An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia

{ 'indexed': {'date-parts': [[2024, 5, 9]], 'date-time': '2024-05-09T02:58:01Z', 'timestamp': 1715223481108}, 'reference-count': 42, 'publisher': 'Public Library of Science (PLoS)', 'issue': '6', 'license': [ { 'start': { 'date-parts': [[2021, 6, 18]], 'date-time': '2021-06-18T00:00:00Z', 'timestamp': 1623974400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}], 'funder': [{'name': 'State Intelligence Agency (BIN) of Republic of Indonesia'}], 'content-domain': {'domain': ['www.plosone.org'], 'crossmark-restriction': False}, 'abstract': '<jats:p>A potent therapy for the infectious coronavirus disease COVID-19 is urgently required ' 'with, at the time of writing, research in this area still ongoing. This study aims to ' 'evaluate the in vitro anti-viral activities of combinations of certain commercially available ' 'drugs that have recently formed part of COVID-19 therapy. Dual combinatory drugs, namely; ' 'Lopinavir-Ritonavir (LOPIRITO)-Clarithromycin (CLA), LOPIRITO-Azithromycin (AZI), ' 'LOPIRITO-Doxycycline (DOXY), Hydroxychloroquine (HCQ)-AZI, HCQ-DOXY, Favipiravir (FAVI)-AZI, ' 'HCQ-FAVI, and HCQ-LOPIRITO, were prepared. These drugs were mixed at specific ratios and ' 'evaluated for their safe use based on the cytotoxicity concentration ' '(CC<jats:sub>50</jats:sub>) values of human umbilical cord mesenchymal stem cells. The ' 'anti-viral efficacy of these combinations in relation to Vero cells infected with SARS-CoV-2 ' 'virus isolated from a patient in Universitas Airlangga hospital, Surabaya, Indonesia and ' 'evaluated for IC<jats:sub>50</jats:sub> 24, 48, and 72 hours after viral inoculation was ' 'subsequently determined. Observation of the viral load in qRT-PCR was undertaken, the results ' 'of which indicated the absence of high levels of cytotoxicity in any samples and that dual ' 'combinatory drugs produced lower cytotoxicity than single drugs. In addition, these ' 'combinations demonstrated considerable effectiveness in reducing the copy number of the virus ' 'at 48 and 72 hours, while even at 24 hours, post-drug incubation resulted in low ' 'IC<jats:sub>50</jats:sub> values. Most combination drugs reduced pro-inflammatory markers, ' 'i.e. IL-6 and TNF-α, while increasing the anti-inflammatory response of IL-10. According to ' 'these results, the descending order of effective dual combinatory drugs is one of ' 'LOPIRITO-AZI&gt;LOPIRITO-DOXY&gt;HCQ-AZI&gt;HCQ-FAVI&gt;LOPIRITO-CLA&gt;HCQ-DOX. It can be ' 'suggested that dual combinatory drugs, e.g. LOPIRITO-AZI, can potentially be used in the ' 'treatment of COVID-19 infectious diseases.</jats:p>', 'DOI': '10.1371/journal.pone.0252302', 'type': 'journal-article', 'created': {'date-parts': [[2021, 6, 18]], 'date-time': '2021-06-18T17:31:45Z', 'timestamp': 1624037505000}, 'page': 'e0252302', 'update-policy': 'http://dx.doi.org/10.1371/journal.pone.corrections_policy', 'source': 'Crossref', 'is-referenced-by-count': 17, 'title': 'An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or ' 'hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, ' 'Indonesia', 'prefix': '10.1371', 'volume': '16', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-6144-2481', 'authenticated-orcid': True, 'family': 'Purwati', 'sequence': 'first', 'affiliation': []}, {'given': 'Andang', 'family': 'Miatmoko', 'sequence': 'additional', 'affiliation': []}, {'family': 'Nasronudin', 'sequence': 'additional', 'affiliation': []}, {'given': 'Eryk', 'family': 'Hendrianto', 'sequence': 'additional', 'affiliation': []}, {'given': 'Deya', 'family': 'Karsari', 'sequence': 'additional', 'affiliation': []}, {'given': 'Aristika', 'family': 'Dinaryanti', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nora', 'family': 'Ertanti', 'sequence': 'additional', 'affiliation': []}, {'given': 'Igo Syaiful', 'family': 'Ihsan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Disca Sandyakala', 'family': 'Purnama', 'sequence': 'additional', 'affiliation': []}, {'given': 'Tri Pudy', 'family': 'Asmarawati', 'sequence': 'additional', 'affiliation': []}, {'given': 'Erika', 'family': 'Marfiani', 'sequence': 'additional', 'affiliation': []}, {'family': 'Yulistiani', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alfian Nur', 'family': 'Rosyid', 'sequence': 'additional', 'affiliation': []}, { 'given': 'Prastuti Asta', 'family': 'Wulaningrum', 'sequence': 'additional', 'affiliation': []}, {'given': 'Herley Windo', 'family': 'Setiawan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Imam', 'family': 'Siswanto', 'sequence': 'additional', 'affiliation': []}, { 'given': 'Ni Nyoman', 'family': 'Tri Puspaningsih', 'sequence': 'additional', 'affiliation': []}], 'member': '340', 'published-online': {'date-parts': [[2021, 6, 18]]}, 'reference': [ { 'issue': '10223', 'key': 'pone.0252302.ref001', 'doi-asserted-by': 'crossref', 'first-page': '497', 'DOI': '10.1016/S0140-6736(20)30183-5', 'article-title': 'Clinical features of patients infected with 2019 novel coronavirus in ' 'Wuhan, China', 'volume': '395', 'author': 'C Huang', 'year': '2020', 'journal-title': 'Lancet'}, { 'issue': '10224', 'key': 'pone.0252302.ref002', 'doi-asserted-by': 'crossref', 'first-page': '565', 'DOI': '10.1016/S0140-6736(20)30251-8', 'article-title': 'Genomic characterisation and epidemiology of 2019 novel coronavirus: ' 'implications for virus origins and receptor binding', 'volume': '395', 'author': 'R Lu', 'year': '2020', 'journal-title': 'Lancet'}, { 'key': 'pone.0252302.ref003', 'doi-asserted-by': 'crossref', 'first-page': '727', 'DOI': '10.1056/NEJMoa2001017', 'article-title': 'A novel coronavirus from patients with pneumonia in China, 2019', 'volume': '382', 'author': 'N Zhu', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'pone.0252302.ref004', 'doi-asserted-by': 'crossref', 'first-page': 'e360', 'DOI': '10.1016/j.wneu.2020.05.124', 'article-title': 'Neurosurgery services in Dr. Sardjito General Hospital, Yogyakarta, ' 'Indonesia, during COVID-19 pandemic: an experience from a developing ' 'country', 'volume': '140', 'author': 'W Manusubroto', 'year': '2020', 'journal-title': 'World Neurosurg'}, { 'issue': '4', 'key': 'pone.0252302.ref005', 'doi-asserted-by': 'crossref', 'first-page': 'e13823', 'DOI': '10.5812/archcid.13823', 'article-title': 'Lopinavir; a potent drug against coronavirus infection: insight from ' 'molecular docking study', 'volume': '12', 'author': 'MR Dayer', 'year': '2017', 'journal-title': 'Arch Clin Infect Dis'}, { 'issue': '1', 'key': 'pone.0252302.ref006', 'doi-asserted-by': 'crossref', 'first-page': '58', 'DOI': '10.5582/ddt.2020.01012', 'article-title': 'Discovering drugs to treat coronavirus disease 2019 (COVID-19)', 'volume': '14', 'author': 'L Dong', 'year': '2020', 'journal-title': 'Drug Discov Ther'}, { 'issue': '1', 'key': 'pone.0252302.ref007', 'first-page': '4', 'article-title': 'A rapid advice guideline for the diagnosis and treatment of 2019 novel ' 'coronavirus (2019-nCoV) infected pneumonia (standard version)', 'volume': '7', 'author': 'Y-H Jin', 'year': '2020', 'journal-title': 'Mil Med Res'}, { 'key': 'pone.0252302.ref008', 'volume-title': 'KG. 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