Peripheral Blood Inflammatory Cells in Severe COVID-19 Patients: A Sentinel?","volume":"508","author":"Sun","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1515\/cclm-2020-0188","article-title":"Prominent Changes in Blood Coagulation of Patients with SARS-CoV-2 Infection","volume":"58","author":"Han","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1038\/s41591-020-1038-6","article-title":"A Dynamic COVID-19 Immune Signature Includes Associations with Poor Prognosis","volume":"26","author":"Laing","year":"2020","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"205rv1","DOI":"10.1126\/scitranslmed.3006667","article-title":"High-Throughput Methods for Combinatorial Drug Discovery","volume":"5","author":"Sun","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/s41467-019-09186-x","article-title":"Network-Based Prediction of Drug Combinations","volume":"10","author":"Cheng","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Disease Networks. Uncovering Disease-Disease Relationships through the Incomplete Interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1080\/22221751.2020.1746200","article-title":"Renin-Angiotensin System Inhibitors Improve the Clinical Outcomes of COVID-19 Patients with Hypertension","volume":"9","author":"Meng","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41586-020-2196-x","article-title":"Virological Assessment of Hospitalized Patients with COVID-2019","volume":"581","author":"Woelfel","year":"2020","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3892\/ijmm.2020.4636","article-title":"A Dissection of SARSCoV2 with Clinical Implications (Review)","volume":"46","author":"Stancioiu","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ferraz, W.R., Gomes, R.A., S Novaes, A.L., and Goulart Trossini, G.H. (2020). Ligand and Structure-Based Virtual Screening Applied to the SARS-CoV-2 Main Protease: An in Silico Repurposing Study. Future Med. Chem.","DOI":"10.4155\/fmc-2020-0165"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1056\/NEJM199105163242002","article-title":"Differentiation Therapy of Acute Promyelocytic Leukemia with Tretinoin (All-Trans-Retinoic Acid)","volume":"324","author":"Warrell","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Riva, L., Yuan, S., Yin, X., Martin-Sancho, L., Matsunaga, N., Pache, L., Burgstaller-Muehlbacher, S., De Jesus, P.D., Teriete, P., and Hull, M.V. (2020). Discovery of SARS-CoV-2 Antiviral Drugs through Large-Scale Compound Repurposing. Nature.","DOI":"10.1038\/s41586-020-2577-1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.virol.2018.06.011","article-title":"Cyclophilins and Cyclophilin Inhibitors in Nidovirus Replication","volume":"522","author":"Pham","year":"2018","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Glowacka, P., Rudnicka, L., Warszawik-Hendzel, O., Sikora, M., Goldust, M., Gajda, P., Stochmal, A., Blicharz, L., Rakowska, A., and Olszewska, M. (2020). The Antiviral Properties of Cyclosporine. Focus on Coronavirus, Hepatitis C Virus, Influenza Virus, and Human Immunodeficiency Virus Infections. Biology, 9.","DOI":"10.3390\/biology9080192"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"109891","DOI":"10.1016\/j.mehy.2020.109891","article-title":"Immunopharmacological Management of COVID-19: Potential Therapeutic Role of Valproic Acid","volume":"143","author":"Unal","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s40265-018-0927-1","article-title":"Fostamatinib: First Global Approval","volume":"78","author":"Markham","year":"2018","journal-title":"Drugs"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Alimova, M., Sidhom, E.H., Satyam, A., Dvela-Levitt, M., Melanson, M., Chamberlain, B.T., Alper, S.L., Santos, J., Gutierrez, J., and Subramanian, A. (2020). A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 Pandemic. bioRxiv.","DOI":"10.1016\/j.xcrm.2020.100137"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Risner, K.H., Tieu, K.V., Wang, Y., Bakovic, A., Alem, F., Bhalla, N., Nathan, S., Conway, D.E., Macklin, P., and Narayanan, A. (2020). Maraviroc Inhibits SARS-CoV-2 Multiplication and s-Protein Mediated Cell Fusion in Cell Culture. bioRxiv.","DOI":"10.1101\/2020.08.12.246389"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cmet.2020.06.015","article-title":"In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19","volume":"32","author":"Zhang","year":"2020","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1186\/s13054-020-03154-4","article-title":"Atorvastatin Associated with Decreased Hazard for Death in COVID-19 Patients Admitted to an ICU: A Retrospective Cohort Study","volume":"24","author":"Chung","year":"2020","journal-title":"Crit. Care"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104051","DOI":"10.1016\/j.compbiomed.2020.104051","article-title":"Multi-Omics-Based Identification of SARS-CoV-2 Infection Biology and Candidate Drugs against COVID-19","volume":"126","author":"Barh","year":"2020","journal-title":"Comput. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.2165\/00003495-198733040-00002","article-title":"Nicardipine. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy, in the Treatment of Angina Pectoris, Hypertension and Related Cardiovascular Disorders","volume":"33","author":"Sorkin","year":"1987","journal-title":"Drugs"},{"key":"ref_55","first-page":"e7343","article-title":"Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19)","volume":"12","author":"Solaimanzadeh","year":"2020","journal-title":"Cureus"},{"key":"ref_56","first-page":"e8069","article-title":"Nifedipine and Amlodipine Are Associated with Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19","volume":"12","author":"Solaimanzadeh","year":"2020","journal-title":"Cureus"},{"key":"ref_57","unstructured":"Southard, B.T., and Al Khalili, Y. (2020). Promethazine, StatPearls."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-Cell Landscape of Bronchoalveolar Immune Cells in Patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1007\/s10637-014-0109-2","article-title":"Phase I Study on the Safety, Pharmacokinetic Profile, and Efficacy of the Combination of TSU-68, an Oral Antiangiogenic Agent, and S-1 in Patients with Advanced Hepatocellular Carcinoma","volume":"32","author":"Ikeda","year":"2014","journal-title":"Investig. New Drugs"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1158\/1535-7163.MCT-19-0958","article-title":"Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas","volume":"19","author":"Gilardi","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ciliberto, G., Mancini, R., and Paggi, M.G. (2020). Drug Repurposing against COVID-19: Focus on Anticancer Agents. J. Exp. Clin. Cancer Res., 39.","DOI":"10.1186\/s13046-020-01590-2"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"110091","DOI":"10.1016\/j.mehy.2020.110091","article-title":"COVID-19 Infection Can Cause Chemotherapy Resistance Development in Patients with Breast Cancer and Tamoxifen May Cause Susceptibility to COVID-19 Infection","volume":"143","author":"Vatansev","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"L1280","DOI":"10.1152\/ajplung.00153.2020","article-title":"Estrogen Regulates the Expression of SARS-CoV-2 Receptor ACE2 in Differentiated Airway Epithelial Cells","volume":"318","author":"Stelzig","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1056\/NEJMsr2005760","article-title":"Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19","volume":"382","author":"Vaduganathan","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41581-020-0279-4","article-title":"Controversies of Renin-Angiotensin System Inhibition during the COVID-19 Pandemic","volume":"16","author":"South","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.gendis.2020.06.009","article-title":"Coronavirus Disease 2019 (COVID-19): Cytokine Storms, Hyper-Inflammatory Phenotypes, and Acute Respiratory Distress Syndrome","volume":"7","author":"Lin","year":"2020","journal-title":"Genes Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s12031-016-0785-9","article-title":"Raloxifene and Tamoxifen Reduce PARP Activity, Cytokine and Oxidative Stress Levels in the Brain and Blood of Ovariectomized Rats","volume":"60","author":"Yazgan","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1046\/j.1365-2567.1997.00122.x","article-title":"The Beneficial Effects of Treatment with Tamoxifen and Anti-Oestradiol Antibody on Experimental Systemic Lupus Erythematosus Are Associated with Cytokine Modulations","volume":"90","author":"Dayan","year":"1997","journal-title":"Immunology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/ijc.2910260208","article-title":"Establishment and Characterization of a Human Acute Monocytic Leukemia Cell Line (THP-1)","volume":"26","author":"Tsuchiya","year":"1980","journal-title":"Int. J. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1001\/jama.2020.12839","article-title":"Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review","volume":"324","author":"Wiersinga","year":"2020","journal-title":"JAMA"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/4\/545\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:47:43Z","timestamp":1760161663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/4\/545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,14]]},"references-count":71,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["pharmaceutics13040545"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13040545","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,14]]}}}