Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations
Kunlakanya Jitobaom, Chompunuch Boonarkart, Suwimon Manopwisedjaroen, Nuntaya Punyadee, Suparerk Borwornpinyo, Arunee Thitithanyanont, Panisadee Avirutnan, Prasert Auewarakul
BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8
Background: COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness.
Methods: The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3. Results: All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration (IC 50 ) values compared to individual drugs. Among these combinations, niclosamideivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamideivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells.
Conclusions: The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials.
Abbreviations
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s40360-022-00580-8.
Additional file 1. Authors' contributions KJ performed drug treatment experiments, viral quantifications, analysis and was a major contributor in writing and revising the manuscript. CB performed virus infection, viral quantifications, and the optimization of the plaque assay for SARS-CoV-2 and prepared virus stock. SM performed virus isolation and the optimization of the plaque assay for SARS-CoV-2. NP performed analysis and prepared drug stock solutions. SB prepared cell lines and drug stock solutions. AT designed the study and edited the manuscript. PA 3, 4 reviewed and edited the manuscript. PA 1* designed and supervised the study, performed funding acquisitions, writing, and editing the manuscript. All authors read and approved the final manuscript.
Declarations Ethics approval and consent to participate Not applicable. This work does not involve the use of human subjects and animals. All the procedures do not require IRB approval.
Consent for publication Not applicable. This work does not contain data from any individual person.
Competing interests The authors declare that they have no competing interests. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types •..
References
Ahmed, Karim, Ross, Hossain, Clemens et al., A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int J Infect Dis
Andrews, Thyssen, Lorke, The biology and toxicology of molluscicides, Bayluscide, Pharmacol Ther
Arshad, Pertinez, Box, Tatham, Rajoli et al., Prioritization of anti-SARS-CoV-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics, Clin Pharmacol Ther
Baraka, Mahmoud, Marschke, Geary, Homeida et al., Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus, Eur J Clin Pharmacol
Barrows, Campos, Powell, Prasanth, Schott-Lerner et al., A screen of FDA-approved drugs for inhibitors of Zika virus infection, Cell Host Microbe
Behera, Patro, Singh, Chandanshive, Ravikumar et al., Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: a matched case-control study, PLoS One
Bobrowski, Chen, Eastman, Itkin, Shinn et al., Synergistic and antagonistic drug combinations against SARS-CoV-2, Mol Ther
Bryant, Lawrie, Dowswell, Fordham, Mitchell et al., Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines, Am J Ther
Burock, Daum, Keilholz, Neumann, Walther et al., Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or sychronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial, BMC Cancer
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antivir Res
Chaccour, Casellas, Blanco-Di Matteo, Pineda, Fernandez-Montero et al., The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial, EClinicalMedicine
Chiu, Green, Baylis, Eline, Rosegay et al., Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, sheep, and rat, J Agric Food Chem
Dyer, Covid-19: study claims real global deaths are twice official figures, BMJ
Elalfy, Besheer, El-Mesery, El-Gilany, Elazez et al., Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19, J Med Virol
Ganguly, Rottet, Yee, Smith, Khin et al., SYBR green one-step qRT-PCR for the detection of SARS-CoV-2 RNA in saliva, bioRxiv,
doi:10.1101/2020.05.29.109702Gassen, Niemeyer, Muth, Corman, Martinelli et al., SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-coronavirus infection, Nat Commun
Götz, Magar, Dornfeld, Giese, Pohlmann et al., Influenza a viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Sci Rep
Hoffmann, Mösbauer, Hofmann-Winkler, Kaul, Kleine-Weber et al., Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature
Jans, Wagstaff, The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2 ?, Biochem Biophys Res Commun
Jeon, Ko, Lee, Choi, Byun et al., Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob, Agents Chemother
Jurgeit, Mcdowell, Moese, Meldrum, Schwendener et al., Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects, PLoS Pathog
Kanjanasirirat, Suksatu, Manopwisedjaroen, Munyoo, Tuchinda et al., High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin a as anti-SARS-CoV-2 agents, Sci Rep
Kongmanas, Punyadee, Wasuworawong, Songjaeng, Prommool et al., Immortalized stem cell-derived hepatocyte-like cells: an alternative model for studying dengue pathogenesis and therapy, PLoS Negl Trop Dis
Kory, Meduri, Varon, Iglesias, Marik, Review of the emerging evidence demonstrating the efficacy of Ivermectin in the prophylaxis and treatment of COVID-19, Am J Ther
Lehrer, Rheinstein, Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2, Vivo
Li, Li, Roberts, Arend, Samant et al., Multitargeted therapy of cancer by niclosamide: a new application for an old drug, Cancer Lett
Lifschitz, Virkel, Sallovitz, Sutra, Galtier et al., Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle, Vet Parasitol
Lim, Hor, Tay, Jelani, Tan et al., Efficacy of Ivermectin treatment on disease progression among adults with mild to moderate COVID-19 and comorbidities: the I-TECH randomized clinical trial, JAMA Intern Med
Lima-Morales, Méndez-Hernández, Flores, Osorno-Romero, Cuecuecha-Rugerio et al., Effectiveness of a multidrug therapy consisting of ivermectin, azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico, Int J Infect Dis
Loewe, The problem of synergism and antagonism of combined drugs, Arzneimittelforschung
Madrid, Panchal, Warren, Shurtleff, Endsley et al., Evaluation of Ebola virus inhibitors for drug repurposing, ACS Infect Dis
Mathieu, Ritchie, Ortiz-Ospina, Roser, Hasell et al., A global database of COVID-19 vaccinations, Nat Hum Behav
Mostafa, Kandeil, Elshaier, Kutkat, Moatasim et al., FDA-approved drugs with potent in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2, Pharm J
Muñoz, Ballester, Antonijoan, Gich, Rodríguez et al., Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers, PLoS Negl Trop Dis
Niyomdecha, Suptawiwat, Boonarkart, Jitobaom, Auewarakul, Inhibition of human immunodeficiency virus type 1 by niclosamide through mTORC1 inhibition, Heliyon
Pizzorno, Padey, Dubois, Julien, Traversier et al., In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2, Antivir Res
Popp, Metzendorf, Gould, Kranke, Meybohm et al., Ivermectin for preventing and treating COVID-19, Cochrane Database Syst Rev
Reed, Muench, A simple method of estimating fifty percent enpoint, Am J Epidemiol
Remme, Sole, Dadzie, Alley, Baker et al., Large scale ivermectin distribution and its epidemiological consequences, Acta Leiden
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Schmith, Zhou, Lohmer, The approved dose of Ivermectin alone is not the ideal dose for the treatment of COVID-19, Clin Pharmacol Ther
Schweizer, Haugk, Mckiernan, Gulati, Cheng et al., A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer, PLoS One
Singh, Ryan, Kredo, Chaplin, Fletcher, Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19, Cochrane Database Syst Rev,
doi:10.1002/14651858.CD013587Stachulski, Pidathala, Row, Sharma, Berry et al., Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication, J Med Chem
Suputtamongkol, Avirutnan, Mairiang, Angkasekwinai, Niwattayakul et al., Ivermectin accelerates circulating nonstructural protein 1 (NS1) clearance in adult dengue patients: a combined phase 2/3 randomized double-blinded placebo controlled trial, Clin Infect Dis
Tay, Fraser, Chan, Moreland, Rathore et al., Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin, Antivir Res
Thomson, COVID-19: social distancing, ACE 2 receptors, protease inhibitors and beyond?, Int J Clin Pract
Vallejos, Zoni, Bangher, Villamandos, Bobadilla et al., Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial, BMC Infect Dis
Wagstaff, Rawlinson, Hearps, Jans, An AlphaScreen ® -based assay for high-throughput screening for specific inhibitors of nuclear import, J Biomol Screen
Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem J
Wang, Chen, Tissue distributions of antiviral drugs affect their capabilities of reducing viral loads in COVID-19 treatment, Eur J Pharmacol
Wen, Kuo, Liang, Wang, Liu, Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus, J Med Chem
Wu, Chen, Hsieh, Hwang, Liu, Inhibition of severe acute respiratory syndrome coronavirus replication by Niclosamide, Antimicrob Agents Chemother
Xu, Han, Liu, Pang, Zheng et al., Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus, PLoS Negl Trop Dis
Xu, Lee, Wen, Cheng, Huang et al., Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen, Nat Med
Xu, Shi, Li, Zhou, Broad Spectrum antiviral agent Niclosamide and its therapeutic potential, ACS Infect Dis
Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antivir Res
Zaidi, Dehgani-Mobaraki, The mechanisms of action of ivermectin against SARS-CoV-2-an extensive review, J Antibiot
Zheng, Wang, Aldahdooh, Malyutina, Shadbahr et al., SynergyFinder plus: toward better interpretation and annotation of drug combination screening datasets, Genomics Proteomics Bioinformatics
{ 'indexed': {'date-parts': [[2022, 6, 18]], 'date-time': '2022-06-18T09:43:01Z', 'timestamp': 1655545381613},
'reference-count': 61,
'publisher': 'Springer Science and Business Media LLC',
'issue': '1',
'license': [ { 'start': { 'date-parts': [[2022, 6, 18]],
'date-time': '2022-06-18T00:00:00Z',
'timestamp': 1655510400000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'},
{ 'start': { 'date-parts': [[2022, 6, 18]],
'date-time': '2022-06-18T00:00:00Z',
'timestamp': 1655510400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'}],
'funder': [ { 'DOI': '10.13039/501100004192',
'name': 'National Science and Technology Development Agency',
'doi-asserted-by': 'publisher',
'award': ['P-20-52262']},
{ 'DOI': '10.13039/501100013238',
'name': 'Faculty of Medicine Siriraj Hospital, Mahidol University',
'doi-asserted-by': 'publisher'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2022, 12]]},
'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>COVID-19 pandemic has claimed millions of lives and devastated the '
'health service system, livelihood, and economy in many countries worldwide. Despite the '
'vaccination programs in many countries, the spread of the pandemic continues, and effective '
'treatment is still urgently needed. Although some antiviral drugs have been shown to be '
'effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro '
'anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. '
'Combination of these drugs is a plausible way to enhance their effectiveness.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, '
'ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, '
'Calu-3.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>All the two-drug combinations showed higher potency resulting in up '
'to 4-fold reduction in the half maximal inhibitory concentration (IC<jats:sub>50</jats:sub>) '
'values compared to individual drugs. Among these combinations, niclosamide-ivermectin '
'achieved the highest inhibitory level of over 99%. Combination synergy analysis showed '
'niclosamide-ivermectin combination to have the best synergy score with a mean Loewe synergy '
'score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy '
'score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>The present study demonstrated the benefit of drug combinations on '
'anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and '
'should be further tested in clinical trials.</jats:p>\n'
' </jats:sec>',
'DOI': '10.1186/s40360-022-00580-8',
'type': 'journal-article',
'created': {'date-parts': [[2022, 6, 18]], 'date-time': '2022-06-18T09:02:54Z', 'timestamp': 1655542974000},
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations',
'prefix': '10.1186',
'volume': '23',
'author': [ {'given': 'Kunlakanya', 'family': 'Jitobaom', 'sequence': 'first', 'affiliation': []},
{'given': 'Chompunuch', 'family': 'Boonarkart', 'sequence': 'additional', 'affiliation': []},
{'given': 'Suwimon', 'family': 'Manopwisedjaroen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Nuntaya', 'family': 'Punyadee', 'sequence': 'additional', 'affiliation': []},
{'given': 'Suparerk', 'family': 'Borwornpinyo', 'sequence': 'additional', 'affiliation': []},
{'given': 'Arunee', 'family': 'Thitithanyanont', 'sequence': 'additional', 'affiliation': []},
{'given': 'Panisadee', 'family': 'Avirutnan', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-4745-4291',
'authenticated-orcid': False,
'given': 'Prasert',
'family': 'Auewarakul',
'sequence': 'additional',
'affiliation': []}],
'member': '297',
'published-online': {'date-parts': [[2022, 6, 18]]},
'reference': [ { 'key': '580_CR1',
'doi-asserted-by': 'publisher',
'first-page': 'n1188',
'DOI': '10.1136/bmj.n1188',
'volume': '373',
'author': 'O Dyer',
'year': '2021',
'unstructured': 'Dyer O. Covid-19: study claims real global deaths are twice official '
'figures. BMJ. 2021;373:n1188.',
'journal-title': 'BMJ'},
{ 'key': '580_CR2',
'doi-asserted-by': 'publisher',
'first-page': '947',
'DOI': '10.1038/s41562-021-01122-8',
'volume': '5',
'author': 'E Mathieu',
'year': '2021',
'unstructured': 'Mathieu E, Ritchie H, Ortiz-Ospina E, Roser M, Hasell J, Appel C, et al. '
'A global database of COVID-19 vaccinations. Nat Hum Behav. '
'2021;5:947–53.',
'journal-title': 'Nat Hum Behav'},
{ 'key': '580_CR3',
'unstructured': 'FDA Approves First Treatment for COVID-19. '
'https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. '
'Accessed 15 Dec 2021.'},
{ 'key': '580_CR4',
'unstructured': 'Coronavirus (COVID-19) Update: FDA Authorizes Drug Combination for '
'Treatment of COVID-19. '
'https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19. '
'Accessed 1 Dec 2021.'},
{ 'key': '580_CR5',
'doi-asserted-by': 'publisher',
'first-page': '173634',
'DOI': '10.1016/j.ejphar.2020.173634',
'volume': '889',
'author': 'Y Wang',
'year': '2020',
'unstructured': 'Wang Y, Chen L. Tissue distributions of antiviral drugs affect their '
'capabilities of reducing viral loads in COVID-19 treatment. Eur J '
'Pharmacol. 2020;889:173634.',
'journal-title': 'Eur J Pharmacol'},
{ 'key': '580_CR6',
'doi-asserted-by': 'publisher',
'first-page': '775',
'DOI': '10.1002/cpt.1909',
'volume': '108',
'author': 'U Arshad',
'year': '2020',
'unstructured': 'Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, et al. '
'Prioritization of anti-SARS-CoV-2 drug repurposing opportunities based '
'on plasma and target site concentrations derived from their established '
'human pharmacokinetics. Clin Pharmacol Ther. 2020;108:775–90.',
'journal-title': 'Clin Pharmacol Ther'},
{ 'issue': '7',
'key': '580_CR7',
'doi-asserted-by': 'publisher',
'first-page': 'e00819',
'DOI': '10.1128/AAC.00819-20',
'volume': '64',
'author': 'S Jeon',
'year': '2020',
'unstructured': 'Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, et al. Identification of '
'antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. '
'Antimicrob Agents Chemother. 2020;64(7):e00819–20.',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'issue': '2',
'key': '580_CR8',
'doi-asserted-by': 'publisher',
'first-page': 'CD013587',
'DOI': '10.1002/14651858.CD013587',
'volume': '2',
'author': 'B Singh',
'year': '2021',
'unstructured': 'Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or '
'hydroxychloroquine for prevention and treatment of COVID-19. Cochrane '
'Database Syst Rev. 2021;2(2):CD013587. '
'https://doi.org/10.1002/14651858.CD013587.',
'journal-title': 'Cochrane Database Syst Rev'},
{ 'key': '580_CR9',
'doi-asserted-by': 'publisher',
'first-page': '214',
'DOI': '10.1016/j.ijid.2020.11.191',
'volume': '103',
'author': 'S Ahmed',
'year': '2021',
'unstructured': 'Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, et al. A '
'five-day course of ivermectin for the treatment of COVID-19 may reduce '
'the duration of illness. Int J Infect Dis. 2021;103:214–6.',
'journal-title': 'Int J Infect Dis'},
{ 'key': '580_CR10',
'doi-asserted-by': 'publisher',
'first-page': 'e0247163',
'DOI': '10.1371/journal.pone.0247163',
'volume': '16',
'author': 'P Behera',
'year': '2021',
'unstructured': 'Behera P, Patro BK, Singh AK, Chandanshive PD, Ravikumar SR, Pradhan SK, '
'et al. Role of ivermectin in the prevention of SARS-CoV-2 infection '
'among healthcare workers in India: a matched case-control study. PLoS '
'One. 2021;16:e0247163.',
'journal-title': 'PLoS One'},
{ 'key': '580_CR11',
'doi-asserted-by': 'publisher',
'first-page': '100720',
'DOI': '10.1016/j.eclinm.2020.100720',
'volume': '32',
'author': 'C Chaccour',
'year': '2021',
'unstructured': 'Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero '
'A, Ruiz-Castillo P, et al. The effect of early treatment with ivermectin '
'on viral load, symptoms and humoral response in patients with non-severe '
'COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical '
'trial. EClinicalMedicine. 2021;32:100720.',
'journal-title': 'EClinicalMedicine'},
{ 'key': '580_CR12',
'doi-asserted-by': 'publisher',
'first-page': '598',
'DOI': '10.1016/j.ijid.2021.02.014',
'volume': '105',
'author': 'R Lima-Morales',
'year': '2021',
'unstructured': 'Lima-Morales R, Méndez-Hernández P, Flores YN, Osorno-Romero P, '
'Cuecuecha-Rugerio E, Nava-Zamora A, et al. Effectiveness of a multidrug '
'therapy consisting of ivermectin, azithromycin, montelukast and '
'acetylsalicylic acid to prevent hospitalization and death among '
'ambulatory COVID-19 cases in Tlaxcala, Mexico. Int J Infect Dis. '
'2021;105:598–605.',
'journal-title': 'Int J Infect Dis'},
{ 'key': '580_CR13',
'doi-asserted-by': 'publisher',
'first-page': 'e299',
'DOI': '10.1097/MJT.0000000000001377',
'volume': '28',
'author': 'P Kory',
'year': '2021',
'unstructured': 'Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the emerging '
'evidence demonstrating the efficacy of Ivermectin in the prophylaxis and '
'treatment of COVID-19. Am J Ther. 2021;28:e299–318.',
'journal-title': 'Am J Ther'},
{ 'key': '580_CR14',
'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': '580_CR15',
'doi-asserted-by': 'publisher',
'first-page': '163',
'DOI': '10.1016/j.bbrc.2020.10.042',
'volume': '538',
'author': 'DA Jans',
'year': '2021',
'unstructured': 'Jans DA, Wagstaff KM. The broad spectrum host-directed agent ivermectin '
'as an antiviral for SARS-CoV-2 ? Biochem Biophys Res Commun. '
'2021;538:163–72.',
'journal-title': 'Biochem Biophys Res Commun'},
{ 'key': '580_CR16',
'doi-asserted-by': 'crossref',
'unstructured': 'Elalfy H, Besheer T, El-Mesery A, El-Gilany A-H, Abd Elazez MS, '
'Alhawarey A, et al. Effect of a combination of nitazoxanide, ribavirin, '
'and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance '
'of mild COVID-19. J Med Virol. 2021;93(5):3176–83.',
'DOI': '10.1002/jmv.26880'},
{ 'key': '580_CR17',
'first-page': '177',
'volume': '59',
'author': 'J Remme',
'year': '1990',
'unstructured': 'Remme J, De Sole G, Dadzie KY, Alley ES, Baker RH, Habbema JD, et al. '
'Large scale ivermectin distribution and its epidemiological '
'consequences. Acta Leiden. 1990;59:177–91.',
'journal-title': 'Acta Leiden'},
{ 'issue': '12',
'key': '580_CR18',
'first-page': '443',
'volume': '13',
'author': 'A Mostafa',
'year': '2020',
'unstructured': 'Mostafa A, Kandeil A, AMME Elshaier Y, Kutkat O, Moatasim Y, Rashad AA, '
'et al. FDA-approved drugs with potent in vitro antiviral activity '
'against severe acute respiratory syndrome coronavirus 2. Pharm J. '
'2020;13(12):443.',
'journal-title': 'Pharm J'},
{ 'key': '580_CR19',
'doi-asserted-by': 'publisher',
'first-page': '909',
'DOI': '10.1021/acsinfecdis.0c00052',
'volume': '6',
'author': 'J Xu',
'year': '2020',
'unstructured': 'Xu J, Shi P-Y, Li H, Zhou J. Broad Spectrum antiviral agent Niclosamide '
'and its therapeutic potential. ACS Infect Dis. 2020;6:909–15.',
'journal-title': 'ACS Infect Dis'},
{ 'key': '580_CR20',
'doi-asserted-by': 'publisher',
'first-page': '19963',
'DOI': '10.1038/s41598-020-77003-3',
'volume': '10',
'author': 'P Kanjanasirirat',
'year': '2020',
'unstructured': 'Kanjanasirirat P, Suksatu A, Manopwisedjaroen S, Munyoo B, Tuchinda P, '
'Jearawuttanakul K, et al. High-content screening of Thai medicinal '
'plants reveals Boesenbergia rotunda extract and its component Panduratin '
'a as anti-SARS-CoV-2 agents. Sci Rep. 2020;10:19963.',
'journal-title': 'Sci Rep'},
{ 'key': '580_CR21',
'doi-asserted-by': 'publisher',
'first-page': '493',
'DOI': '10.1093/oxfordjournals.aje.a118408',
'volume': '27',
'author': 'LJ Reed',
'year': '1938',
'unstructured': 'Reed LJ, Muench H. A simple method of estimating fifty percent enpoint. '
'Am J Epidemiol. 1938;27:493–7.',
'journal-title': 'Am J Epidemiol'},
{ 'key': '580_CR22',
'doi-asserted-by': 'publisher',
'unstructured': 'Ganguly D, Rottet S, Yee S, Hee W, Smith A, Khin N, Millar A, Fahrer A. '
'SYBR green one-step qRT-PCR for the detection of SARS-CoV-2 RNA in '
'saliva. bioRxiv.\xa02020:05.29.109702. '
'https://doi.org/10.1101/2020.05.29.109702.',
'DOI': '10.1101/2020.05.29.109702'},
{ 'key': '580_CR23',
'doi-asserted-by': 'publisher',
'first-page': 'e04050',
'DOI': '10.1016/j.heliyon.2020.e04050',
'volume': '6',
'author': 'N Niyomdecha',
'year': '2020',
'unstructured': 'Niyomdecha N, Suptawiwat O, Boonarkart C, Jitobaom K, Auewarakul P. '
'Inhibition of human immunodeficiency virus type 1 by niclosamide through '
'mTORC1 inhibition. Heliyon. 2020;6:e04050.',
'journal-title': 'Heliyon'},
{ 'issue': '22',
'key': '580_CR24',
'first-page': '00008',
'volume': 'S1672-0229',
'author': 'S Zheng',
'year': '2022',
'unstructured': 'Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, et al. '
'SynergyFinder plus: toward better interpretation and annotation of drug '
'combination screening datasets. Genomics Proteomics Bioinformatics. '
'2022;S1672-0229(22):00008–0.',
'journal-title': 'Genomics Proteomics Bioinformatics'},
{ 'issue': '6',
'key': '580_CR25',
'first-page': '285',
'volume': '3',
'author': 'S Loewe',
'year': '1953',
'unstructured': 'Loewe S. The problem of synergism and antagonism of combined drugs. '
'Arzneimittelforschung. 1953;3(6):285–90 PMID: 13081480.',
'journal-title': 'Arzneimittelforschung'},
{ 'key': '580_CR26',
'doi-asserted-by': 'publisher',
'first-page': '104878',
'DOI': '10.1016/j.antiviral.2020.104878',
'volume': '181',
'author': 'A Pizzorno',
'year': '2020',
'unstructured': 'Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, et al. '
'In vitro evaluation of antiviral activity of single and combined '
'repurposable drugs against SARS-CoV-2. Antivir Res. 2020;181:104878.',
'journal-title': 'Antivir Res'},
{ 'key': '580_CR27',
'doi-asserted-by': 'publisher',
'first-page': '4087',
'DOI': '10.1021/jm070295s',
'volume': '50',
'author': 'C-C Wen',
'year': '2007',
'unstructured': 'Wen C-C, Kuo Y-H, Jan J-T, Liang P-H, Wang S-Y, Liu H-G, et al. Specific '
'plant terpenoids and lignoids possess potent antiviral activities '
'against severe acute respiratory syndrome coronavirus. J Med Chem. '
'2007;50:4087–95.',
'journal-title': 'J Med Chem'},
{ 'key': '580_CR28',
'doi-asserted-by': 'publisher',
'first-page': '2693',
'DOI': '10.1128/AAC.48.7.2693-2696.2004',
'volume': '48',
'author': 'C-J Wu',
'year': '2004',
'unstructured': 'Wu C-J, Jan J-T, Chen C-M, Hsieh H-P, Hwang D-R, Liu H-W, et al. '
'Inhibition of severe acute respiratory syndrome coronavirus replication '
'by Niclosamide. Antimicrob Agents Chemother. 2004;48:2693–6.',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'key': '580_CR29',
'doi-asserted-by': 'publisher',
'first-page': '5770',
'DOI': '10.1038/s41467-019-13659-4',
'volume': '10',
'author': 'NC Gassen',
'year': '2019',
'unstructured': 'Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, et al. '
'SKP2 attenuates autophagy through Beclin1-ubiquitination and its '
'inhibition reduces MERS-coronavirus infection. Nat Commun. 2019;10:5770.',
'journal-title': 'Nat Commun'},
{ 'key': '580_CR30',
'doi-asserted-by': 'publisher',
'first-page': '1101',
'DOI': '10.1038/nm.4184',
'volume': '22',
'author': 'M Xu',
'year': '2016',
'unstructured': 'Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of '
'small-molecule inhibitors of Zika virus infection and induced neural '
'cell death via a drug repurposing screen. Nat Med. 2016;22:1101–7.',
'journal-title': 'Nat Med'},
{ 'key': '580_CR31',
'doi-asserted-by': 'publisher',
'first-page': '8670',
'DOI': '10.1021/jm201264t',
'volume': '54',
'author': 'AV Stachulski',
'year': '2011',
'unstructured': 'Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Lawrenson AS, et '
'al. Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C '
'virus replication. J Med Chem. 2011;54:8670–80.',
'journal-title': 'J Med Chem'},
{ 'key': '580_CR32',
'doi-asserted-by': 'publisher',
'first-page': '317',
'DOI': '10.1021/acsinfecdis.5b00030',
'volume': '1',
'author': 'PB Madrid',
'year': '2015',
'unstructured': 'Madrid PB, Panchal RG, Warren TK, Shurtleff AC, Endsley AN, Green CE, et '
'al. Evaluation of Ebola virus inhibitors for drug repurposing. ACS '
'Infect Dis. 2015;1:317–26.',
'journal-title': 'ACS Infect Dis'},
{ 'key': '580_CR33',
'first-page': 'e13503',
'volume': '74',
'author': 'G Thomson',
'year': '2020',
'unstructured': 'Thomson G. COVID-19: social distancing, ACE 2 receptors, protease '
'inhibitors and beyond? Int J Clin Pract. 2020;74:e13503.',
'journal-title': 'Int J Clin Pract'},
{ 'key': '580_CR34',
'doi-asserted-by': 'publisher',
'first-page': 'e1002976',
'DOI': '10.1371/journal.ppat.1002976',
'volume': '8',
'author': 'A Jurgeit',
'year': '2012',
'unstructured': 'Jurgeit A, McDowell R, Moese S, Meldrum E, Schwendener R, Greber UF. '
'Niclosamide is a proton carrier and targets acidic endosomes with broad '
'antiviral effects. PLoS Pathog. 2012;8:e1002976.',
'journal-title': 'PLoS Pathog'},
{ 'key': '580_CR35',
'doi-asserted-by': 'publisher',
'first-page': 'e0198389',
'DOI': '10.1371/journal.pone.0198389',
'volume': '13',
'author': 'MT Schweizer',
'year': '2018',
'unstructured': 'Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, et al. '
'A phase I study of niclosamide in combination with enzalutamide in men '
'with castration-resistant prostate cancer. PLoS One. 2018;13:e0198389–9.',
'journal-title': 'PLoS One'},
{ 'key': '580_CR36',
'doi-asserted-by': 'publisher',
'first-page': '245',
'DOI': '10.1016/0163-7258(82)90064-X',
'volume': '19',
'author': 'P Andrews',
'year': '1982',
'unstructured': 'Andrews P, Thyssen J, Lorke D. The biology and toxicology of '
'molluscicides, Bayluscide. Pharmacol Ther. 1982;19:245–95.',
'journal-title': 'Pharmacol Ther'},
{ 'key': '580_CR37',
'doi-asserted-by': 'publisher',
'first-page': '8',
'DOI': '10.1016/j.canlet.2014.04.003',
'volume': '349',
'author': 'Y Li',
'year': '2014',
'unstructured': 'Li Y, Li PK, Roberts MJ, Arend RC, Samant RS, Buchsbaum DJ. '
'Multi-targeted therapy of cancer by niclosamide: a new application for '
'an old drug. Cancer Lett. 2014;349:8–14.',
'journal-title': 'Cancer Lett'},
{ 'key': '580_CR38',
'doi-asserted-by': 'publisher',
'first-page': '297',
'DOI': '10.1186/s12885-018-4197-9',
'volume': '18',
'author': 'S Burock',
'year': '2018',
'unstructured': 'Burock S, Daum S, Keilholz U, Neumann K, Walther W, Stein U. Phase II '
'trial to investigate the safety and efficacy of orally applied '
'niclosamide in patients with metachronous or sychronous metastases of a '
'colorectal cancer progressing after therapy: the NIKOLO trial. BMC '
'Cancer. 2018;18:297.',
'journal-title': 'BMC Cancer'},
{ 'key': '580_CR39',
'doi-asserted-by': 'publisher',
'first-page': '722',
'DOI': '10.1016/S1473-3099(03)00806-5',
'volume': '3',
'author': 'A Savarino',
'year': '2003',
'unstructured': 'Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of '
'chloroquine on viral infections: an old drug against today’s diseases? '
'Lancet Infect Dis. 2003;3:722–7.',
'journal-title': 'Lancet Infect Dis'},
{ 'key': '580_CR40',
'doi-asserted-by': 'publisher',
'first-page': '588',
'DOI': '10.1038/s41586-020-2575-3',
'volume': '585',
'author': 'M Hoffmann',
'year': '2020',
'unstructured': 'Hoffmann M, Mösbauer K, Hofmann-Winkler H, Kaul A, Kleine-Weber H, '
'Krüger N, et al. Chloroquine does not inhibit infection of human lung '
'cells with SARS-CoV-2. Nature. 2020;585:588–90.',
'journal-title': 'Nature'},
{ 'key': '580_CR41',
'doi-asserted-by': 'publisher',
'first-page': '104760',
'DOI': '10.1016/j.antiviral.2020.104760',
'volume': '177',
'author': 'SNY Yang',
'year': '2020',
'unstructured': 'Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, 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': '580_CR42',
'doi-asserted-by': 'publisher',
'first-page': '259',
'DOI': '10.1016/j.chom.2016.07.004',
'volume': '20',
'author': 'NJ Barrows',
'year': '2016',
'unstructured': 'Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, '
'Soto-Acosta R, et al. A screen of FDA-approved drugs for inhibitors of '
'Zika virus infection. Cell Host Microbe. 2016;20:259–70.',
'journal-title': 'Cell Host Microbe'},
{ 'key': '580_CR43',
'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': '580_CR44',
'doi-asserted-by': 'publisher',
'first-page': '301',
'DOI': '10.1016/j.antiviral.2013.06.002',
'volume': '99',
'author': 'MY Tay',
'year': '2013',
'unstructured': 'Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. '
'Nuclear localization of dengue virus (DENV) 1-4 non-structural protein '
'5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. '
'Antivir Res. 2013;99:301–6.',
'journal-title': 'Antivir Res'},
{ 'key': '580_CR45',
'doi-asserted-by': 'publisher',
'first-page': 'e0006934',
'DOI': '10.1371/journal.pntd.0006934',
'volume': '12',
'author': 'T-L Xu',
'year': '2018',
'unstructured': 'Xu T-L, Han Y, Liu W, Pang X-Y, Zheng B, Zhang Y, 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': '580_CR46',
'doi-asserted-by': 'publisher',
'first-page': '192',
'DOI': '10.1177/1087057110390360',
'volume': '16',
'author': 'KM Wagstaff',
'year': '2011',
'unstructured': 'Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An AlphaScreen®-based '
'assay for high-throughput screening for specific inhibitors of nuclear '
'import. J Biomol Screen. 2011;16:192–200.',
'journal-title': 'J Biomol Screen'},
{ 'key': '580_CR47',
'doi-asserted-by': 'publisher',
'first-page': '23138',
'DOI': '10.1038/srep23138',
'volume': '6',
'author': 'V Götz',
'year': '2016',
'unstructured': 'Götz V, Magar L, Dornfeld D, Giese S, Pohlmann A, Höper D, et al. '
'Influenza a viruses escape from MxA restriction at the expense of '
'efficient nuclear vRNP import. Sci Rep. 2016;6:23138–8.',
'journal-title': 'Sci Rep'},
{ 'key': '580_CR48',
'doi-asserted-by': 'publisher',
'first-page': '3023',
'DOI': '10.21873/invivo.12134',
'volume': '34',
'author': 'S Lehrer',
'year': '2020',
'unstructured': 'Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike '
'receptor-binding domain attached to ACE2. In Vivo. 2020;34:3023–6.',
'journal-title': 'In Vivo'},
{ 'key': '580_CR49',
'doi-asserted-by': 'publisher',
'first-page': '60',
'DOI': '10.1038/s41429-021-00491-6',
'volume': '75',
'author': 'AK Zaidi',
'year': '2022',
'unstructured': 'Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of ivermectin '
'against SARS-CoV-2—an extensive review. J Antibiot. 2022;75:60–71.',
'journal-title': 'J Antibiot'},
{ 'key': '580_CR50',
'first-page': 'CD015017',
'volume': '28',
'author': 'MSM Popp',
'year': '2021',
'unstructured': 'Popp MSM, Metzendorf MI, Gould S, Kranke P, Meybohm P, Skoetz N, et al. '
'Ivermectin for preventing and treating COVID-19. Cochrane Database Syst '
'Rev. 2021;28:CD015017.',
'journal-title': 'Cochrane Database Syst Rev'},
{ 'key': '580_CR51',
'doi-asserted-by': 'publisher',
'first-page': '635',
'DOI': '10.1186/s12879-021-06348-5',
'volume': '21',
'author': 'J Vallejos',
'year': '2021',
'unstructured': 'Vallejos J, Zoni R, Bangher M, Villamandos S, Bobadilla A, Plano F, et '
'al. Ivermectin to prevent hospitalizations in patients with COVID-19 '
'(IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. '
'BMC Infect Dis. 2021;21:635.',
'journal-title': 'BMC Infect Dis'},
{ 'issue': '4',
'key': '580_CR52',
'doi-asserted-by': 'publisher',
'first-page': '426',
'DOI': '10.1001/jamainternmed.2022.0189',
'volume': '182',
'author': 'SCL Lim',
'year': '2022',
'unstructured': 'Lim SCL, Hor CP, Tay KH, Mat Jelani A, Tan WH, Ker HB, et al. Efficacy '
'of Ivermectin treatment on disease progression among adults with mild to '
'moderate COVID-19 and comorbidities: the I-TECH randomized clinical '
'trial. JAMA Intern Med. 2022;182(4):426–35.',
'journal-title': 'JAMA Intern Med'},
{ 'key': '580_CR53',
'doi-asserted-by': 'publisher',
'first-page': 'e434',
'DOI': '10.1097/MJT.0000000000001402',
'volume': '28',
'author': 'A Bryant',
'year': '2021',
'unstructured': 'Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, et al. '
'Ivermectin for prevention and treatment of COVID-19 infection: a '
'systematic review, meta-analysis, and trial sequential analysis to '
'inform clinical guidelines. Am J Ther. 2021;28:e434–60.',
'journal-title': 'Am J Ther'},
{ 'key': '580_CR54',
'doi-asserted-by': 'publisher',
'first-page': 'e0006020',
'DOI': '10.1371/journal.pntd.0006020',
'volume': '12',
'author': 'J Muñoz',
'year': '2018',
'unstructured': 'Muñoz J, Ballester MR, Antonijoan RM, Gich I, Rodríguez M, Colli E, et '
'al. Safety and pharmacokinetic profile of fixed-dose ivermectin with an '
'innovative 18mg tablet in healthy adult volunteers. PLoS Negl Trop Dis. '
'2018;12:e0006020.',
'journal-title': 'PLoS Negl Trop Dis'},
{ 'key': '580_CR55',
'doi-asserted-by': 'publisher',
'first-page': '407',
'DOI': '10.1007/s002280050131',
'volume': '50',
'author': 'OZ Baraka',
'year': '1996',
'unstructured': 'Baraka OZ, Mahmoud BM, Marschke CK, Geary TG, Homeida MM, Williams JF. '
'Ivermectin distribution in the plasma and tissues of patients infected '
'with Onchocerca volvulus. Eur J Clin Pharmacol. 1996;50:407–10.',
'journal-title': 'Eur J Clin Pharmacol'},
{ 'key': '580_CR56',
'doi-asserted-by': 'publisher',
'first-page': '762',
'DOI': '10.1002/cpt.1889',
'volume': '108',
'author': 'VD Schmith',
'year': '2020',
'unstructured': 'Schmith VD, Zhou J, Lohmer LRL. The approved dose of Ivermectin alone is '
'not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. '
'2020;108:762–5.',
'journal-title': 'Clin Pharmacol Ther'},
{ 'key': '580_CR57',
'doi-asserted-by': 'publisher',
'first-page': '327',
'DOI': '10.1016/S0304-4017(99)00175-2',
'volume': '87',
'author': 'A Lifschitz',
'year': '2000',
'unstructured': 'Lifschitz A, Virkel G, Sallovitz J, Sutra JF, Galtier P, Alvinerie M, et '
'al. Comparative distribution of ivermectin and doramectin to parasite '
'location tissues in cattle. Vet Parasitol. 2000;87:327–38.',
'journal-title': 'Vet Parasitol'},
{ 'key': '580_CR58',
'doi-asserted-by': 'publisher',
'first-page': '2072',
'DOI': '10.1021/jf00101a015',
'volume': '38',
'author': 'SHL Chiu',
'year': '1990',
'unstructured': 'Chiu SHL, Green ML, Baylis FP, Eline D, Rosegay A, Meriwether H, et al. '
'Absorption, tissue distribution, and excretion of tritium-labeled '
'ivermectin in cattle, sheep, and rat. J Agric Food Chem. 1990;38:2072–8.',
'journal-title': 'J Agric Food Chem'},
{ 'key': '580_CR59',
'doi-asserted-by': 'publisher',
'first-page': 'e0008835',
'DOI': '10.1371/journal.pntd.0008835',
'volume': '14',
'author': 'K Kongmanas',
'year': '2020',
'unstructured': 'Kongmanas K, Punyadee N, Wasuworawong K, Songjaeng A, Prommool T, '
'Pewkliang Y, et al. Immortalized stem cell-derived hepatocyte-like '
'cells: an alternative model for studying dengue pathogenesis and '
'therapy. PLoS Negl Trop Dis. 2020;14:e0008835.',
'journal-title': 'PLoS Negl Trop Dis'},
{ 'key': '580_CR60',
'doi-asserted-by': 'publisher',
'first-page': 'e586',
'DOI': '10.1093/cid/ciaa1332',
'volume': '72',
'author': 'Y Suputtamongkol',
'year': '2021',
'unstructured': 'Suputtamongkol Y, Avirutnan P, Mairiang D, Angkasekwinai N, Niwattayakul '
'K, Yamasmith E, et al. Ivermectin accelerates circulating nonstructural '
'protein 1 (NS1) clearance in adult dengue patients: a combined phase 2/3 '
'randomized double-blinded placebo controlled trial. Clin Infect Dis. '
'2021;72:e586–93.',
'journal-title': 'Clin Infect Dis'},
{ 'key': '580_CR61',
'doi-asserted-by': 'publisher',
'first-page': '873',
'DOI': '10.1016/j.ymthe.2020.12.016',
'volume': '29',
'author': 'T Bobrowski',
'year': '2021',
'unstructured': 'Bobrowski T, Chen L, Eastman RT, Itkin Z, Shinn P, Chen CZ, et al. '
'Synergistic and antagonistic drug combinations against SARS-CoV-2. Mol '
'Ther. 2021;29:873–85.',
'journal-title': 'Mol Ther'}],
'container-title': 'BMC Pharmacology and Toxicology',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/article/10.1186/s40360-022-00580-8/fulltext.html',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 6, 18]],
'date-time': '2022-06-18T09:12:48Z',
'timestamp': 1655543568000},
'score': 1,
'resource': { 'primary': { 'URL': 'https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-022-00580-8'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 6, 18]]},
'references-count': 61,
'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}},
'alternative-id': ['580'],
'URL': 'http://dx.doi.org/10.1186/s40360-022-00580-8',
'relation': {},
'ISSN': ['2050-6511'],
'subject': ['Pharmacology (medical)', 'Pharmacology'],
'container-title-short': 'BMC Pharmacol Toxicol',
'published': {'date-parts': [[2022, 6, 18]]},
'assertion': [ { 'value': '5 January 2022',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '9 June 2022',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '18 June 2022',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}},
{ 'value': 'Not applicable. This work does not involve the use of human subjects and '
'animals. All the procedures do not require IRB approval.',
'order': 2,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}},
{ 'value': 'Not applicable. This work does not contain data from any individual person.',
'order': 3,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}},
{ 'value': 'The authors declare that they have no competing interests.',
'order': 4,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}],
'article-number': '41'}
