{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:39:09Z","timestamp":1790419149136,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:00:00Z","timestamp":1593388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1009 \u201cBreaking Barriers\u201d, Project A06 (to U.R.) and B02 (to S.L.), CRC 1348 \u201cDynamic Cellular Interfaces\u201d, Project A11 (to U.R.), DFG Lu477\/23-1 (to S.L.),"],"award-info":[{"award-number":["CRC1009 \u201cBreaking Barriers\u201d, Project A06 (to U.R.) and B02 (to S.L.), CRC 1348 \u201cDynamic Cellular Interfaces\u201d, Project A11 (to U.R.), DFG Lu477\/23-1 (to S.L.),"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004870","name":"Medizinische Fakult\u00e4t,\u00a0Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster","doi-asserted-by":"publisher","award":["IZKF Re2\/022\/20"],"award-info":[{"award-number":["IZKF Re2\/022\/20"]}],"id":[{"id":"10.13039\/501100004870","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009139","name":"Deutsches Zentrum f\u00fcr Infektionsforschung","doi-asserted-by":"publisher","award":["DZIF, TTU 01.806 to S.P."],"award-info":[{"award-number":["DZIF, TTU 01.806 to S.P."]}],"id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["SFB1021, TP C01"],"award-info":[{"award-number":["SFB1021, TP C01"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza virus infections and their associated morbidity and mortality are a major threat to global health. Vaccination is an effective influenza prevention measure; however, the effectiveness is challenged by the rapid changes in the influenza virus genome leading to viral adaptation. Emerging viral resistance to the neuraminidase inhibitor oseltamivir limits the treatment of acute influenza infections. Targeting influenza virus-host interactions is a new and emerging field, and therapies based on the combination of virus- and host-directed drugs might significantly improve treatment success. We therefore assessed the combined treatment with oseltamivir and the repurposed antifungal drug itraconazole on infection of polarized broncho-epithelial Calu-3 cells with pdm09 or Panama influenza A virus strains. We detected significantly stronger antiviral activities in the combined treatment compared to monotherapy with oseltamivir, permitting lower concentrations of the drug than required for the single treatments. Bliss independence drug interaction analysis indicated that both drugs acted independently of each other. The additional antiviral effect of itraconazole might safeguard patients infected with influenza virus strains with heightened oseltamivir resistance.<\/jats:p>","DOI":"10.3390\/v12070703","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T09:04:59Z","timestamp":1593507899000},"page":"703","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection"],"prefix":"10.3390","volume":"12","author":[{"given":"Sebastian","family":"Schloer","sequence":"first","affiliation":[{"name":"Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation and \u201cCells in Motion\u201d Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Goretzko","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation and \u201cCells in Motion\u201d Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Pleschka","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, Justus-Liebig-Universit\u00e4t, Schuberststr. 81, D-35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-3052","authenticated-orcid":false,"given":"Stephan","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Virology (IVM) and \u201cCells in Motion\u201d Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8892-319X","authenticated-orcid":false,"given":"Ursula","family":"Rescher","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation and \u201cCells in Motion\u201d Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.cell.2014.03.023","article-title":"Peering into the crystal ball: Influenza pandemics and vaccine efficacy","volume":"157","author":"Miller","year":"2014","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.antiviral.2012.12.016","article-title":"Influenza antiviral resistance in the Asia-Pacific region during 2011","volume":"97","author":"Leang","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1586\/eri.12.125","article-title":"Influenza antivirals and resistance: The next 10 years?","volume":"10","author":"Hurt","year":"2012","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6852","DOI":"10.1016\/j.vaccine.2007.07.027","article-title":"Influenza vaccine: The challenge of antigenic drift","volume":"25","author":"Carrat","year":"2007","journal-title":"Vaccine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.cell.2006.02.010","article-title":"Emerging and re-emerging infectious diseases: Influenza as a prototype of the host-pathogen balancing act","volume":"124","author":"Fauci","year":"2006","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Villal\u00f3n-Letelier, F., Brooks, A.G., Saunders, P.M., Londrigan, S.L., and Reading, P.C. (2017). Host cell restriction factors that limit influenza a infection. Viruses, 9.","DOI":"10.3390\/v9120376"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza viruses","volume":"26","author":"Bouvier","year":"2008","journal-title":"Vaccine"},{"key":"ref_8","first-page":"1289","article-title":"Virus entry at a glance","volume":"126","author":"Yamauchi","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1099\/vir.0.059477-0","article-title":"Entry of influenza A virus: Host factors and antiviral targets","volume":"95","author":"Edinger","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_10","first-page":"69","article-title":"Compounds with anti-influenza activity: Present and future of strategies for the optimal treatment and management of influenza. Part I: Influenza life-cycle and currently available drugs","volume":"55","author":"Gasparini","year":"2014","journal-title":"J. Prev. Med. Hyg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2174\/0929867003374886","article-title":"Discovery and development of GS 4104 (oseltamivir): An orally active influenza neuraminidase inhibitor","volume":"7","author":"Lew","year":"2000","journal-title":"Curr. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3345\/kjp.2013.56.4.165","article-title":"Occurrence and characterization of oseltamivir-resistant influenza virus in children between 2007\u20132008 and 2008\u20132009 seasons","volume":"56","author":"Kim","year":"2013","journal-title":"Korean J. Pediatr."},{"key":"ref_13","first-page":"CD008965","article-title":"Neuraminidase inhibitors for preventing and treating influenza in adults and children","volume":"2014","author":"Jefferson","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8488","DOI":"10.1038\/s41598-017-08282-6","article-title":"Susceptibility of influenza A(H1N1)\/pdm2009, seasonal A(H3N2) and B viruses to Oseltamivir in Guangdong, China between 2009 and 2014","volume":"7","author":"Liu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mukherjee, A., Nayak, M.K., Dutta, S., Panda, S., Satpathi, B.R., and Chawla-Sarkar, M. (2016). Genetic characterization of circulating 2015 A(H1N1)pdm09 influenza viruses from Eastern India. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168464"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa1716197","article-title":"Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents","volume":"379","author":"Hayden","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.antiviral.2017.01.006","article-title":"An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses","volume":"140","author":"Hu","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.antiviral.2007.08.007","article-title":"Amantadine-resistance among H5N1 avian influenza viruses isolated in Northern China","volume":"77","author":"He","year":"2008","journal-title":"Antivir. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/rmv.703","article-title":"The host interactome of influenza virus presents new potential targets for antiviral drugs","volume":"21","author":"Shaw","year":"2011","journal-title":"Rev. Med. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"282","DOI":"10.2174\/187152607783018745","article-title":"Influenza viruses: Basic biology and potential drug targets","volume":"7","author":"Basler","year":"2007","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13073-014-0115-1","article-title":"Virus-host interactomics: New insights and opportunities for antiviral drug discovery","volume":"6","author":"Vonderscher","year":"2014","journal-title":"Genome Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrd.2017.162","article-title":"Host-directed therapies for bacterial and viral infections","volume":"17","author":"Kaufmann","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jinf.2011.01.014","article-title":"Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia","volume":"62","author":"Viasus","year":"2011","journal-title":"J. Infect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/22221751.2018.1559709","article-title":"The clinically licensed antifungal drug itraconazole inhibits influenza virus in vitro and in vivo","volume":"8","author":"Schloer","year":"2019","journal-title":"Emerg. Microbes Infect."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e01345-18","DOI":"10.1128\/mBio.01345-18","article-title":"Late endosomal\/lysosomal cholesterol accumulation is a host cell-protective mechanism inhibiting endosomal escape of influenza A virus","volume":"9","author":"Musiol","year":"2018","journal-title":"MBio"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00608-13","DOI":"10.1128\/mBio.00608-13","article-title":"Annexin A6-balanced late endosomal cholesterol controls influenza a replication and propagation","volume":"4","author":"Musiol","year":"2013","journal-title":"MBio"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Melville, K., Rodriguez, T., and Dobrovolny, H.M. (2018). Investigating different mechanisms of action in combination therapy for influenza. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01207"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S1473-3099(14)70821-7","article-title":"Antiviral combinations for severe influenza","volume":"14","author":"Dunning","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","first-page":"357","article-title":"Combined Therapy of Influenza with Antiviral Drugs with a Different Mechanism of Action in Comparison with Monotherapy","volume":"10","author":"Popov","year":"2018","journal-title":"J. Pharm. Sci. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"Volume 39","author":"Faul","year":"2007","journal-title":"Proceedings of the Behavior Research Methods"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ianevski, A., Giri, A.K., and Aittokallio, T. (2020). SynergyFinder 2.0: Visual analytics of multi-drug combination synergies. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkaa216"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1073\/pnas.1619571114","article-title":"Triazoles inhibit cholesterol export from lysosomes by binding to NPC1","volume":"114","author":"Trinh","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1080\/19466315.2018.1437071","article-title":"Evaluation of Drug Combination Effect Using a Bliss Independence Dose\u2013Response Surface Model","volume":"10","author":"Liu","year":"2018","journal-title":"Stat. Biopharm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1469-0691.2006.01611.x","article-title":"Therapeutic drug monitoring of itraconazole and the relevance of pharmacokinetic interactions","volume":"12","author":"Navarro","year":"2006","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1128\/AAC.48.5.1756-1762.2004","article-title":"Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect","volume":"48","author":"Shin","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1111\/1440-1681.12822","article-title":"Pharmacokinetic evaluation of oral itraconazole for antifungal prophylaxis in children","volume":"44","author":"Allegra","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1517\/17425255.2013.794785","article-title":"Itraconazole: An update on pharmacology and clinical use for treatment of invasive and allergic fungal infections","volume":"9","author":"Lestner","year":"2013","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1177\/0091270010365557","article-title":"Increased Oral Bioavailability of Itraconazole and Its Active Metabolite, 7-Hydroxyitraconazole, When Coadministered With a Vitamin C Beverage in Healthy Participants","volume":"51","author":"Bae","year":"2011","journal-title":"J. Clin. Pharmacol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/7\/703\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:44:46Z","timestamp":1760175886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/7\/703"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,29]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["v12070703"],"URL":"https:\/\/doi.org\/10.3390\/v12070703","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,29]]}}}