Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model

{ 'indexed': {'date-parts': [[2023, 4, 26]], 'date-time': '2023-04-26T05:01:39Z', 'timestamp': 1682485299130}, 'reference-count': 40, 'publisher': 'Springer Science and Business Media LLC', 'license': [ { 'start': { 'date-parts': [[2023, 4, 25]], 'date-time': '2023-04-25T00:00:00Z', 'timestamp': 1682380800000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2023, 4, 25]], 'date-time': '2023-04-25T00:00:00Z', 'timestamp': 1682380800000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>COVID-19, caused by SARS-CoV-2 infection, is ' 'currently among the most important public health concerns worldwide. Although several ' 'effective vaccines have been developed, there is an urgent clinical need for effective ' 'pharmaceutical treatments for treatment of COVID-19. Ivermectin, a chemical derivative of ' 'avermectin produced by <jats:italic>Streptomyces avermitilis</jats:italic>, is a macrocyclic ' 'lactone with antiparasitic activity. Recent studies have shown that ivermectin inhibits ' 'SARS-CoV-2 replication in vitro. In the present study, we investigated the in vivo effects of ' 'ivermectin in a hamster model of SARS-CoV-2 infection. The results of the present study ' 'demonstrate oral administration of ivermectin prior to SARS-CoV-2 infection in hamsters was ' 'associated with decreased weight loss and pulmonary inflammation. In addition, the ' 'administration of ivermectin reduced pulmonary viral titers and mRNA expression level of ' 'pro-inflammatory cytokines associated with severe COVID-19 disease. The administration of ' 'ivermectin rapidly induced the production of virus-specific neutralizing antibodies in the ' 'late stage of viral infection. Zinc concentrations leading to immune quiescence were also ' 'significantly higher in the lungs of ivermectin-treated hamsters compared to controls. These ' 'results indicate that ivermectin may have efficacy in reducing the development and severity ' 'of COVID-19 by affecting host immunity in a hamster model of SARS-CoV-2 infection.</jats:p>', 'DOI': '10.1038/s41429-023-00623-0', 'type': 'journal-article', 'created': {'date-parts': [[2023, 4, 25]], 'date-time': '2023-04-25T10:03:30Z', 'timestamp': 1682417010000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian ' 'Hamster Model', 'prefix': '10.1038', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-3680-7231', 'authenticated-orcid': False, 'given': 'Takayuki', 'family': 'Uematsu', 'sequence': 'first', 'affiliation': []}, {'given': 'Tomomi', 'family': 'Takano', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-0099-3340', 'authenticated-orcid': False, 'given': 'Hidehito', 'family': 'Matsui', 'sequence': 'additional', 'affiliation': []}, {'given': 'Noritada', 'family': 'Kobayashi', 'sequence': 'additional', 'affiliation': []}, {'given': 'Satoshi', 'family': 'Ōmura', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hideaki', 'family': 'Hanaki', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2023, 4, 25]]}, 'reference': [ { 'key': '623_CR1', 'doi-asserted-by': 'publisher', 'first-page': '782', 'DOI': '10.1001/jama.2020.12839', 'volume': '324', 'author': 'WJ Wiersinga', 'year': '2020', 'unstructured': 'Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. ' 'Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus ' 'Disease 2019 (COVID-19): A Review. JAMA. 2020;324:782–93.', 'journal-title': 'JAMA'}, { 'key': '623_CR2', 'doi-asserted-by': 'publisher', 'first-page': '315', 'DOI': '10.1038/s41584-021-00608-z', 'volume': '17', 'author': 'M Ramos-Casals', 'year': '2021', 'unstructured': 'Ramos-Casals M, Brito-Zerón P, Mariette X. Systemic and organ-specific ' 'immune-related manifestations of COVID-19. Nat Rev Rheumatol. ' '2021;17:315–32.', 'journal-title': 'Nat Rev Rheumatol'}, { 'key': '623_CR3', 'doi-asserted-by': 'publisher', 'first-page': '1265', 'DOI': '10.1001/jamacardio.2020.3557', 'volume': '5', 'author': 'VO Puntmann', 'year': '2020', 'unstructured': 'Puntmann VO, et al. Outcomes of Cardiovascular Magnetic Resonance ' 'Imaging in Patients Recently Recovered from Coronavirus Disease 2019 ' '(COVID-19). JAMA Cardiol. 2020;5:1265–73.', 'journal-title': 'JAMA Cardiol'}, { 'key': '623_CR4', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s12913-020-06001-y', 'volume': '20', 'author': 'E Ladds', 'year': '2020', 'unstructured': 'Ladds E, et al. Persistent symptoms after Covid-19: qualitative study of ' '114 “long Covid” patients and draft quality principles for services. BMC ' 'Health Serv Res. 2020;20:1144.', 'journal-title': 'BMC Health Serv Res'}, { 'key': '623_CR5', 'doi-asserted-by': 'publisher', 'first-page': '585354', 'DOI': '10.3389/fimmu.2020.585354', 'volume': '11', 'author': 'O Sharma', 'year': '2020', 'unstructured': 'Sharma O, Sultan AA, Ding H, Triggle CR. A Review of the Progress and ' 'Challenges of Developing a Vaccine for COVID-19. Front Immunol. ' '2020;11:585354.', 'journal-title': 'Front Immunol'}, { 'key': '623_CR6', 'doi-asserted-by': 'publisher', 'first-page': '173751', 'DOI': '10.1016/j.ejphar.2020.173751', 'volume': '892', 'author': 'K Rawat', 'year': '2021', 'unstructured': 'Rawat K, Kumari P, Saha L. COVID-19 vaccine: A recent update in pipeline ' 'vaccines, their design and development strategies. Eur J Pharm. ' '2021;892:173751.', 'journal-title': 'Eur J Pharm'}, { 'key': '623_CR7', 'doi-asserted-by': 'publisher', 'first-page': '136', 'DOI': '10.1038/s41586-021-03412-7', 'volume': '593', 'author': 'DA Collier', 'year': '2021', 'unstructured': 'Collier DA, et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA ' 'vaccine-elicited antibodies. Nature. 2021;593:136–41.', 'journal-title': 'Nature'}, { 'key': '623_CR8', 'doi-asserted-by': 'publisher', 'first-page': 'e067873', 'DOI': '10.1136/bmj-2021-067873', 'volume': '375', 'author': 'A Israel', 'year': '2021', 'unstructured': 'Israel A, et al. Elapsed time since BNT162b2 vaccine and risk of ' 'SARS-CoV-2 infection: test negative design study. BMJ. 2021;375:e067873.', 'journal-title': 'BMJ'}, { 'key': '623_CR9', 'doi-asserted-by': 'publisher', 'first-page': '984', 'DOI': '10.1038/nrmicro1048', 'volume': '2', 'author': 'S Õmura', 'year': '2004', 'unstructured': 'Õmura S, Crump A. The life and times of ivermectin—A success story. Nat ' 'Rev Microbiol. 2004;2:984–9.', 'journal-title': 'Nat Rev Microbiol'}, { 'key': '623_CR10', 'doi-asserted-by': 'publisher', 'first-page': '13', 'DOI': '10.2183/pjab.87.13', 'volume': '87', 'author': 'A Crump', 'year': '2011', 'unstructured': 'Crump A, Omura S. Ivermectin, ‘Wonder drug’ from Japan: The human use ' 'perspective. Proc Jpn Acad Sers B Phys Biol Sci. 2011;87:13–28.', 'journal-title': 'Proc Jpn Acad Sers B Phys Biol Sci'}, { 'key': '623_CR11', 'doi-asserted-by': 'publisher', 'first-page': '104787', 'DOI': '10.1016/j.antiviral.2020.104787', 'volume': '178', 'author': 'L Caly', 'year': '2020', 'unstructured': 'Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ' 'ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res. ' '2020;178:104787.', 'journal-title': 'Antivir Res'}, { 'key': '623_CR12', 'first-page': 'CD015017', 'volume': '6', 'author': 'M Popp', 'year': '2022', 'unstructured': 'Popp M, et al. Ivermectin for preventing and treating COVID-19. Cochrane ' 'Database Syst Rev. 2022;6:CD015017.', 'journal-title': 'Cochrane Database Syst Rev'}, { 'key': '623_CR13', 'doi-asserted-by': 'publisher', 'first-page': '834', 'DOI': '10.1038/s41586-020-2342-5', 'volume': '583', 'author': 'SF Sia', 'year': '2020', 'unstructured': 'Sia SF, et al. Pathogenesis and transmission of SARS-CoV-2 in golden ' 'hamsters. Nature. 2020;583:834–8.', 'journal-title': 'Nature'}, { 'key': '623_CR14', 'doi-asserted-by': 'publisher', 'first-page': '16587', 'DOI': '10.1073/pnas.2009799117', 'volume': '117', 'author': 'M Imai', 'year': '2020', 'unstructured': 'Imai M, et al. Syrian hamsters as a small animal model for SARS-CoV-2 ' 'infection and countermeasure development. Proc Nat Acad Sci USA. ' '2020;117:16587–95.', 'journal-title': 'Proc Nat Acad Sci USA'}, { 'key': '623_CR15', 'doi-asserted-by': 'publisher', 'first-page': '2428', 'DOI': '10.1093/cid/ciaa644', 'volume': '71', 'author': 'JF-W Chan', 'year': '2020', 'unstructured': 'Chan JF-W, et al. Simulation of the clinical and pathological ' 'manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian ' 'hamster model: implications for disease pathogenesis and ' 'transmissibility. Clin Infect Dis. 2020;71:2428–46.', 'journal-title': 'Clin Infect Dis'}, { 'key': '623_CR16', 'doi-asserted-by': 'publisher', 'first-page': '109218', 'DOI': '10.1016/j.celrep.2021.109218', 'volume': '35', 'author': 'T Ebisudani', 'year': '2021', 'unstructured': 'Ebisudani T, et al. Direct derivation of human alveolospheres for ' 'SARS-CoV-2 infection modeling and drug screening. Cell Rep. ' '2021;35:109218.', 'journal-title': 'Cell Rep'}, { 'key': '623_CR17', 'doi-asserted-by': 'publisher', 'first-page': '7001', 'DOI': '10.1073/pnas.2002589117', 'volume': '117', 'author': 'S Matsuyama', 'year': '2020', 'unstructured': 'Matsuyama S, et al. Enhanced isolation of SARS-CoV-2 by ' 'TMPRSS2-expressing cells. Proc Nat Acad Sci USA. 2020;117:7001–3.', 'journal-title': 'Proc Nat Acad Sci USA'}, { 'key': '623_CR18', 'doi-asserted-by': 'publisher', 'first-page': '1671', 'DOI': '10.1016/j.cell.2021.02.029', 'volume': '184', 'author': 'JL Schultze', 'year': '2021', 'unstructured': 'Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune ' 'system. Cell. 2021;184:1671–92.', 'journal-title': 'Cell'}, { 'key': '623_CR19', 'doi-asserted-by': 'publisher', 'first-page': '425', 'DOI': '10.1038/s41579-021-00542-7', 'volume': '19', 'author': 'T Flerlage', 'year': '2021', 'unstructured': 'Flerlage T, Boyd DF, Meliopoulos V, Thomas PG, Schultz-Cherry S. ' 'Influenza virus and SARS-CoV-2: pathogenesis and host responses in the ' 'respiratory tract. Nat Rev Microbiol. 2021;19:425–41.', 'journal-title': 'Nat Rev Microbiol'}, { 'key': '623_CR20', 'doi-asserted-by': 'publisher', 'first-page': 'E71', 'DOI': '10.1073/pnas.1517188113', 'volume': '113', 'author': 'M Nishio', 'year': '2016', 'unstructured': 'Nishio M, et al. Dysregulated YAP1/TAZ and TGF-β signaling mediate ' 'hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci USA. ' '2016;113:E71–80.', 'journal-title': 'Proc Natl Acad Sci USA'}, { 'key': '623_CR21', 'doi-asserted-by': 'publisher', 'first-page': '107666', 'DOI': '10.18632/oncotarget.22587', 'volume': '8', 'author': 'S Nambara', 'year': '2017', 'unstructured': 'Nambara S, et al. Antitumor effects of the antiparasitic agent ' 'ivermectin via inhibition of Yes-associated protein 1 expression in ' 'gastric cancer. Oncotarget. 2017;8:107666–77.', 'journal-title': 'Oncotarget'}, { 'key': '623_CR22', 'doi-asserted-by': 'publisher', 'first-page': '851', 'DOI': '10.1042/BJ20120150', 'volume': '443', 'author': 'KM Wagstaff', 'year': '2012', 'unstructured': 'Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is ' 'a specific inhibitor of importin α/β-mediated nuclear import able to ' 'inhibit replication of HIV-1 and dengue virus. Biochem J. ' '2012;443:851–6.', 'journal-title': 'Biochem J'}, { 'key': '623_CR23', 'doi-asserted-by': 'publisher', 'first-page': 'e0006934', 'DOI': '10.1371/journal.pntd.0006934', 'volume': '12', 'author': 'TL Xu', 'year': '2018', 'unstructured': 'Xu TL, et al. Antivirus effectiveness of ivermectin on dengue virus type ' '2 in Aedes albopictus. PLoS Negl Trop Dis. 2018;12:e0006934.', 'journal-title': 'PLoS Negl Trop Dis'}, { 'key': '623_CR24', 'doi-asserted-by': 'publisher', 'first-page': '104760', 'DOI': '10.1016/j.antiviral.2020.104760', 'volume': '177', 'author': 'SNY Yang', 'year': '2020', 'unstructured': 'Yang SNY, et al. The broad spectrum antiviral ivermectin targets the ' 'host nuclear transport importin α/β1 heterodimer. Antivir Res. ' '2020;177:104760.', 'journal-title': 'Antivir Res'}, { 'key': '623_CR25', 'doi-asserted-by': 'publisher', 'first-page': '1320', 'DOI': '10.1002/jmv.26610', 'volume': '93', 'author': 'CW Stratton', 'year': '2021', 'unstructured': 'Stratton CW, Tang YW, Lu H. Pathogenesis-directed therapy of 2019 novel ' 'coronavirus disease. J Med Virol. 2021;93:1320–42.', 'journal-title': 'J Med Virol'}, { 'key': '623_CR26', 'doi-asserted-by': 'publisher', 'first-page': '2091', 'DOI': '10.1080/22221751.2020.1823890', 'volume': '9', 'author': 'P Wang', 'year': '2020', 'unstructured': 'Wang P, et al. SARS-CoV-2 neutralizing antibody responses are more ' 'robust in patients with severe disease. Emerg Microbes Infect. ' '2020;9:2091–3.', 'journal-title': 'Emerg Microbes Infect'}, { 'key': '623_CR27', 'doi-asserted-by': 'publisher', 'first-page': 'e14122', 'DOI': '10.15252/emmm.202114122', 'volume': '13', 'author': 'GD de Melo', 'year': '2021', 'unstructured': 'de Melo GD, et al. Attenuation of clinical and immunological outcomes ' 'during SARS-CoV-2 infection by ivermectin. EMBO Mol Med. 2021;13:e14122.', 'journal-title': 'EMBO Mol Med'}, { 'key': '623_CR28', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-021-86679-0', 'volume': '11', 'author': 'AP Arévalo', 'year': '2021', 'unstructured': 'Arévalo AP, et al. Ivermectin reduces in vivo coronavirus infection in a ' 'mouse experimental model. Sci Rep. 2021;11:7132.', 'journal-title': 'Sci Rep'}, { 'key': '623_CR29', 'doi-asserted-by': 'publisher', 'first-page': 'e1006955', 'DOI': '10.1371/journal.ppat.1006955', 'volume': '14', 'author': 'H Namkoong', 'year': '2018', 'unstructured': 'Namkoong H, et al. Clarithromycin expands CD11b+Gr-1+ cells via the ' 'STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza ' 'bacterial pneumonia. PLoS Pathog. 2018;14:e1006955.', 'journal-title': 'PLoS Pathog'}, { 'key': '623_CR30', 'doi-asserted-by': 'publisher', 'first-page': '174191', 'DOI': '10.1016/j.ejphar.2021.174191', 'volume': '905', 'author': 'MR Khezri', 'year': '2021', 'unstructured': 'Khezri MR, Zolbanin NM, Ghasemnejad-berenji M, Jafari R. Azithromycin: ' 'Immunomodulatory and antiviral properties for SARS-CoV-2 infection. Eur ' 'J Pharm. 2021;905:174191.', 'journal-title': 'Eur J Pharm'}, { 'key': '623_CR31', 'doi-asserted-by': 'publisher', 'first-page': '574425', 'DOI': '10.3389/fimmu.2021.574425', 'volume': '12', 'author': 'VJ Venditto', 'year': '2021', 'unstructured': 'Venditto VJ, et al. Immunomodulatory Effects of Azithromycin Revisited: ' 'Potential Applications to COVID-19. Front Immunol. 2021;12:574425.', 'journal-title': 'Front Immunol'}, { 'key': '623_CR32', 'doi-asserted-by': 'publisher', 'first-page': '2438', 'DOI': '10.3390/microorganisms10122438', 'volume': '10', 'author': 'JM Blondeau', 'year': '2022', 'unstructured': 'Blondeau JM. Immunomodulatory Effects of Macrolides Considering Evidence ' 'from Human and Veterinary Medicine. Microorganisms. 2022;10:2438.', 'journal-title': 'Microorganisms'}, { 'key': '623_CR33', 'doi-asserted-by': 'publisher', 'first-page': '736', 'DOI': '10.1007/s43440-020-00195-y', 'volume': '73', 'author': 'H Kaur', 'year': '2021', 'unstructured': 'Kaur H, et al. Ivermectin as a potential drug for treatment of COVID-19: ' 'an in-sync review with clinical and computational attributes. Pharm Rep. ' '2021;73:736–49.', 'journal-title': 'Pharm Rep'}, { 'key': '623_CR34', 'doi-asserted-by': 'publisher', 'first-page': '149', 'DOI': '10.1016/S0065-2776(08)00003-5', 'volume': '97', 'author': 'T Hirano', 'year': '2008', 'unstructured': 'Hirano T, et al. Roles of Zinc and Zinc Signaling in Immunity: Zinc as ' 'an Intracellular Signaling Molecule. Adv Immunol. 2008;97:149–76.', 'journal-title': 'Adv Immunol'}, { 'key': '623_CR35', 'doi-asserted-by': 'publisher', 'first-page': '21', 'DOI': '10.1038/ni.f.220', 'volume': '10', 'author': 'M Vig', 'year': '2009', 'unstructured': 'Vig M, Kinet JP. Calcium signaling in immune cells. Nat Immunol. ' '2009;10:21–7.', 'journal-title': 'Nat Immunol'}, { 'key': '623_CR36', 'doi-asserted-by': 'publisher', 'first-page': 'e1001176', 'DOI': '10.1371/journal.ppat.1001176', 'volume': '6', 'author': 'AJW te Velthuis', 'year': '2010', 'unstructured': 'te Velthuis AJW, et al. Zn2+ Inhibits Coronavirus and Arterivirus RNA ' 'Polymerase Activity In Vitro and Zinc Ionophores Block the Replication ' 'of These Viruses in Cell Culture. PLoS Pathog. 2010;6:e1001176.', 'journal-title': 'PLoS Pathog'}, { 'key': '623_CR37', 'doi-asserted-by': 'publisher', 'first-page': '109848', 'DOI': '10.1016/j.mehy.2020.109848', 'volume': '144', 'author': 'A Kumar', 'year': '2020', 'unstructured': 'Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of zinc ' 'supplementation in prophylaxis and treatment of COVID-19. Med ' 'Hypotheses. 2020;144:109848.', 'journal-title': 'Med Hypotheses'}, { 'key': '623_CR38', 'doi-asserted-by': 'publisher', 'first-page': '971', 'DOI': '10.1038/ni1373', 'volume': '7', 'author': 'H Kitamura', 'year': '2006', 'unstructured': 'Kitamura H, et al. Toll-like receptor-mediated regulation of zinc ' 'homeostasis influences dendritic cell function. Nat Immunol. ' '2006;7:971–7.', 'journal-title': 'Nat Immunol'}, { 'key': '623_CR39', 'doi-asserted-by': 'publisher', 'first-page': '134', 'DOI': '10.1038/s41586-022-05594-0', 'volume': '615', 'author': 'T Brevini', 'year': '2023', 'unstructured': 'Brevini T, et al. FXR inhibition may protect from SARS-CoV-2 infection ' 'by reducing ACE2. Nature. 2023;615:134–42.', 'journal-title': 'Nature'}, { 'key': '623_CR40', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/ncomms2924', 'volume': '4', 'author': 'L Jin', 'year': '2013', 'unstructured': 'Jin L, et al. The antiparasitic drug ivermectin is a novel FXR ligand ' 'that regulates metabolism. 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