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Safi D, Khouri F, Zareef R, Arabi M. Antivirals in COVID-19: A Focus on Pediatric Cardiac Patients. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2025; 2025:4573096. [PMID: 40196380 PMCID: PMC11972864 DOI: 10.1155/cjid/4573096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/17/2025] [Indexed: 04/09/2025]
Abstract
The COVID-19 pandemic created an unprecedented public health crisis, driven by its rapid global spread and the urgent need for worldwide collaborative interventions to contain it. This urgency spurred the search for therapeutic agents to prevent or manage the infection. Among these, various types of antivirals emerged as a prominent treatment option, supported by a wealth of observational studies and randomized controlled trials. The results from such studies conflict, with some concluding efficacy and others the lack thereof, with variability also occurring depending on the severity of COVID-19 in the studied population. In addition, many agents have been explored using randomized controlled trials-the gold standard in evaluating the efficacy of an intervention-to only a limited degree, with most of the evidence behind their use concluded using observational studies. Thus, the sheer volume of data has made it challenging to resolve inconsistencies and determine true efficacy. Furthermore, there is a paucity in the literature regarding the use of antivirals in the pediatric population infected with COVID-19, with their use being extrapolated from the results of studies done on adult patients. As such, additional trials are needed to solidify the effectiveness of antivirals in managing COVID-19, particularly in the underexplored and especially vulnerable pediatric cardiac patients. Therefore, utilizing the results from randomized controlled trials, this narrative review evaluates the rationale behind the use of antivirals, summarizes the findings from the literature, and concludes with a focused discussion on their application in pediatric cardiac patients.
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Affiliation(s)
- Dalia Safi
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Farah Khouri
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rana Zareef
- Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mariam Arabi
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Huang W, Liu W, Yu T, Zhang Z, Zhai L, Huang P, Lu Y. Effect of anti-COVID-19 drugs on patients with cancer. Eur J Med Chem 2024; 268:116214. [PMID: 38367490 DOI: 10.1016/j.ejmech.2024.116214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/11/2024] [Accepted: 02/01/2024] [Indexed: 02/19/2024]
Abstract
The clinical treatment of patients with cancer who are also diagnosed with coronavirus disease (COVID-19) has been a challenging issue since the outbreak of COVID-19. Therefore, it is crucial to understand the effects of commonly used drugs for treating COVID-19 in patients with cancer. Hence, this review aims to provide a reference for the clinical treatment of patients with cancer to minimize the losses caused by the COVID-19 pandemic. In this study, we also focused on the relationship between COVID-19, commonly used drugs for treating COVID-19, and cancer. We specifically investigated the effect of these drugs on tumor cell proliferation, migration, invasion, and apoptosis. The potential mechanisms of action of these drugs were discussed and evaluated. We found that most of these drugs showed inhibitory effects on tumors, and only in a few cases had cancer-promoting effects. Furthermore, inappropriate usage of these drugs may lead to irreversible kidney and heart damage. Finally, we have clarified the use of different drugs, which can provide useful guidance for the clinical treatment of cancer patients diagnosed with COVID-19.
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Affiliation(s)
- Weicai Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Wenyu Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Tingting Yu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Zhaoyang Zhang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Lingyun Zhai
- Gynecology Department, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Panpan Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
| | - Yao Lu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
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Kuang K, Li Y, Chen Y, Ji Y, Jia N. A simplified molecularly imprinted ECL sensor based on Mn 2SnO 4 nanocubes for sensitive detection of ribavirin. Analyst 2024; 149:1318-1326. [PMID: 38251970 DOI: 10.1039/d3an02077k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
Conventional single-signal or emerging sandwich-type double-signal electrochemiluminescence (ECL) immunosensors/aptasensors have offered accurate detection of small molecules, yet suffer from complicated setup, long processing time, and non-reusability. Here, we demonstrate a simplified molecularly imprinted ECL sensor based on Mn2SnO4 nanocubes. As an n-type semiconductor, Mn2SnO4 has numerous active sites that can capture electrons to accelerate chemical reactions, resulting in enhanced ECL activity and stability. For the first time, we verify a robust cathodic ECL emission of Mn2SnO4 luminophores in the presence of K2S2O8 coreactants. The proposed ECL sensor applies to the sensitive detection of ribavirin (RBV), endowing a wide linear range (1-2000 ng mL-1), low detection limit (0.85 ng mL-1, S/N = 3), high stability, specificity, and reproducibility, and the detection capability in real milk and chicken samples. This work highlights single semiconductor luminophore-driven molecularly imprinted ECL sensors, meeting the original aspiration of uncomplicated but high-performance sensing in food safety inspection.
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Affiliation(s)
- Kaida Kuang
- The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
| | - Ya Li
- The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
| | - Yang Chen
- The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
| | - Yu Ji
- The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
| | - Nengqin Jia
- The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
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Haddadzadeh Shoushtari M, Raji H, Borsi SH, Tavakol H, Cheraghian B, Moeinpour M. Evaluating the Therapeutic Effect of Sofosbuvir in Outpatients with COVID-19: A Randomized Clinical Trial Study. Galen Med J 2024; 13:e3035. [PMID: 39554397 PMCID: PMC11568422 DOI: 10.31661/gmj.v12i.3035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/25/2023] [Accepted: 07/14/2023] [Indexed: 11/19/2024] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has engendered scores of deaths worldwide. Just as the development of varying procedures during the pandemic has helped inhibit the disease, none is considered a definitive treatment protocol for this problem, as each induces some clinical complications pertinent to the disease. This study thus assessed the early use of sofosbuvir in outpatients with mild COVID-19. MATERIALS AND METHODS This randomized clinical trial study was conducted on 360 patients with mild COVID-19 infection at 17 Shahrivar Ahvaz Health Center. These patients were randomly divided into the intervention and control groups. Both the control and intervention groups received 400 mg of sofosbuvir and a placebo for seven days, respectively. After 14 days from the onset of the treatment, the duration of symptoms, the necessity of hospitalization, the mean of hospitalization duration, and mortality were assessed. RESULTS The most common symptoms in the intervention and control groups were coughs with a frequency of 46 (25.6%) and 54(30%), respectively. The two groups showed no statistically significant difference in the frequency of the first observed clinical symptom related to the disease (P=0.2). The mean days that the patients were symptomatic in the control group were 14±4.17, whereas, in the intervention group, it was 12.12±3.15 (P=0.08). The frequency of hospitalization in the control and intervention groups was 7 (3.8%) and 4 (2.22%), respectively (P=0.11). Moreover, the mean days of hospitalization in the control and the intervention groups were 4±1.1 and 3±0.8, respectively (P=0.15). In addition, the two groups had a similar frequency of hospitalization in the ICU (0) and mortality rate (0). CONCLUSION Sofosbuvir alone cannot play a significant role in the treatment of outpatients with mild COVID-19.
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Affiliation(s)
- Maryam Haddadzadeh Shoushtari
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University
of Medical Sciences, Ahvaz, Iran
| | - Hanieh Raji
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University
of Medical Sciences, Ahvaz, Iran
| | - Seyed Hamid Borsi
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University
of Medical Sciences, Ahvaz, Iran
| | - Heshmatollah Tavakol
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University
of Medical Sciences, Ahvaz, Iran
| | - Bahman Cheraghian
- Department of Biostatics and Public Health, Ahvaz Jundishapur University of Medical
Sciences, Ahvaz, Iran
| | - Mahtab Moeinpour
- Department of Pulmonology, School of Medicine, Ahvaz Jundishapur University of
Medical Sciences, Ahvaz, Iran
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Arman BY, Brun J, Hill ML, Zitzmann N, von Delft A. An Update on SARS-CoV-2 Clinical Trial Results-What We Can Learn for the Next Pandemic. Int J Mol Sci 2023; 25:354. [PMID: 38203525 PMCID: PMC10779148 DOI: 10.3390/ijms25010354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/21/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.
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Affiliation(s)
- Benediktus Yohan Arman
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Juliane Brun
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Michelle L. Hill
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK;
| | - Nicole Zitzmann
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Annette von Delft
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
- Centre for Medicine Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
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Lan Q, Yan Y, Zhang G, Xia S, Zhou J, Lu L, Jiang S. Clinical development of antivirals against SARS-CoV-2 and its variants. CURRENT RESEARCH IN MICROBIAL SCIENCES 2023; 6:100208. [PMID: 38149085 PMCID: PMC10750039 DOI: 10.1016/j.crmicr.2023.100208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
The unceasing global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls for the development of novel therapeutics. Although many newly developed antivirals and repurposed antivirals have been applied to the treatment of coronavirus disease 2019 (COVID-19), antivirals showing satisfactory clinical efficacy are few in number. In addition, the loss of sensitivity to variants of concern (VOCs) and lack of oral bioavailability have also limited the clinical application of some antivirals. These facts remind us to develop more potent and broad-spectrum antivirals with better pharmacokinetic/pharmacodynamic properties to fight against infections from SARS-CoV-2, its variants, and other human coronaviruses (HCoVs). In this review, we summarize the latest advancements in the clinical development of antivirals against infections by SARS-CoV-2 and its variants.
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Affiliation(s)
- Qiaoshuai Lan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Yan Yan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Guangxu Zhang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Shuai Xia
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Jie Zhou
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
| | - Lu Lu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
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7
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Kumar S, Basu M, Ghosh P, Pal U, Ghosh MK. COVID-19 therapeutics: Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery. Genes Dis 2023; 10:1402-1428. [PMID: 37334160 PMCID: PMC10079314 DOI: 10.1016/j.gendis.2022.12.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
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Affiliation(s)
- Sunny Kumar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, West Bengal 743372, India
| | - Pratyasha Ghosh
- Department of Economics, Bethune College, University of Calcutta, Kolkata 700006, India
| | - Uttam Pal
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K. Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
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Maia IS, Marcadenti A, Veiga VC, Miranda TA, Gomes SPC, Carollo MBS, Negrelli KL, Gomes JO, Tramujas L, Abreu-Silva EO, Westphal GA, Fernandes RP, Horta JGA, Oliveira DC, Flato UAP, Paoliello RCR, Fernandes C, Zandonai CL, Coelho JC, Barros WC, Lemos JC, Bolan RS, Dutra MM, Gebara OCE, Lopes ATA, Alencar Filho MS, Arraes JA, Hamamoto VA, Hernandes ME, Golin NA, Santos TM, Santos RHN, Damiani LP, Zampieri FG, Gesto J, Machado FR, Rosa RG, Azevedo LCP, Avezum A, Lopes RD, Souza TML, Berwanger O, Cavalcanti AB. Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial. LANCET REGIONAL HEALTH. AMERICAS 2023; 20:100466. [PMID: 36908503 PMCID: PMC9991866 DOI: 10.1016/j.lana.2023.100466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/18/2023] [Accepted: 02/17/2023] [Indexed: 03/14/2023]
Abstract
Background Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).
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Affiliation(s)
- Israel S Maia
- HCor Research Institute, São Paulo, SP, Brazil.,ICU Nereu Ramos, Hospital Nereu Ramos, Florianópolis, SC, Brazil.,Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Divisão de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - Viviane C Veiga
- Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,BP ICU - A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Camilo Fernandes
- ICU Nereu Ramos, Hospital Nereu Ramos, Florianópolis, SC, Brazil
| | | | - Juliana C Coelho
- BP ICU - A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | | | | | - Renata S Bolan
- Research Institute Baía Sul, Hospital Baía Sul, Florianópolis, SC, Brazil
| | - Marcela M Dutra
- Research Institute Baía Sul, Hospital Baía Sul, Florianópolis, SC, Brazil
| | | | | | | | | | - Victor A Hamamoto
- Research Institute, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil.,International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil
| | | | | | - Tiago M Santos
- HCor Research Institute, São Paulo, SP, Brazil.,Insper-Institute of Education and Research, São Paulo, SP, Brazil
| | | | - Lucas P Damiani
- HCor Research Institute, São Paulo, SP, Brazil.,Academic Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Fernando G Zampieri
- Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Academic Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - João Gesto
- Instituto Nacional de Ciência e Tecnologia de Inovação Em Doenças de Populações Negligenciadas, Centro de Desenvolvimento Tecnológico Em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.,SESI-Innovation Center for Occupational Health, Rio de Janeiro, RJ, Brazil
| | - Flávia R Machado
- Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Departamento de Anestesiologia, Dor e Medicina Intensiva, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Régis G Rosa
- Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Moinhos de Vento Research Institute, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil
| | - Luciano C P Azevedo
- Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Instituto de Pesquisa e Educação, Hospital Sírio-Libanês, São Paulo, SP, Brazil.,Disciplina de Emergências Clínicas, Universidade de São Paulo, São Paulo, Brazil
| | - Alvaro Avezum
- International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil
| | - Renato D Lopes
- Brazilian Clinical Research Institute (BCRI), São Paulo, SP, Brazil.,Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA
| | - Thiago M L Souza
- Instituto Nacional de Ciência e Tecnologia de Inovação Em Doenças de Populações Negligenciadas, Centro de Desenvolvimento Tecnológico Em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.,Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Otávio Berwanger
- Academic Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Alexandre B Cavalcanti
- HCor Research Institute, São Paulo, SP, Brazil.,Brazilian Intensive Care Research Network, BricNet, São Paulo, Brazil.,Divisão de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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9
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COVID-19 signalome: Potential therapeutic interventions. Cell Signal 2023; 103:110559. [PMID: 36521656 PMCID: PMC9744501 DOI: 10.1016/j.cellsig.2022.110559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles, which have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both drug and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.
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10
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Oliver JC, Silva EN, Soares LM, Scodeler GC, Santos ADS, Corsetti PP, Prudêncio CR, de Almeida LA. Different drug approaches to COVID-19 treatment worldwide: an update of new drugs and drugs repositioning to fight against the novel coronavirus. Ther Adv Vaccines Immunother 2022; 10:25151355221144845. [PMID: 36578829 PMCID: PMC9791004 DOI: 10.1177/25151355221144845] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/18/2022] [Indexed: 12/25/2022] Open
Abstract
According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine's effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.
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Affiliation(s)
| | | | | | | | - Ana de Souza Santos
- Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas, Alfenas, Brazil
| | - Patrícia Paiva Corsetti
- Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas, Alfenas, Brazil
| | - Carlos Roberto Prudêncio
- Laboratory of Immunotechnology , Center of Immunology, Instituto Adolfo Lutz Institute, São Paulo, Brazil
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11
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Sharun K, Tiwari R, Yatoo MI, Natesan S, Megawati D, Singh KP, Michalak I, Dhama K. A comprehensive review on pharmacologic agents, immunotherapies and supportive therapeutics for COVID-19. NARRA J 2022; 2:e92. [PMID: 38449903 PMCID: PMC10914132 DOI: 10.52225/narra.v2i3.92] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 12/06/2022] [Indexed: 03/08/2024]
Abstract
The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, India
| | - Ruchi Tiwari
- Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-Anusandhan Sansthan (DUVASU), Mathura, India
| | - Mohd I. Yatoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, Shuhama, Alusteng Srinagar, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Jammu and Kashmir, India
| | - Senthilkumar Natesan
- Department of Infectious Diseases, Indian Institute of Public Health Gandhinagar, Opp to Airforce station HQ, Gandhinagar, India
| | - Dewi Megawati
- Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar, Indonesia
- Department of Medical Microbiology and Immunology, University of California, Davis, California, USA
| | - Karam P. Singh
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, India
| | - Izabela Michalak
- Faculty of Chemistry, Department of Advanced Material Technologies, Wrocław University of Science and Technology, Wrocław, Poland
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, India
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12
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Nandi S, Nayak BS, Khede MK, Saxena AK. Repurposing of Chemotherapeutics to Combat COVID-19. Curr Top Med Chem 2022; 22:2660-2694. [PMID: 36453483 DOI: 10.2174/1568026623666221130142517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/16/2022] [Accepted: 10/06/2022] [Indexed: 12/05/2022]
Abstract
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a novel strain of SARS coronavirus. The COVID-19 disease caused by this virus was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 mainly spreads through droplets sprayed by coughs or sneezes of the infected to a healthy person within the vicinity of 6 feet. It also spreads through asymptomatic carriers and has negative impact on the global economy, security and lives of people since 2019. Numerous lives have been lost to this viral infection; hence there is an emergency to build up a potent measure to combat SARS-CoV-2. In view of the non-availability of any drugs or vaccines at the time of its eruption, the existing antivirals, antibacterials, antimalarials, mucolytic agents and antipyretic paracetamol were used to treat the COVID-19 patients. Still there are no specific small molecule chemotherapeutics available to combat COVID-19 except for a few vaccines approved for emergency use only. Thus, the repurposing of chemotherapeutics with the potential to treat COVID-19 infected people is being used. The antiviral activity for COVID-19 and biochemical mechanisms of the repurposed drugs are being explored by the biological assay screening and structure-based in silico docking simulations. The present study describes the various US-FDA approved chemotherapeutics repositioned to combat COVID-19 along with their screening for biological activity, pharmacokinetic and pharmacodynamic evaluation.
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Affiliation(s)
- Sisir Nandi
- Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur, 244713, India
| | - Bhabani Shankar Nayak
- Department of Pharmaceutics, Institute of Pharmacy and Technology, Salipur, Affiliated to Biju Patnaik University of Technology, Odisha, 754202, India
| | - Mayank Kumar Khede
- Department of Pharmaceutics, Institute of Pharmacy and Technology, Salipur, Affiliated to Biju Patnaik University of Technology, Odisha, 754202, India
| | - Anil Kumar Saxena
- Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur, 244713, India
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13
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Chandiwana N, Kruger C, Johnstone H, Chughlay MF, Ju C, Kim B, Dineka Y, Arbe-Barnes S, Miller R, Owen A, Hill A, Windgassen D, Abla N, Marrast AC, Duparc S, Francois Venter WD. Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial. EBioMedicine 2022; 86:104322. [PMID: 36332361 PMCID: PMC9624152 DOI: 10.1016/j.ebiom.2022.104322] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/09/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Background This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19. Methods This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18–65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population. Findings The mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ). Interpretation There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated. Funding 10.13039/501100004167Medicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with 10.13039/100004440Wellcome, the 10.13039/100000865Bill and Melinda Gates Foundation, and Mastercard.
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Affiliation(s)
- Nomathemba Chandiwana
- Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa,Corresponding author. Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Building C, Sunnyside Office Park, 32 Princess of Wales Terrace, Parktown, Johannesburg, South Africa
| | - Chelsea Kruger
- Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | | | | | - Chung Ju
- Shin Poong Pharm. Co. Ltd., Seoul, Republic of Korea,Graduate School of Clinical Pharmacy, CHA University, Pocheon-si, Gyeonggi-do, Republic of Korea
| | - Byungsu Kim
- Shin Poong Pharm. Co. Ltd., Seoul, Republic of Korea
| | - Yengiwe Dineka
- Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | | | | | - Andrew Owen
- Department of Molecular and Clinical Pharmacology, Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, Liverpool, United Kingdom
| | - Andrew Hill
- Department of Molecular and Clinical Pharmacology, Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, Liverpool, United Kingdom
| | | | - Nada Abla
- Medicines for Malaria Venture, Geneva, Switzerland
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14
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Garbern SC, Relan P, O’Reilly GM, Bills CB, Schultz M, Trehan I, Kivlehan SM, Becker TK. A systematic review of acute and emergency care interventions for adolescents and adults with severe acute respiratory infections including COVID-19 in low- and middle-income countries. J Glob Health 2022; 12:05039. [DOI: 10.7189/jogh.12.05039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Stephanie Chow Garbern
- Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Pryanka Relan
- Department of Emergency Medicine, Emory Healthcare Network, Atlanta, Georgia, USA
| | - Gerard M O’Reilly
- Emergency and Trauma Centre, The Alfred, Melbourne, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Corey B Bills
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Megan Schultz
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Indi Trehan
- Departments of Pediatrics, Global Health, and Epidemiology, University of Washington, Seattle, Washington, USA
| | - Sean M Kivlehan
- Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Humanitarian Initiative, Cambridge, Massachusetts, USA
| | - Torben K Becker
- Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA
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15
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Taibe NS, Kord MA, Badawy MA, Shytaj IL, Elhefnawi MM. Progress, pitfalls, and path forward of drug repurposing for COVID-19 treatment. Ther Adv Respir Dis 2022; 16:17534666221132736. [PMID: 36282077 PMCID: PMC9597285 DOI: 10.1177/17534666221132736] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
On 30 January 2020, the World Health Organization (WHO) declared the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic a public health emergency of international concern. The viral outbreak led in turn to an exponential growth of coronavirus disease 2019 (COVID-19) cases, that is, a multiorgan disease that has led to more than 6.3 million deaths worldwide, as of June 2022. There are currently few effective drugs approved for treatment of SARS-CoV-2/COVID-19 patients. Many of the compounds tested so far have been selected through a drug repurposing approach, that is, by identifying novel indications for drugs already approved for other conditions. We here present an up-to-date review of the main Food and Drug Administration (FDA)-approved drugs repurposed against SARS-CoV-2 infection, discussing their mechanism of action and their most important preclinical and clinical results. Reviewed compounds were chosen to privilege those that have been approved for use in SARS-CoV-2 patients or that have completed phase III clinical trials. Moreover, we also summarize the evidence on some novel and promising repurposed drugs in the pipeline. Finally, we discuss the current stage and possible steps toward the development of broadly effective drug combinations to suppress the onset or progression of COVID-19.
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Affiliation(s)
- Noha Samir Taibe
- Biotechnology-Biomolecular Chemistry Program, Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Maimona A. Kord
- Department of Botany, Faculty of Science, Cairo University, Giza, Egypt
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16
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Identification of Suitable Drug Combinations for Treating COVID-19 Using a Novel Machine Learning Approach: The RAIN Method. Life (Basel) 2022; 12:life12091456. [PMID: 36143492 PMCID: PMC9505329 DOI: 10.3390/life12091456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary This study follows an improved approach to systematic reviews, called the Systematic Review and Artificial Intelligence Network Meta-Analysis (RAIN), registered within PROSPERO (CRD42021256797), in which, the PRISMA criterion is still considered. Drugs used in the treatment of COVID-19 were searched in the databases of ScienceDirect, Web of Science (WoS), ProQuest, Embase, Medline (PubMed), and Scopus. In addition, using artificial intelligence and the measurement of the p-value between human genes affected by COVID-19 and drugs that have been suggested by clinical experts, and reported within the identified research papers, suitable drug combinations are proposed for the treatment of COVID-19. During the systematic review process, 39 studies were selected. Our analysis shows that most of the reported drugs, such as azithromycin and hydroxyl-chloroquine on their own, do not have much of an effect on the recovery of COVID-19 patients. Based on the result of the new artificial intelligence, on the other hand, at a significance level of less than 0.05, the combination of the two drugs therapeutic corticosteroid + camostat with a significance level of 0.02, remdesivir + azithromycin with a significance level of 0.03, and interleukin 1 receptor antagonist protein + camostat with a significance level 0.02 are considered far more effective for the treatment of COVID-19 and are therefore recommended. Abstract COVID-19 affects several human genes, each with its own p-value. The combination of drugs associated with these genes with small p-values may lead to an estimation of the combined p-value between COVID-19 and some drug combinations, thereby increasing the effectiveness of these combinations in defeating the disease. Based on human genes, we introduced a new machine learning method that offers an effective drug combination with low combined p-values between them and COVID-19. This study follows an improved approach to systematic reviews, called the Systematic Review and Artificial Intelligence Network Meta-Analysis (RAIN), registered within PROSPERO (CRD42021256797), in which, the PRISMA criterion is still considered. Drugs used in the treatment of COVID-19 were searched in the databases of ScienceDirect, Web of Science (WoS), ProQuest, Embase, Medline (PubMed), and Scopus. In addition, using artificial intelligence and the measurement of the p-value between human genes affected by COVID-19 and drugs that have been suggested by clinical experts, and reported within the identified research papers, suitable drug combinations are proposed for the treatment of COVID-19. During the systematic review process, 39 studies were selected. Our analysis shows that most of the reported drugs, such as azithromycin and hydroxyl-chloroquine on their own, do not have much of an effect on the recovery of COVID-19 patients. Based on the result of the new artificial intelligence, on the other hand, at a significance level of less than 0.05, the combination of the two drugs therapeutic corticosteroid + camostat with a significance level of 0.02, remdesivir + azithromycin with a significance level of 0.03, and interleukin 1 receptor antagonist protein + camostat with a significance level 0.02 are considered far more effective for the treatment of COVID-19 and are therefore recommended. Additionally, at a significance level of less than 0.01, the combination of interleukin 1 receptor antagonist protein + camostat + azithromycin + tocilizumab + oseltamivir with a significance level of 0.006, and the combination of interleukin 1 receptor antagonist protein + camostat + chloroquine + favipiravir + tocilizumab7 with corticosteroid + camostat + oseltamivir + remdesivir + tocilizumab at a significant level of 0.009 are effective in the treatment of patients with COVID-19 and are also recommended. The results of this study provide sets of effective drug combinations for the treatment of patients with COVID-19. In addition, the new artificial intelligence used in the RAIN method could provide a forward-looking approach to clinical trial studies, which could also be used effectively in the treatment of diseases such as cancer.
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17
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Wattanakul T, Chotsiri P, Scandale I, Hoglund RM, Tarning J. A pharmacometric approach to evaluate drugs for potential repurposing as COVID-19 therapeutics. Expert Rev Clin Pharmacol 2022; 15:945-958. [PMID: 36017624 DOI: 10.1080/17512433.2022.2113388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Developing and evaluating novel compounds for treatment or prophylaxis of emerging infectious diseases is costly and time-consuming. Repurposing of already available marketed compounds is an appealing option as they already have an established safety profile. This approach could substantially reduce cost and time required to make effective treatments available to fight the COVID-19 pandemic. However, this approach is challenging since many drug candidates show efficacy in in vitro experiments, but fail to deliver effect when evaluated in clinical trials. Better approaches to evaluate in vitro data are needed, in order to prioritize drugs for repurposing. AREAS COVERED This article evaluates potential drugs that might be of interest for repurposing in the treatment of patients with COVID-19 disease. A pharmacometric simulation-based approach was developed to evaluate in vitro activity data in combination with expected clinical drug exposure, in order to evaluate the likelihood of achieving effective concentrations in patients. EXPERT OPINION The presented pharmacometric approach bridges in vitro activity data to clinically expected drug exposures, and could therefore be a useful compliment to other methods in order to prioritize repurposed drugs for evaluation in prospective randomized controlled clinical trials.
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Affiliation(s)
- Thanaporn Wattanakul
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Palang Chotsiri
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Ivan Scandale
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
| | - Richard M Hoglund
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.,Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Joel Tarning
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.,Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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18
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Pitre T, Van Alstine R, Chick G, Leung G, Mikhail D, Cusano E, Khalid F, Zeraatkar D. Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis. CMAJ 2022; 194:E969-E980. [PMID: 35878897 PMCID: PMC9328465 DOI: 10.1503/cmaj.220471] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear. METHODS We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir-ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir-ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty). INTERPRETATION Molnupiravir and nirmatrelvir-ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir-ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.
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Affiliation(s)
- Tyler Pitre
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Rebecca Van Alstine
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Genevieve Chick
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Gareth Leung
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - David Mikhail
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Ellen Cusano
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Faran Khalid
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont
| | - Dena Zeraatkar
- Division of Internal Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Medicine (Pitre, Van Alstine, Chick), Grand River Hospital, Kitchener, Ont.; Michael G. DeGroote School of Medicine (Pitre, Van Alstine, Chick, Khalid), McMaster University, Hamilton, Ont.; Faculty of Medicine (Leung), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Mikhail), McMaster University, Hamilton, Ont.; Division of Hematology and Hematological Malignancies (Cusano), Department of Medicine, University of Calgary, Alta.; Harvard Medical School (Zeraatkar), Harvard University, Boston, Mass.; Health Research Methods, Evidence and Impact, Faculty of Health Sciences (Zeraatkar), McMaster University, Hamilton, Ont.
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19
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Chen CK, Weng TS, Chen YH, Kao JH, Chao CM. Clinical efficacy of sofosbuvir/daclatasvir in patients with COVID-19: a systematic review and meta-analysis of randomized trials. Expert Rev Clin Pharmacol 2022; 15:997-1002. [DOI: 10.1080/17512433.2022.2103539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Chao-Kun Chen
- Department of Thoracic Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Teng-Song Weng
- Department of Pharmacy, Chi Mei Medical Center, Liouying, Taiwan
| | - Yu-Hung Chen
- Department of Pharmacy, Chi Mei Medical Center, Liouying, Taiwan
| | - Jui- Heng Kao
- Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Chien-Ming Chao
- Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
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20
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Zein AFMZ, Sulistiyana CS, Raffaello WM, Wibowo A, Pranata R. Sofosbuvir with daclatasvir and the outcomes of patients with COVID-19: a systematic review and meta-analysis with GRADE assessment. Postgrad Med J 2022; 98:509-514. [PMID: 37066509 PMCID: PMC8189832 DOI: 10.1136/postgradmedj-2021-140287] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 12/20/2022]
Abstract
PURPOSE This systematic review and meta-analysis aimed to evaluate the effect of sofosbuvir/daclatasvir (SOF/DCV) on mortality, the need for intensive care unit (ICU) admission or invasive mechanical ventilation (IMV) and clinical recovery in patients with COVID-19. METHODS We performed a systematic literature search through the PubMed, Scopus and Embase from the inception of databases until 6 April 2021. The intervention group was SOF/DCV, and the control group was standard of care. The primary outcome was mortality, defined as clinically validated death. The secondary outcomes were (1) the need for ICU admission or IMV and (2) clinical recovery. The pooled effect estimates were reported as risk ratios (RRs). RESULTS There were four studies with a total of 231 patients in this meta-analysis. Three studies were randomised controlled trial, and one study was non-randomised. SOF/DCV was associated with lower mortality (RR: 0.31 (0.12, 0.78); p=0.013; I2: 0%) and reduced need for ICU admission or IMV (RR: 0.35 (0.18, 0.69); p=0.002; I2: 0%). Clinical recovery was achieved more frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37); p=0.011; I2: 21.1%). There was a moderate certainty of evidence for mortality and need for ICU/IMV outcome, and a low certainty of evidence for clinical recovery. The absolute risk reductions were 140 fewer per 1000 for mortality and 186 fewer per 1000 for the need for ICU/IMV. The increase in clinical recovery was 146 more per 1000. CONCLUSION SOF/DCV may reduce mortality rate and need for ICU/IMV in patients with COVID-19 while increasing the chance for clinical recovery. PROTOCOL REGISTRATION PROSPERO: CRD42021247510.
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Affiliation(s)
- Ahmad Fariz Malvi Zamzam Zein
- Department of Internal Medicine, Faculty of Medicine Universitas Swadaya Gunung Jati, Cirebon, Indonesia
- Department of Internal Medicine, Waled General Hospital, Cirebon, Indonesia
| | - Catur Setiya Sulistiyana
- Department of Internal Medicine, Faculty of Medicine Universitas Swadaya Gunung Jati, Cirebon, Indonesia
- Department of Internal Medicine, Waled General Hospital, Cirebon, Indonesia
| | | | - Arief Wibowo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Bandung, Jawa Barat, Indonesia
| | - Raymond Pranata
- Faculty of Medicine Universitas Pelita Harapan, Tangerang, Indonesia
- Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Bandung, Jawa Barat, Indonesia
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21
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Liu C, Qie M, Hu X, Wang H, Fang G, Wang S. Construction of a piezoelectric immunosensor for ultra-sensitive and highly selective detection of ribavirin in animal-derived foods. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2022; 14:2497-2503. [PMID: 35703169 DOI: 10.1039/d2ay00771a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
In this work, a suppressive piezoelectric immunosensor based on the ultra-sensitive quartz crystal microbalance and highly specific immunosorbent assay was constructed for the detection of ribavirin for the first time. The carboxyl group was modified on the surface of the gold electrode by electropolymerization, and then the carboxyl group was combined with the amino-modified antigen, and then the corresponding antibody was able to bind to it according to the principle of immune recognition, which interlocked to cause the frequency change of the piezoelectric sensor. The preparation conditions of the sensor and the antibody concentration were optimized, and the performance of the sensor was evaluated. Under the optimal conditions, a wide linear range of 1-750 μg L-1, a low detection limit (IC15) of 2.64 μg L-1, and a good sensitivity (IC50) of 31.49 μg L-1 were obtained. The sensor was used for the detection of ribavirin in chicken and milk samples, and the recovery rate ranged from 88.01 to 94.42%, which shows satisfactory consistency with the detection results of high performance liquid chromatography. It was suggested that the proposed piezoelectric immunosensor has good sensitivity and selectivity for ribavirin, and can be applied to the detection of actual food samples.
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Affiliation(s)
- Chang Liu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Meili Qie
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Xuelian Hu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Haiyang Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Guozhen Fang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Shuo Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
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22
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Bozorgmehr R, Amiri F, Hosein Zadeh M, Ghorbani F, Khameneh Bagheri A, Yazdi E, Nekooghadam SM, Pourdowlat G, Fatemi A. Effect of Sofosbuvir on Length of Hospital Stay in Moderate COVID-19 Cases; a Randomized Controlled Trial. ARCHIVES OF ACADEMIC EMERGENCY MEDICINE 2022; 10:e46. [PMID: 35765613 PMCID: PMC9206832 DOI: 10.22037/aaem.v10i1.1621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Efforts to control the COVID-19 pandemic are still on. This study aimed to evaluate the effect of sofosbuvir on length of hospital stay and complications in COVID-19 cases with moderate severity. METHODS This randomized clinical trial was done on moderate COVID-19 cases, who were admitted to Shohadaye Tajrish Hospital, Tehran, Iran, from 4/2021 to 9/2021. Eligible patients were randomly allocated into two groups of intervention (sofosbuvir) and control, and their outcomes were compared regarding the length of hospital stay and complications. RESULTS 100 COVID-19 cases were randomly divided into two groups of 50 patients, as the intervention and control groups. The mean age of patients was 50.56 ± 12.23 and 57.1±14.1 years in the intervention and control groups, respectively (p = 0.02). The two groups were similar regarding distribution of gender (p = 0.15), underlying diseases (p = 0.08), the severity of COVID-19 (p = 0.80) at the time of admission, signs and symptoms (p > 0.05), and essential laboratory profile (p > 0.05). The length of hospital stay in the control and intervention groups was 7.7 ± 4.09 days and 4.7±1.6 days, respectively (p = 0.02). None of our patients needed ICU or mechanical ventilation. CONCLUSION Sofosbuvir may decrease the length of hospital stay of COVID-19 cases with moderate severity, without a significant effect on the rate of intensive care unit (ICU) need and mortality.
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Affiliation(s)
- Rama Bozorgmehr
- Clinical Research Development Unit, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farbod Amiri
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Corresponding author: Farbod Amiri; Shohada-e Tajrish Hospital, Shahrdari St, Tehran, Iran. Postal Code: 19899 34148
| | - Mohammad Hosein Zadeh
- Department of internal medicine, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Ghorbani
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Khameneh Bagheri
- Department of Radiology, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Esmat Yazdi
- Department of internal medicine, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sayyed Mojtaba Nekooghadam
- Department of internal medicine, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Guitti Pourdowlat
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Fatemi
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Sezer A, Halilović-Alihodžić M, Vanwieren AR, Smajkan A, Karić A, Djedović H, Šutković J. A review on drug repurposing in COVID-19: from antiviral drugs to herbal alternatives. J Genet Eng Biotechnol 2022; 20:78. [PMID: 35608704 PMCID: PMC9127474 DOI: 10.1186/s43141-022-00353-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND COVID-19 is an illness caused by severe acute respiratory syndrome coronavirus 2. Due to its rapid spread, in March 2020 the World Health Organization (WHO) declared pandemic. Since the outbreak of pandemic many governments, scientists, and institutions started to work on new vaccines and finding of new and repurposing drugs. Drug repurposing is an excellent option for discovery of already used drugs, effective against COVID-19, lowering the cost of production, and shortening the period of delivery, especially when preclinical safety studies have already been performed. There are many approved drugs that showed significant results against COVID-19, like ivermectin and hydrochloroquine, including alternative treatment options against COVID-19, utilizing herbal medicine. SHORT CONCLUSION This article summarized 11 repurposing drugs, their positive and negative health implications, along with traditional herbal alternatives, that harvest strong potential in efficient treatments options against COVID-19, with small or no significant side effects. Out of 11 repurposing drugs, four drugs are in status of emergency approval, most of them being in phase IV clinical trials. The first repurposing drug approved for clinical usage is remdesivir, whereas chloroquine and hydrochloroquine approval for emergency use was revoked by FDA for COVID-19 treatment in June 2020.
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Affiliation(s)
- Abas Sezer
- Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | | | - Annissa Rachel Vanwieren
- Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Adna Smajkan
- Fakultät Chemie und Pharmazie, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Amina Karić
- Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Husein Djedović
- Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Jasmin Šutković
- Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
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24
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Scavone C, Mascolo A, Rafaniello C, Sportiello L, Trama U, Zoccoli A, Bernardi FF, Racagni G, Berrino L, Castaldo G, Coscioni E, Rossi F, Capuano A. Therapeutic strategies to fight COVID-19: Which is the status artis? Br J Pharmacol 2022; 179:2128-2148. [PMID: 33960398 PMCID: PMC8239658 DOI: 10.1111/bph.15452] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated and evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real-life context is strongly needed. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.
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Affiliation(s)
- Cristina Scavone
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Annamaria Mascolo
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Concetta Rafaniello
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Liberata Sportiello
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Ugo Trama
- Regional Pharmaceutical UnitU.O.D. 06 Politica del Farmaco e DispositiviNaplesItaly
| | - Alice Zoccoli
- Clinical Innovation OfficeUniversità Campus Bio‐MedicoRomeItaly
| | - Francesca Futura Bernardi
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
- Regional Pharmaceutical UnitU.O.D. 06 Politica del Farmaco e DispositiviNaplesItaly
| | - Giorgio Racagni
- Department of Pharmacological and Biomolecular SciencesUniversity of MilanMilanItaly
| | - Liberato Berrino
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Giuseppe Castaldo
- Department of Molecular Medicine and Medical BiotechnologyUniversity of Napoli Federico IINaplesItaly
- CEINGE—Advanced Biotechnology ScarlNaplesItaly
| | | | - Francesco Rossi
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
- Clinical Innovation OfficeUniversità Campus Bio‐MedicoRomeItaly
| | - Annalisa Capuano
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
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25
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Atyabi SMH, Rommasi F, Ramezani MH, Ghane Ezabadi MF, Arani MA, Sadeghi MH, Ahmed MM, Rajabi A, Dehghan N, Sohrabi A, Seifi M, Nasiri MJ. Relationship between blood clots and COVID-19 vaccines: A literature review. Open Life Sci 2022; 17:401-415. [PMID: 35582622 PMCID: PMC9055170 DOI: 10.1515/biol-2022-0035] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/17/2022] [Accepted: 01/17/2022] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 pandemic is one of the most critical pandemics during human civilization. Several therapeutic strategies for COVID-19 management have been offered; nonetheless, none of them seems to be sufficiently beneficial. In effect, vaccines have been proffered as a viable option. The critical issue now is to concentrate on protecting individuals against illness through immunization. One of the causes for concern among the researchers, physicians, and generally the whole community from the onset of vaccination has been the adverse effects (specifically blood clots) that may be observed after the injection of the COVID-19 vaccine. In some countries, such concerns have even resulted in the temporary or permanent discontinuation or abandonment of the application of some vaccines (especially AstraZeneca and Janssen). By evaluating rigorous studies published on this subject, the present article is aimed at identifying the association between blood clot incidence and COVID-19 vaccination. Various methods for producing the COVID-19 vaccines are analyzed, along with their possible pros and cons as well as common and rare side effects, especially VITT and blood clots. Finally, the differences of various vaccines on thrombotic events, WHO recommendations for VITT treatment, and blood clots statics are discussed.
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Affiliation(s)
| | - Foad Rommasi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | | | | | | | | | - Mohammad Mehdi Ahmed
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Rajabi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Dehghan
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Sohrabi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojtaba Seifi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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26
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Elgohary MAS, Hasan EM, Ibrahim AA, Abdelsalam MFA, Abdel-Rahman RZ, Zaki AI, Elaatar MB, Elnagar MT, Emam ME, Hamada MM, Abdel-Hamid TM, Abdel-Hafez AS, Seadawy MG, Fatoh AR, Elsaied MA, Sakr MAR, Elkady AO, Shehata MM, Nawar OM, Selem MAE, Abd-aal MS, Lotfy HH, Elnagdy TR, Helmy S, Mubark MA. Efficacy of Sofosbuvir plus Ledipasvir in Egyptian patients with COVID-19 compared to standard treatment: a randomized controlled trial. J Med Life 2022; 15:350-358. [PMID: 35449996 PMCID: PMC9015168 DOI: 10.25122/jml-2021-0175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/18/2021] [Indexed: 11/05/2022] Open
Abstract
COVID-19 is a pandemic disease caused by SARS-CoV-2, which is an RNA virus similar to the hepatitis C virus (HCV) in the replication process. Sofosbuvir/ledipasvir is an approved drug to treat HCV infection. This study investigates the efficacy of Sofosbuvir/ledipasvir as a treatment for patients with moderate COVID-19 infection. This is a single-blinded parallel-randomized controlled trial. The participants were randomized equally into the intervention group that received Sofosbuvir/ledipasvir (S.L. group), and the control group received Oseltamivir, Hydroxychloroquine, and Azithromycin (OCH group). The primary outcomes were the cure rate over time and the incidence of serious adverse events. The secondary outcomes included the laboratory findings. 250 patients were divided equally into each group. Both groups were similar regarding gender, but age was higher in the S.L. group (p=0.001). In the S.L. group, 89 (71.2%) patients were cured, while only 51 (40.8%) patients were cured in the OCH group. The cure rate was significantly higher in the S.L. group (RR=1.75, p<0.001). Kaplan-Meir plot showed a considerably higher cure over time in the S.L. group (Log-rank test, p=0.032). There were no deaths in the S.L. group, but there were six deaths (4.8%) in the OCH group (RR=0.08, p=0.013). Seven patients (5.6%) in the S.L. group and six patients (4.8%) in the OCH group were admitted to the intensive care unit (ICU) (RR=1.17, P=0.776). There were no significant differences between treatment groups regarding total leukocyte and neutrophils count, lymph, and urea. Sofosbuvir/ledipasvir is suggestive of being effective in treating patients with moderate COVID-19 infection. Further studies are needed to compare Sofosbuvir/ledipasvir with new treatment protocols.
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Affiliation(s)
| | - Eman Medhat Hasan
- Tropical Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amany Ahmad Ibrahim
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | | | | | | | | | | | | | | | | | - Mohamed Gomaa Seadawy
- Biological Prevention Department, Egyptian Army, Cairo, Egypt,Corresponding Author: Mohamed Gomaa Seadawy, Biological Prevention Department, Egyptian Army, Cairo, Egypt. E-mail:
| | | | | | | | | | | | | | | | | | | | | | - Sherine Helmy
- Research & Development, PHARCO Pharmaceuticals, Alexandria, Egypt
| | - Magdy Amin Mubark
- Egyptian Military Medical Services Department, Egyptian Army, Cairo, Egypt
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27
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Khamees A, Bani-Issa J, Zoubi MSA, Qasem T, AbuAlArjah MI, Alawadin SA, Al-Shami K, Hussein FE, Hussein E, Bashayreh IH, Tambuwala MM, Al-Saghir M, Cornelison CT. SARS-CoV-2 and Coronavirus Disease Mitigation: Treatment Options, Vaccinations and Variants. Pathogens 2022; 11:275. [PMID: 35215217 PMCID: PMC8876838 DOI: 10.3390/pathogens11020275] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 01/27/2023] Open
Abstract
COVID-19 is caused by a novel coronavirus (2019-nCoV), which was declared as a pandemic after it emerged in China 2019. A vast international effort has been conducted to prevent and treat COVID-19 due to its high transmissibility and severe morbidity and mortality rates, particularly in individuals with chronic co-morbidities. In addition, polymorphic variants increased the need for proper vaccination to overcome the infectivity of new variants that are emerging across the globe. Many treatment options have been proposed and more than 25 vaccines are in various stages of development; however, the infection peaks are oscillating periodically, which raises a significant question about the effectiveness of the prevention measures and the persistence of this pandemic disease. In this review, we are exploring the most recent knowledge and advances in the treatment and vaccination options as well as the new emerging variants of 2019-nCoV and the possible mitigation of one of the most aggressive pandemics in the last centuries.
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Affiliation(s)
- Almu’atasim Khamees
- Department of Clinical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (A.K.); (J.B.-I.); (K.A.-S.); (F.E.H.)
| | - Jamal Bani-Issa
- Department of Clinical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (A.K.); (J.B.-I.); (K.A.-S.); (F.E.H.)
| | - Mazhar Salim Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (M.S.A.Z.); (T.Q.); (M.I.A.)
| | - Taqwa Qasem
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (M.S.A.Z.); (T.Q.); (M.I.A.)
| | - Manal Issam AbuAlArjah
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (M.S.A.Z.); (T.Q.); (M.I.A.)
| | | | - Khayry Al-Shami
- Department of Clinical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (A.K.); (J.B.-I.); (K.A.-S.); (F.E.H.)
| | - Farah E. Hussein
- Department of Clinical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan; (A.K.); (J.B.-I.); (K.A.-S.); (F.E.H.)
| | - Emad Hussein
- Department of Food Science and Human Nutrition, A’Sharqiyah University, P.O. Box 42, Ibra 400, Oman;
- Department of Biological Sciences, Faculty of Sciences, Yarmouk University, Irbid 211-63, Jordan
| | - Ibrahim H. Bashayreh
- Nursing Department, Fatima College of Health Sciences, Al-Ain Campus, P.O. Box 24162, Abu-Dhabi 31201, United Arab Emirates;
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK;
| | - Mohannad Al-Saghir
- Department of Biological Sciences, Ohio University, Zanesville, OH 43701, USA;
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28
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El-Bendary M, Abd-Elsalam S, Elbaz T, El-Akel W, Cordie A, Elhadidy T, Elalfy H, Farid K, Elegezy M, El-Badrawy A, Neamatallah M, Abd Elghafar M, Salama M, AbdAllah M, Essam M, El-Shazly M, Esmat G. Efficacy of combined Sofosbuvir and Daclatasvir in the treatment of COVID-19 patients with pneumonia: a multicenter Egyptian study. Expert Rev Anti Infect Ther 2022; 20:291-295. [PMID: 34225541 DOI: 10.1080/14787210.2021.1950532] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/29/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Limited experimental and clinical evidence suggests a potential role for sofosbuvir/daclatasvir in treating COVID19. We aim to evaluate the efficacy of generic sofosbuvir/daclatasvir in treating COVID-19 patients with pneumonia. RESEARCH DESIGN AND METHODS This multicenter prospective study involved 174 patients with COVID-19. Patients were randomized into two groups. Group A (96 patients) received sofosbuvir (400 mg)/daclatasvir (60 mg) for 14 days in combination with conventional therapy. Group B (78 patients) received conventional therapy alone. Clinical, laboratory, and radiological data were collected at baseline, after 7, 14, and 28 days of therapy. Primary endpoint was rate of clinical/virological cure. RESULTS A lower mortality rate was observed in group (A) (14% vs 21%, P = 0.07). After 1 month of therapy, no differences were found in rates of ICU admission, oxygen therapy, or ventilation. Additionally, a statistically significant shorter duration of hospital stay (9% vs 12%, P < 0.01) and a faster achievement of PCR negativity at day 14 (84% versus 47%, P < 0.01) were noticed in group (A). CONCLUSION Adding sofosbuvir/daclatasvir to conventional therapy of COVID-19 is promising. Their use is associated with shorter hospital stay, faster PCR negativity and may be reduced mortality.
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Affiliation(s)
- Mahmoud El-Bendary
- Tropical medicine and Hepatogastroenterology department, Mansoura University, Mansoura, Egypt
| | - Sherief Abd-Elsalam
- Tropical Medicine and Infectious diseases department, Tanta University, Tanta, Egypt
| | - Tamer Elbaz
- Endemic medicine department, Cairo University Hospitals, Cairo, Egypt
| | - Wafaa El-Akel
- Endemic medicine department, Cairo University Hospitals, Cairo, Egypt
| | - Ahmed Cordie
- Endemic medicine department, Cairo University Hospitals, Cairo, Egypt
| | | | - Hatem Elalfy
- Tropical medicine and Hepatogastroenterology department, Mansoura University, Mansoura, Egypt
| | - Khaled Farid
- Tropical medicine and Hepatogastroenterology department, Mansoura University, Mansoura, Egypt
| | - Mohamed Elegezy
- Tropical medicine and Hepatogastroenterology department, Mansoura University, Mansoura, Egypt
| | | | | | - Mohamed Abd Elghafar
- Anesthesia, Surgical Intensive Care and Pain Medicine Department, Tanta University, Tanta, Egypt
| | - Marwa Salama
- Tropical Medicine and Infectious diseases department, Tanta University, Tanta, Egypt
| | - Mohamed AbdAllah
- Medical Research Division, National Research Center, Giza, Egypt
| | - Mahmoud Essam
- Endemic medicine department, Cairo University Hospitals, Cairo, Egypt
| | | | - Gamal Esmat
- Endemic medicine department, Cairo University Hospitals, Cairo, Egypt
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Hsu CK, Chen CY, Chen WC, Lai CC, Hung SH, Lin WT. The effect of sofosbuvir-based treatment on the clinical outcomes of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents 2022; 59:106545. [PMID: 35134505 PMCID: PMC8817946 DOI: 10.1016/j.ijantimicag.2022.106545] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/16/2021] [Accepted: 01/27/2022] [Indexed: 11/18/2022]
Abstract
This systematic review and meta-analysis examined the efficacy of sofosbuvir-based antiviral treatment against COVID-19 (coronavirus disease 2019). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from inception to 15 August 2021. Studies comparing the clinical efficacy and safety of sofosbuvir-based antiviral regimens (study group) with other antivirals or standard of care (control group) in patients with COVID-19 were included. Overall, 687 patients with COVID-19 were included, of which 377 patients received sofosbuvir-based treatment. Mortality was lower in the study group than in the control group [odds ratio (OR) = 0.49, 95% confidence interval (CI) 0.30–0.79; I2 = 0%]. The overall clinical recovery rate was higher in the study group than in the control group (OR = 1.82, 95% CI 1.20–2.76; I2 = 28%). The study group presented a lower requirement for mechanical ventilation (OR = 0.33, 95% CI 0.13–0.89; I2 = 0%) and intensive care unit admission (OR = 0.42, 95% CI 0.25–0.70; I2 = 0%) than the control group. Furthermore, the study group exhibited a shorter hospital length of stay [mean deviation (MD), –1.49, 95% CI –2.62 to –0.37; I2 = 56%] and recovery time (MD, –1.34, 95% CI –2.29 to –0.38; I2 = 46%) than the control group. Sofosbuvir-based treatment may help reduce mortality in patients with COVID-19 and improve associated clinical outcomes. Furthermore, sofosbuvir-based treatment was as safe as the comparator in patients with COVID-19. However, further large-scale studies are warranted to validate these findings.
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30
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Vegivinti CTR, Evanson KW, Lyons H, Akosman I, Barrett A, Hardy N, Kane B, Keesari PR, Pulakurthi YS, Sheffels E, Balasubramanian P, Chibbar R, Chittajallu S, Cowie K, Karon J, Siegel L, Tarchand R, Zinn C, Gupta N, Kallmes KM, Saravu K, Touchette J. Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials. BMC Infect Dis 2022; 22:107. [PMID: 35100985 PMCID: PMC8802260 DOI: 10.1186/s12879-022-07068-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. METHODS A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. RESULTS Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. CONCLUSIONS Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.
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Affiliation(s)
- Charan Thej Reddy Vegivinti
- Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, Bronx, NY, USA
| | - Kirk W Evanson
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
| | - Hannah Lyons
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
- Ohio University Heritage College of Osteopathic Medicine, 6775 Bobcat Way, Dublin, OH, 43016, USA
| | - Izzet Akosman
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
- Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA
| | - Averi Barrett
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Nicole Hardy
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Bernadette Kane
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
| | - Praneeth Reddy Keesari
- Kamineni Academy of Medical Sciences and Research Center, Hyderabad, Telangana, 500068, India
| | | | - Erin Sheffels
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA.
| | - Prasanth Balasubramanian
- Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, Bronx, NY, USA
| | - Richa Chibbar
- Department of Medicine, Lakeridge Health, 1 Hospital Crt, Oshawa, ON, L1G 2B9, Canada
| | | | - Kathryn Cowie
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - J Karon
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Lauren Siegel
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Ranita Tarchand
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Caleb Zinn
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Nitin Gupta
- Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Kevin M Kallmes
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Kavitha Saravu
- Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Jillienne Touchette
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
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Asili P, Mirahmad M, Tabatabaei-Malazy O, Manayi A, Haghighat E, Mahdavi M, Larijani B. Characteristics of published/registered clinical trials on COVID-19 treatment: A systematic review. Daru 2021; 29:449-467. [PMID: 34762250 PMCID: PMC8581284 DOI: 10.1007/s40199-021-00422-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 10/13/2021] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES Due to the rapid spread of COVID-19 worldwide, many countries have designed clinical trials to find efficient treatments. We aimed to critically report the characteristics of all the registered and published randomized clinical trials (RCTs) conducted on COVID-19, and summarize the evaluation of potential therapies developed in various regions. EVIDENCE ACQUISITION We comprehensively searched PubMed, Cochrane Library, Web of Science, Scopus, and Clinicaltrial.gov databases to retrieve all the relevant studies up to July 19, 2021, in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. We included all English-language published/registered RCTs on COVID-19, and excluded non-RCT, in-vitro/in-vivo, editorials, and review studies. Two reviewers independently evaluated all the records, and then analyzed by using SPSS 17. RESULTS Within 3018 included studies, 2801 (92.8%) and 217 (7.2%) were registered or published RCTs consisting of about 600 synthetic drugs. Herbal medicines have been studied in 23 trials (10.6%) among the published RCTs and in 357 registered RCTs (12.7%). Hydroxychloroquine 23 (10.6%) and convalescent plasma 194 (6.9%) alone or in combination with other agents were the most frequently used interventions in published and registered RCTs, respectively. Most published RCTs have been conducted in Western Pacific Region (WPRO) (50 trials, 23.0%) including 45 trials from China. Also, a greater proportion of registered RCTs have been conducted in the Region of the Americas (PAHO) (885 trials, 31.6%) including 596 RCTs from the United States (U.S). Globally, 283 registered trials have been conducted to assess new developed vaccines for COVID or previously established for other disorders. CONCLUSION The present study highlighted the wide range of potential therapeutic agents in published and registered COVID-19 clinical trials across a wide range of regions. However, it is urgently required to global coordination in order to conduct more well-designed trials and progress in discovering safe and effective treatments.
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Affiliation(s)
- Pooria Asili
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mirahmad
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Manayi
- Medicinal Plants Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Haghighat
- Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahdavi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Mobarak S, Salasi M, Hormati A, Khodadadi J, Ziaee M, Abedi F, Ebrahimzadeh A, Azarkar Z, Mansour-Ghanaei F, Joukar F, Yeganeh S, Yaghubi Kalurazi T, Naghipour M, Mehrabi Z, Bahadori AR, Yaghoubi S, Moslemi R, Abbaspour Kasgari H, Fakheri H, Moghimi M, Shabani AM, Nekoukar Z, Babamahmoodi F, Davoudi Badabi AR, Davoodi L, Hassaniazad M, Barahimi E, Tousi A, Sadeghi A, Hosamirudsari H, Ali Asgari A, Abdollahi M, Anushiravani A, Shabani M, Shokouhi S, Khajavirad N, Salehi M, Dehghan Manshadi SA, Mousavi H, Zolfaghari F, Azimi E, Zeinali A, Akbarpour E, Merat D, Eslami G, Mousaviasl S, Sayar S, Radmanesh E, Ebrahimzadeh M, Arizavi Z, Jelvay S, Salmanzadeh S, Esmaeilian H, Mobarak M, Karimi J, Poormontaseri Z, Hasooni Bahrini N, Bonyadi A, Dehghani F, Mirzaei H, Noori Jangi M, Pourmasoomi H, Rezaie Keikhaie L, Afshari M, Nateghi Baygi A, Nateghi Baygi H, Levi J, McCann K, Wentzel H, Simmons B, Hill A, Merat S. Evaluation of the effect of sofosbuvir and daclatasvir in hospitalized COVID-19 patients: a randomized double-blind clinical trial (DISCOVER). J Antimicrob Chemother 2021; 77:758-766. [PMID: 34849957 PMCID: PMC8690191 DOI: 10.1093/jac/dkab433] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022] Open
Abstract
Background The combination of sofosbuvir and daclatasvir has shown preliminary efficacy for hospitalized patients with COVID-19 in four open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir/daclatasvir to standard care improved clinical outcomes in hospitalized patients with COVID-19. Methods This was a placebo-controlled, double-blind, randomized clinical trial in adults hospitalized with COVID-19 at 19 hospitals in Iran. Patients were randomized to oral sofosbuvir/daclatasvir 400/60 mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O2 saturation <95% and compatible symptoms. The primary outcome was hospital discharge within 10 days of randomization. Secondary outcomes included mortality and time to clinical events. The trial is registered on the Iran Registry of Clinical Trials under IRCT20200624047908N1. Results Between July and October 2020, 1083 patients were randomized to either the sofosbuvir/daclatasvir arm (n = 541) or the placebo arm (n = 542). No significant difference was observed in the primary outcome of hospital discharge within 10 days, which was achieved by 415/541 (77%) in the sofosbuvir/daclatasvir arm and 411/542 (76%) in the placebo arm [risk ratio (RR) 1.01, 95% CI 0.95–1.08, P = 0.734]. In-hospital mortality was 60/541 (11%) in the sofosbuvir/daclatasvir arm versus 55/542 (10%) in the placebo arm (RR 1.09, 95% CI 0.77–1.54, P = 0.615). No differences were observed in time to hospital discharge or time to in-hospital mortality. Conclusions We observed no significant effect of sofosbuvir/daclatasvir versus placebo on hospital discharge or survival in hospitalized COVID-19 patients.
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Affiliation(s)
- Sara Mobarak
- Abadan University of Medical Sciences, Abadan, Iran
| | - Mehdi Salasi
- Imam Khomeini Hospital of Abadan Petroleum Health Organization, Abadan, Iran
| | - Ahmad Hormati
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.,Gastroenterology and Hepatology Disease Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Javad Khodadadi
- Infectious Disease Department, Qom University of Medical Sciences, Qom, Iran
| | - Masood Ziaee
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Farshid Abedi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Azadeh Ebrahimzadeh
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Zohreh Azarkar
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Sara Yeganeh
- Caspian Digestive Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Tofigh Yaghubi Kalurazi
- Department of Health, Nutrition & Infectious Diseases, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammadreza Naghipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Zeinab Mehrabi
- Department of Infectious Diseases, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Reza Bahadori
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Diseases, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Rohollah Moslemi
- Department of Clinical Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Hafez Fakheri
- Gut and Liver Research Center, Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Minoo Moghimi
- Department of Clinical Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amir Mohammad Shabani
- Department of Clinical Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zahra Nekoukar
- Department of Clinical Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Farhang Babamahmoodi
- Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ali Reza Davoudi Badabi
- Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Lotfollah Davoodi
- Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mehdi Hassaniazad
- Infectious and Tropical Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Elham Barahimi
- Infectious and Tropical Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Abdolali Tousi
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Anahita Sadeghi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Ali Asgari
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Anushiravani
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Minoosh Shabani
- Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shervin Shokouhi
- Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasim Khajavirad
- Department of Internal Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Salehi
- Infectious Diseases Department, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hashem Mousavi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farnaz Zolfaghari
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elmira Azimi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Aida Zeinali
- Department of Cardiology, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Akbarpour
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Dorsa Merat
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Sara Sayar
- Abadan University of Medical Sciences, Abadan, Iran
| | | | | | | | - Saeed Jelvay
- Abadan University of Medical Sciences, Abadan, Iran
| | | | | | | | - Jalal Karimi
- Department of Infectious Disease, Fasa University of Medical Sciences, Fasa, Iran
| | - Zahra Poormontaseri
- Department of Infectious Disease, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Atefeh Bonyadi
- Imam Khomeini Hospital of Abadan Petroleum Health Organization, Abadan, Iran
| | - Fatemeh Dehghani
- Imam Khomeini Hospital of Abadan Petroleum Health Organization, Abadan, Iran
| | - Hadi Mirzaei
- Department of Biotechnology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Masoome Noori Jangi
- Department of Infectious Diseases, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Hossein Pourmasoomi
- Department of Infectious Diseases, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Lili Rezaie Keikhaie
- Department of Infectious Diseases, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Mahdi Afshari
- Pediatric Gastroenterology and Hepatology Research Center, Zabol University of Medical Sciences, Zabol, Iran
| | - Alireza Nateghi Baygi
- Research and Development Department, Fanavaran Rojan Mohaghegh Darou Co., Tehran, Iran
| | - Helia Nateghi Baygi
- Research and Development Department, Fanavaran Rojan Mohaghegh Darou Co., Tehran, Iran
| | - Jacob Levi
- Department of Intensive Care, University College London Hospital, London, UK
| | - Kaitlyn McCann
- School of Public Health, Imperial College London, London, UK
| | - Hannah Wentzel
- School of Public Health, Imperial College London, London, UK
| | - Bryony Simmons
- Department of Infectious Diseases, Imperial College London, London, UK
| | - Andrew Hill
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Shahin Merat
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Kow CS, Javed A, Ramachandram D, Hasan SS. Clinical outcomes of sofosbuvir-based antivirals in patients with COVID-19: a systematic review and meta-analysis of randomized trials. Expert Rev Anti Infect Ther 2021; 20:567-575. [PMID: 34719324 DOI: 10.1080/14787210.2022.2000861] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19. METHODS A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI). RESULTS The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir-daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22). CONCLUSION Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.
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Affiliation(s)
- Chia Siang Kow
- School of Pharmacy, Monash University Malaysia, Petaling Jaya, Malaysia
| | - Amaan Javed
- University College of Medical Sciences, University of Delhi, Delhi, India
| | | | - Syed Shahzad Hasan
- School of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, UK.,School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
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Honarmand K, Penn J, Agarwal A, Siemieniuk R, Brignardello-Petersen R, Bartoszko JJ, Zeraatkar D, Agoritsas T, Burns K, Fernando SM, Foroutan F, Ge L, Lamontagne F, Jimenez-Mora MA, Murthy S, Yepes-Nuñez JJ, Vandvik PO, Ye Z, Rochwerg B. Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality. J Clin Epidemiol 2021; 139:68-79. [PMID: 34274489 PMCID: PMC8280397 DOI: 10.1016/j.jclinepi.2021.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/16/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. STUDY DESIGN We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. RESULTS We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. CONCLUSIONS There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. REGISTRATION CRD42020192095.
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Affiliation(s)
- Kimia Honarmand
- Division of Critical Care, Department of Medicine, Western University, 1151 Richmond Street London, Ontario, N6A 3K7, Canada.
| | - Jeremy Penn
- Faculty of Health Sciences, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Arnav Agarwal
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, University of Toronto, 27 King's College Circle, Toronto, Ontario, M5S 1A1, Canada
| | - Reed Siemieniuk
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Romina Brignardello-Petersen
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Jessica J Bartoszko
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Dena Zeraatkar
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Biomedical Informatics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA, 02115, USA
| | - Thomas Agoritsas
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Division General Internal Medicine, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4 1205, Geneva, Switzerland
| | - Karen Burns
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Unity Health Toronto, St. Michael's Hospital, Li Ka Shing Knowledge Institute, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada
| | - Shannon M Fernando
- Division of Critical Care, Department of Medicine, University of Ottawa, 75 Laurier Ave. E, Ottawa, Ontario, K1N 6N5, Canada
| | - Farid Foroutan
- Ted Rogers Centre for Heart Research, University Health Network, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada
| | - Long Ge
- Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, 222 Tianshui S Rd, Chengguan District, Lanzhou, Gansu, China
| | - Francois Lamontagne
- Department of Medicine and Centre de recherche du CHU de Sherbrooke, 12e Avenue N Porte 6, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Mario A Jimenez-Mora
- School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia
| | - Srinivas Murthy
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada
| | - Juan Jose Yepes-Nuñez
- School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia; Pulmonology Service, Internal Medicine Section, Fundación Santa Fe de Bogotá University Hospital, Cra. 7b (#)12390, Bogotá D.C, Colombia
| | - Per O Vandvik
- Department of Health and Society, Faculty of Medicine, University of Oslo, Problemveien 7, 0315, Oslo, Norway
| | - Zhikang Ye
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Bram Rochwerg
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
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Lai CC, Chao CM, Hsueh PR. Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2021; 54:767-775. [PMID: 34253490 PMCID: PMC8233451 DOI: 10.1016/j.jmii.2021.05.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.
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Affiliation(s)
- Chih-Cheng Lai
- Department of Internal Medicine, Kaohsiung Veterans General Hospital, Tainan Branch, Tainan, Taiwan
| | - Chien-Ming Chao
- Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Po-Ren Hsueh
- Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
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36
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Aslan AT, Akova M. Current status of therapeutic alternatives for COVID-19: A narrative review. LE INFEZIONI IN MEDICINA 2021; 29:312-327. [PMID: 35146336 PMCID: PMC8805505 DOI: 10.53854/liim-2903-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/10/2021] [Indexed: 01/08/2023]
Abstract
Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has exploded and led to a global crisis. Currently, the global case numbers topped 200 million, and toll of dead exceeded 4 million around the world. The pathogenesis of coronavirus disease 2019 (COVID-19) is driven by two processes. During the first stage of the infection that lasts around 5-7 days, replication of SARS-CoV-2 occurs. In the second stage, the disease may progress due to an exaggerated inflammatory response leading to tissue damage. Therefore, it is anticipated that antiviral agents would be effective during the early phase of the disease, while immunomodulator agents are likely to be more beneficial in the second stage of COVID-19. This basic concept of disease development led to explore several antiviral and immunomodulator agents for the treatment of COVID-19. Currently, remdesivir is the only available Food and Drug Administration-approved antiviral agent for the treatment of COVID-19. However, some other agents have been approved by various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug applications, compassionate use or expanded access programs. In addition, a variety of repurposed agents that were approved for other indications are being investigated for the treatment of COVID19 in clinical trials. A myriad of publications including randomized controlled trials (RCTs) are emerging continuously and are accessible as peer-reviewed, pre-print and press release formats. Considering the critical importance of RCTs in generating evidence and providing further guidance on COVID-19 treatment, we herein reviewed only RCTs and meta-analyses. The discussion includes antiviral agents (hydroxychloroquine, lopinavir/ritonavir, remdesivir, favipiravir and ivermectin) and, various immunomodulatory drugs (corticosteroids, tocilizumab, baricitinib, and IL-1 inhibitors). Other investigational therapies including darunavir/cobicistat, umifenovir, sofosbuvir/daclatasvir, sofobuvir/ledipasvir, ribavirin, nitazoxanide and interferon-based regimens were not evaluated due to insufficient data on the efficacy and safety of these agents.
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Affiliation(s)
| | - Murat Akova
- Department of Infectious Diseases and Clinical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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37
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Abbass S, Kamal E, Salama M, Salman T, Sabry A, Abdel-Razek W, Helmy S, Abdelgwad A, Sakr N, Elgazzar M, Einar M, Farouk M, Saif M, Shehab I, El-Hosieny E, Mansour M, Mahdi D, Tharwa ES, Salah M, Elrouby O, Waked I. Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID-19: A randomized controlled trial. J Med Virol 2021; 93:6750-6759. [PMID: 34379337 PMCID: PMC8426808 DOI: 10.1002/jmv.27264] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 12/23/2022]
Abstract
Only a few treatments are approved for coronavirus disease‐2019 (COVID‐19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID‐19 infection. Multicentre parallel randomized controlled open‐label trial. One hundred and twenty eligible patients with moderate and severe COVID‐19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF‐DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF‐DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF‐DCV with a lower incidence of mortality. On the other hand, adding SOF‐RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF‐DCV as an add‐on to SOC for the treatment of moderate to severe COVID‐19 infections.
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Affiliation(s)
- Sherif Abbass
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Ehab Kamal
- Medical Research Division, National Research Centre, Cairo, Egypt
| | - Mohsen Salama
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Tary Salman
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | - Alyaa Sabry
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | | | | | | | - Neamt Sakr
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
| | | | | | | | | | | | | | | | | | | | | | | | - Imam Waked
- National Liver Institute, Shebeen El-Kom, Menoufia, Egypt
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38
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Gil Martínez V, Avedillo Salas A, Santander Ballestín S. Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review. Pharmaceuticals (Basel) 2021; 14:736. [PMID: 34451833 PMCID: PMC8398077 DOI: 10.3390/ph14080736] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Due to the lack of an etiologic treatment for SARS-CoV-2 and the difficulties involved in developing new drugs, some drugs already approved for other diseases or with efficacy against SARS and MERS, have been used in patients with COVID-19. This systematic review aims to summarize evidence on the efficacy and safety of five antivirals applied to patients with COVID-19, that have proven to be effective either in vitro studies or in studies on SARS-CoV and MERS.; An intensive search of different databases (Pub Med, WoS, MEDLINE and Cochrane COVID-19 Study Register) has been carried out until the end of April 2021. This systematic review has been conducted according to the PRISMA statement. From each of the included studies, the characteristics of the intervention and comparison groups, demographic data and results were extracted independently; Remdesivir is well tolerated and helps to accelerate clinical improvement but is ineffective in reducing mortality. Favipiravir is safe and shows promising results regarding symptom resolution but does not improve viral clearance. The use of lopinavir/ritonavir has been associated with an increased risk of gastrointestinal adverse events and it has not proven to be effective. No significant differences were observed between patients treated with ribavirin or umifenovir and their respective control groups; Remdesivir and favipiravir are well tolerated and effective in accelerating clinical improvement. This systematic review does not support the use of lopinavir/ritonavir, ribavirin and umifenovir in hospitalized patients with COVID-19.
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Affiliation(s)
| | | | - Sonia Santander Ballestín
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain; (V.G.M.); (A.A.S.)
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39
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M Mansour S, N Shamma R, A Ahmed K, A Sabry N, Esmat G, A Mahmoud A, Maged A. Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study. Int Immunopharmacol 2021; 99:108004. [PMID: 34333358 PMCID: PMC8299187 DOI: 10.1016/j.intimp.2021.108004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/13/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023]
Abstract
Introduction SARS-CoV-2 replication in cell cultures has been shown to be inhibited by ivermectin. However, ivermectin's low aqueous solubility and bioavailability hinders its application in COVID-19 treatment. Also, it has been suggested that best outcomes for this medication can be achieved via direct administration to the lung. Objectives This study aimed at evaluating the safety of a novel ivermectin inhalable formulation in rats as a pre-clinical step. Methods Hydroxy propyl-β-cyclodextrin (HP-β-CD) was used to formulate readily soluble ivermectin lyophilized powder. Adult male rats were used to test lung toxicity for ivermectin-HP-β-CD formulations in doses of 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg for 3 successive days. Results The X-ray diffraction for lyophilized ivermectin-HP-β-CD revealed its amorphous structure that increased drug aqueous solubility 127-fold and was rapidly dissolved within 5 s in saline. Pulmonary administration of ivermectin-HP-β-CD in doses of 0.2, 0.4 and 0.8 mg/kg showed dose-dependent increase in levels of TNF-α, IL-6, IL-13 and ICAM-1 as well as gene expression of MCP-1, protein expression of PIII-NP and serum levels of SP-D paralleled by reduction in IL-10. Moreover, lungs treated with ivermectin (0.2 mg/kg) revealed mild histopathological alterations, while severe pulmonary damage was seen in rats treated with ivermectin at doses of 0.4 and 0.8 mg/kg. However, ivermectin-HP-β-CD formulation administered in doses of 0.05 and 0.1 mg/kg revealed safety profiles. Conclusion The safety of inhaled ivermectin-HP-β-CD formulation is dose-dependent. Nevertheless, use of low doses (0.05 and 0.1 mg/kg) could be considered as a possible therapeutic regimen in COVID-19 cases.
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Affiliation(s)
- Suzan M Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt; Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Rehab N Shamma
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
| | - Kawkab A Ahmed
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Azza A Mahmoud
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Amr Maged
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt; Pharmaceutical Factory, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
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40
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Sayad B, Khodarahmi R, Najafi F, Miladi R, Mohseni Afshar Z, Mansouri F, Rahimi Z, Shirvani M, Salimi M, Vaziri S, Janbakhsh A, Khosravi Shadmani F, Bozorgomid A, Zamanian MH, Afsharian M. Efficacy and safety of sofosbuvir/velpatasvir versus the standard of care in adults hospitalized with COVID-19: a single-centre, randomized controlled trial. J Antimicrob Chemother 2021; 76:2158-2167. [PMID: 34037760 PMCID: PMC8194643 DOI: 10.1093/jac/dkab152] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 04/13/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. The majority of patients experience asymptomatic to mild self-limited disease, but some cases progress to respiratory and multi-organ failure. However, so far, no approved antiviral therapy has been available for treatment of COVID-19. Sofosbuvir/velpatasvir (SOF/VEL) is an approved anti-HCV drug that is capable of suppressing other families of positive-sense RNA viruses with conserved polymerase and may be effective against SARS-CoV-2. This study was conducted to evaluate the efficacy of the SOF/VEL combination in addition to the national standard of care versus the national standard of care alone (hydroxychloroquine and lopinavir/ritonavir as well as supportive care) in patients with moderate to severe COVID-19 infection. Methods This single-centre, randomized, open-labelled, prospective clinical trial was done in patients with moderate to severe COVID-19 admitted to Farabi Hospital in Kermanshah Province, Iran. Eligible patients were randomly assigned in a 1:1 ratio to the SOF/VEL arm (SOF/VEL plus the national standard of care) or the control arm (the national standard of care alone). The main outcome of the study was the mortality on Day 28 after randomization. Secondary outcomes were time from the start of medication to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and conversion of RT–PCR results from positive to negative from the time of randomization to discharge. Adverse events were evaluated in all patients who started their assigned treatment. Results Between 11 April and 8 June 2020, 80 patients were recruited and randomly assigned into the SOF/VEL (n = 40) and control (n = 40) arms. The primary outcome was not significantly different between the two arms (P = 1.00). Secondary outcomes, including time to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and RT–PCR conversion, were not significantly different between arms either (P > 0.05). SOF/VEL treatment and the national standard of care were tolerated similarly. Conclusions Although treatment with SOF/VEL was safe, adding SOF/VEL to the standard of care did not improve the clinical status or reduce mortality in patients with moderate to severe COVID-19. However, larger randomized clinical trials including more parameters are needed for accurate estimation of the efficacy of SOF/VEL.
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Affiliation(s)
- Babak Sayad
- Infectious Diseases Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farid Najafi
- Research Center for Environmental Determinants of Health, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ronak Miladi
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Mohseni Afshar
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Feizollah Mansouri
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zohreh Rahimi
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Maria Shirvani
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehdi Salimi
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Siavash Vaziri
- Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Alireza Janbakhsh
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Khosravi Shadmani
- Research Center for Environmental Determinants of Health, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezoo Bozorgomid
- Infectious Diseases Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hossein Zamanian
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mandana Afsharian
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Maxwell D, Sanders KC, Sabot O, Hachem A, Llanos-Cuentas A, Olotu A, Gosling R, Cutrell JB, Hsiang MS. COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact. Am J Trop Med Hyg 2021; 105:584-595. [PMID: 34270449 PMCID: PMC8592342 DOI: 10.4269/ajtmh.21-0200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/30/2021] [Indexed: 11/29/2022] Open
Abstract
Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States (US), European Union (EU), and World Health Organization (WHO) clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding proposed mechanisms of action, potential limitations, and trial status is summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. We also identified the need for better coordination of trials of accessible agents and their combinations in LMICs. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated efforts in the evaluation and deployment of those agents found to be efficacious.
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Affiliation(s)
- Daniel Maxwell
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kelly C. Sanders
- Pandemic Response Initiative, Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California
- Department of Pediatrics, Stanford University, Stanford, California
| | - Oliver Sabot
- Pandemic Response Initiative, Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California
| | - Ahmad Hachem
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alejandro Llanos-Cuentas
- Institute of Tropical Medicine Alexander von Humbolt, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Ally Olotu
- Clinical Trials and Interventions Unit, Ifakara Health Institute, Bagamoyo, Tanzania
| | - Roly Gosling
- Pandemic Response Initiative, Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California
| | - James B. Cutrell
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Michelle S. Hsiang
- Pandemic Response Initiative, Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pediatrics, University of California, San Francisco, San Francisco, California
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Bokharee N, Khan YH, Khokhar A, Mallhi TH, Alotaibi NH, Rasheed M. Pharmacological interventions for COVID-19: a systematic review of observational studies and clinical trials. Expert Rev Anti Infect Ther 2021; 19:1219-1244. [PMID: 33719819 DOI: 10.1080/14787210.2021.1902805] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Currently, there is no approved therapeutic entity for coronavirus disease 2019 (COVID-19) and clinicians are primarily relying on drug repurposing. However, findings across studies are widely disparate, making it difficult to draw firm conclusions. Since clinicians need accurate evidence to treat COVID-19, this manuscript systematically analyzed the published and ongoing studies evaluating the pharmacological interventions for COVID-19.Areas Covered: A systematic search of observational studies and Clinical Trials on the treatment and prevention of COVID-19 was performed by using various databases from inception to 2 December 2020.Expert Opinion: A total of 460 studies met the inclusion criteria. Of these, 37 were research studies, 386 were ongoing trials, and 37 were completed trials. Anti-virals, steroids, anti-malarial, plasma exchange, and monoclonal antibodies were the most common treatment modalities used alone or in combination in these studies. However, tocilizumab, plasma exchange, and steroids have shown significant improvements in patient's clinical and radiological status. Tocilizumab reported minimum hospital stay of 2 days along with maximum recovery and patient's stability rate. Existing literature demonstrate promising results of tocilizumab, plasma exchange, and steroids among COVID-19 patients. Nevertheless, these studies are accompanied by several methodological disparities which should be considered while interpreting the results.
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Affiliation(s)
- Nida Bokharee
- Institute of Pharmacy, Lahore College for Women University, Lahore, Pakistan
| | - Yusra Habib Khan
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Kingdom of Saudi Arabia
| | - Aisha Khokhar
- Institute of Pharmacy, Lahore College for Women University, Lahore, Pakistan
| | - Tauqeer Hussain Mallhi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Kingdom of Saudi Arabia
| | - Nasser Hadal Alotaibi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Kingdom of Saudi Arabia
| | - Maria Rasheed
- Institute of Pharmacy, Lahore College for Women University, Lahore, Pakistan
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Tian X, Gan W, Nie Y, Ying R, Tan Y, Chen J, Chen M, Zhang C. Clinical efficacy and security of glycyrrhizic acid preparation in the treatment of anti-SARS-CoV-2 drug-induced liver injury: a protocol of systematic review and meta-analysis. BMJ Open 2021; 11:e051484. [PMID: 34244286 PMCID: PMC8275357 DOI: 10.1136/bmjopen-2021-051484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 06/08/2021] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION COVID-19 is a highly infectious acute pneumonia. Glycyrrhizic acid preparation (GAP) has been found to have hepatoprotective and antiviral effects, but there is no supporting evidence on its efficacy and security for patients with COVID-19. METHODS AND ANALYSIS The systematic review methods will be defined by Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This study will start on 1 July 2021 and end on 31 October 2021. A comprehensive electronic search will be conducted with the search of Web of Science, PubMed, Ovid web, China National Knowledge Infrastructure, Chinese Scientific and Journal Database, Wanfang Database and grey literature, and manual search will be conducted to search literature of randomised controlled trials, single-arm trials and retrospective studies about GAP in the treatment of anti-SARS-CoV-2 drug-induced liver injury from 1 December 2019 to 1 July 2021. There is no time limitations of publication and language will be restricted to Chinese and English. Retrieved studies will be independently screened by two researchers and relevant data will be extracted from studies. Interstudy heterogeneity will be assessed using the I2 statistic and explored through meta-regressions and subgroup analyses. Depending on data availability, we plan to conduct subgroup analyses by study population, geographical region and other selected clinical variables of interest. Quality assessment of the studies will be performed. Cochrane Handbook for Systematic Reviews of Interventions will be used to assess the risk of bias, and Grading of Recommendations Assessment, Development and Evaluation will be used to access the confidence in cumulative evidence. ETHICS AND DISSEMINATION Ethical approval will not be required for no primary data of individual patients will be collected. The final report will be shared with the scientific community through publication in a peer-reviewed journal, as well as with key stakeholders, including patients, healthcare professionals and those working on COVID-19 research. PROSPERO REGISTRATION NUMBER CRD42021234647.
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Affiliation(s)
- Xia Tian
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Wenfan Gan
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yisen Nie
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Rongtao Ying
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yongji Tan
- College of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Junli Chen
- College of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Mei Chen
- Department of Respiratory Medicine, Chengdu Fifth People's Hospital, Chengdu, People's Republic of China
| | - Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
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Liatsos GD. Controversies’ clarification regarding ribavirin efficacy in measles and coronaviruses: Comprehensive therapeutic approach strictly tailored to COVID-19 disease stages. World J Clin Cases 2021; 9:5135-5178. [PMID: 34307564 PMCID: PMC8283580 DOI: 10.12998/wjcc.v9.i19.5135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/01/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ribavirin is a broad-spectrum nucleoside antiviral drug with multimodal mechanisms of action, which supports its longevity and quality as a clinical resource. It has been widely administered for measles and coronavirus infections. Despite the large amount of data concerning the use of ribavirin alone or in combination for measles, severe acute respiratory syndrome, Middle East respiratory syndrome, and coronavirus disease 2019 (COVID-19) outbreaks, the conclusions of these studies have been contradictory. Underlying reasons for these discrepancies include possible study design inaccuracies and failures and misinterpretations of data, and these potential confounds should be addressed.
AIM To determine the confounding factors of ribavirin treatment studies and propose a therapeutic scheme for COVID-19.
METHODS PubMed database was searched over a period of five decades utilizing the terms “ribavirin” alone or combined with other compounds in measles, severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 infections. The literature search was performed and described according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles were considered eligible when they reported on ribavirin dose regimens and/or specified outcomes concerning its efficacy and/or possible adverse-effects. In vitro and animal studies were also retrieved. A chapter on ribavirin’s pharmacology was included as well.
RESULTS In addition to the difficulties and pressures of an emerging pandemic, there is the burden of designing and conducting well-organized, double-blind, randomized controlled trials. Many studies have succumbed to specific pitfalls, one of which was identified in naturally ribavirin-resistant Vero cell lines in in vitro studies. Other pitfalls include study design inconsistent with the well-established clinical course of disease; inappropriate pharmacology of applied treatments; and the misinterpretation of study results with misconceived generalizations. A comprehensive treatment for COVID-19 is proposed, documented by thorough, long-term investigation of ribavirin regimens in coronavirus infections.
CONCLUSION A comprehensive treatment strictly tailored to distinct disease stages was proposed based upon studies on ribavirin and coronavirus infections.
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Affiliation(s)
- George D Liatsos
- Department of Internal Medicine, "Hippokration" General Hospital, Athens 11527, Attiki, Greece
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Wang D, Chen L, Wang L, Hua F, Li J, Li Y, Zhang Y, Fan H, Li W, Clarke M. Abstracts for reports of randomised trials of COVID-19 interventions had low quality and high spin. J Clin Epidemiol 2021; 139:107-120. [PMID: 34224834 PMCID: PMC8253697 DOI: 10.1016/j.jclinepi.2021.06.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/22/2021] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To assess the reporting quality of abstracts for published randomized controlled trials (RCTs) of interventions for coronavirus disease 2019 (COVID-19), including the use of spin strategies and the level of spin for RCTs with statistically non-significant primary outcomes, and to explore potential predictors for reporting quality and the severity of spin. STUDY DESIGN AND SETTING PubMed was searched to find RCTs that tested interventions for COVID-19, and the reporting quality and spin in the abstracts were assessed. Linear regression analyses were used to identify potential predictors. RESULTS Forty RCT abstracts were included in our assessment of reporting quality, and a higher word count in the abstract was significantly correlated with higher reporting scores (95% CI 0.044 to 0.658, P=0.026). Multiple spin strategies were identified. Our multivariate analyses showed that geographical origin was associated with severity of spin, with research from non-Asian regions containing fewer spin strategies (95% CI -0.760 to -0.099, P=0.013). CONCLUSIONS The reporting quality of abstracts of RCTs of interventions for COVID-19 is far from satisfactory. A relatively high proportion of the abstracts contained spin, and the findings reported in the results and conclusion sections of these abstracts need to be interpreted with caution.
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Affiliation(s)
- Dongguang Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China
| | - Lingmin Chen
- Department of Anesthesiology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University & The Research Units of West China (2018RU012, Chinese Academy of Medical Sciences), Chengdu, China
| | - Lian Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China
| | - Fang Hua
- Center for Evidenced-Based Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Cochrane Oral Health, Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center, Manchester, UK
| | - Juan Li
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuxi Li
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yonggang Zhang
- Department of Periodical Press, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China.
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China.
| | - Mike Clarke
- Northern Ireland Clinical Trials Unit and Methodology Hub, Centre for Public Health, Queen's University Belfast, Belfast, UK.
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Zhao MZ, Zhao C, Tu SS, Wei XX, Shang HC. Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials. JOURNAL OF INTEGRATIVE MEDICINE 2021; 19:317-326. [PMID: 33789839 PMCID: PMC7970417 DOI: 10.1016/j.joim.2021.03.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 02/22/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND The therapeutic evidence collected from well-designed studies is needed to help manage the global pandemic of the coronavirus disease 2019 (COVID-19). Evaluating the quality of therapeutic data collected during this most recent pandemic is important for improving future clinical research under similar circumstances. OBJECTIVE To assess the methodological quality and variability in implementation of randomized controlled trials (RCTs) for treating COVID-19, and to analyze the support that should be provided to improve data collected during an urgent pandemic situation. SEARCH STRATEGY PubMed, Excerpta Medica Database, China National Knowledge Infrastructure, Wanfang, and Chongqing VIP, and the preprint repositories including Social Science Research Network and MedRxiv were systematically searched, up to September 30, 2020, using the keywords "coronavirus disease 2019 (COVID-19)," "2019 novel coronavirus (2019-nCoV)," "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)," "novel coronavirus pneumonia (NCP)," "randomized controlled trial (RCT)" and "random." INCLUSION CRITERIA RCTs studying the treatment of COVID-19 were eligible for inclusion. DATA EXTRACTION AND ANALYSIS Screening of published RCTs for inclusion and data extraction were each conducted by two researchers. Analysis of general information on COVID-19 RCTs was done using descriptive statistics. Methodological quality was assessed using the risk-of-bias tools in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Variability in implementation was assessed by comparing consistency between RCT reports and registration information. RESULTS A total of 5886 COVID-19 RCTs were identified. Eighty-one RCTs were finally included, of which, 45 had registration information. Methodological quality of the RTCs was not optimal due to deficiencies in five main domains: allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Comparisons of consistency between published protocols and registration information showed that the 45 RCTs with registration information had common deviations in seven items: inclusion and exclusion criteria, sample size, outcomes, research sites of recruitment, interventions, and blinding. CONCLUSION The methodological quality of COVID-19 RCTs conducted in early to mid 2020 was consistently low and variability in implementation was common. More support for implementing high-quality methodology is needed to obtain the quality of therapeutic evidence needed to provide positive guidance for clinical care. We make an urgent appeal for accelerating the construction of a collaborative sharing platform and preparing multidisciplinary talent and professional teams to conduct excellent clinical research when faced with epidemic diseases of the future. Further, variability in RCT implementation should be clearly reported and interpreted to improve the utility of data resulting from those trials.
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Affiliation(s)
- Meng-Zhu Zhao
- Department of Cardiology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Chen Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shuang-Shuang Tu
- Editorial Department of Journals, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xu-Xu Wei
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Hong-Cai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China; International Evidence-based Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
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Khan S, Attar F, Bloukh SH, Sharifi M, Nabi F, Bai Q, Khan RH, Falahati M. A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase. Int J Biol Macromol 2021; 181:605-611. [PMID: 33766591 PMCID: PMC7982646 DOI: 10.1016/j.ijbiomac.2021.03.112] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/19/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
The outbreaks of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in 2019, have highlighted the concerns about the lack of potential vaccines or antivirals approved for inhibition of CoVs infection. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) which is almost preserved across different viral species can be a potential target for development of antiviral drugs, including nucleoside analogues (NA). However, ExoN proofreading activity of CoVs leads to their protection from several NAs. Therefore, potential platforms based on the development of efficient NAs with broad-spectrum efficacy against human CoVs should be explored. This study was then aimed to present an overview on the development of NAs-based drug repurposing for targeting SARS-CoV-2 RdRp by computational analysis. Afterwards, the clinical development of some NAs including Favipiravir, Sofosbuvir, Ribavirin, Tenofovir, and Remdesivir as potential inhibitors of RdRp, were surveyed. Overall, exploring broad-spectrum NAs as promising inhibitors of RdRp may provide useful information about the identification of potential antiviral repurposed drugs against SARS-CoV-2.
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Affiliation(s)
- Suliman Khan
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Farnoosh Attar
- Department of Food Toxicology, Research Center of Food Technology and Agricultural Products, Standard Research Institute (SRI), Karaj, Iran
| | - Samir Haj Bloukh
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, PO Box 346, Ajman, United Arab Emirates; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Majid Sharifi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Faisal Nabi
- Biotechnology Unit, Aligarh Muslim University, India
| | - Qian Bai
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
| | | | - Mojtaba Falahati
- Department of Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Bassetti M, Corcione S, Dettori S, Lombardi A, Lupia T, Vena A, De Rosa FG, Gori A, Giacobbe DR. Antiviral treatment selection for SARS-CoV-2 pneumonia. Expert Rev Respir Med 2021; 15:985-992. [PMID: 33962524 PMCID: PMC8146295 DOI: 10.1080/17476348.2021.1927719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Therapy of coronavirus disease 2019 (COVID-19) involves evolving algorithms that include drugs aimed at reducing disease progression by counteracting two different, but intertwined processes: (i) the damage caused by the virus (with antivirals); (ii) the damage caused by a dysregulated host response (with immunomodulatory agents). AREAS COVERED Herein, we discuss the available evidence on the efficacy and safety of antiviral agents employed over the past months for the treatment of COVID-19, and the reasons to be considered for antiviral selection. EXPERT OPINION The available evidence from randomized controlled trials (RCT) currently discourages the use of lopinavir/ritonavir, hydroxychloroquine, and interferons, which did not show improved efficacy compared to standard care or placebo. Regarding remdesivir, the current body of evidence may conditionally support its use in COVID-19 patients requiring oxygen supplementation but still not requiring invasive mechanical ventilation. Finally, neutralizing monoclonal antibodies have been proven efficacious in reducing the risk of severe disease development if administered early in the course of the disease to patients at risk of progression. The results of the ongoing RCT will certainly be crucial to further improve our understanding of the optimal place in therapy of antiviral agents for COVID-19.
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Affiliation(s)
- Matteo Bassetti
- Department of Health Sciences, University of Genoa, Genoa, Italy.,Clinica Malattie Infettive, San Martino Policlinico Hospital - IRCCS, Genoa, Italy
| | - Silvia Corcione
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Silvia Dettori
- Department of Health Sciences, University of Genoa, Genoa, Italy.,Clinica Malattie Infettive, San Martino Policlinico Hospital - IRCCS, Genoa, Italy
| | - Andrea Lombardi
- Infectious Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Tommaso Lupia
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Antonio Vena
- Clinica Malattie Infettive, San Martino Policlinico Hospital - IRCCS, Genoa, Italy
| | - Francesco Giuseppe De Rosa
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Andrea Gori
- Infectious Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy
| | - Daniele Roberto Giacobbe
- Department of Health Sciences, University of Genoa, Genoa, Italy.,Clinica Malattie Infettive, San Martino Policlinico Hospital - IRCCS, Genoa, Italy
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Mongia A, Saha SK, Chouzenoux E, Majumdar A. A computational approach to aid clinicians in selecting anti-viral drugs for COVID-19 trials. Sci Rep 2021; 11:9047. [PMID: 33907209 PMCID: PMC8079380 DOI: 10.1038/s41598-021-88153-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 04/01/2021] [Indexed: 02/02/2023] Open
Abstract
The year 2020 witnessed a heavy death toll due to COVID-19, calling for a global emergency. The continuous ongoing research and clinical trials paved the way for vaccines. But, the vaccine efficacy in the long run is still questionable due to the mutating coronavirus, which makes drug re-positioning a reasonable alternative. COVID-19 has hence fast-paced drug re-positioning for the treatment of COVID-19 and its symptoms. This work builds computational models using matrix completion techniques to predict drug-virus association for drug re-positioning. The aim is to assist clinicians with a tool for selecting prospective antiviral treatments. Since the virus is known to mutate fast, the tool is likely to help clinicians in selecting the right set of antivirals for the mutated isolate. The main contribution of this work is a manually curated database publicly shared, comprising of existing associations between viruses and their corresponding antivirals. The database gathers similarity information using the chemical structure of drugs and the genomic structure of viruses. Along with this database, we make available a set of state-of-the-art computational drug re-positioning tools based on matrix completion. The tools are first analysed on a standard set of experimental protocols for drug target interactions. The best performing ones are applied for the task of re-positioning antivirals for COVID-19. These tools select six drugs out of which four are currently under various stages of trial, namely Remdesivir (as a cure), Ribavarin (in combination with others for cure), Umifenovir (as a prophylactic and cure) and Sofosbuvir (as a cure). Another unanimous prediction is Tenofovir alafenamide, which is a novel Tenofovir prodrug developed in order to improve renal safety when compared to its original counterpart (older version) Tenofovir disoproxil. Both are under trail, the former as a cure and the latter as a prophylactic. These results establish that the computational methods are in sync with the state-of-practice. We also demonstrate how the drugs to be used against the virus would vary as SARS-Cov-2 mutates over time by predicting the drugs for the mutated strains, suggesting the importance of such a tool in drug prediction. We believe this work would open up possibilities for applying machine learning models to clinical research for drug-virus association prediction and other similar biological problems.
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Affiliation(s)
| | - Sanjay Kr Saha
- Department of Community Medicine, IPGMER Kolkata, Kolkata, India
| | - Emilie Chouzenoux
- CVN, Inria Saclay, University of Paris Saclay, 91190, Gif-sur-Yvette, France.
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Qiu R, Li J, Xiao Y, Gao Z, Weng Y, Zhang Q, Wang C, Gong H, Li W. The therapeutic effect and safety of the drugs for COVID-19: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25532. [PMID: 33879694 PMCID: PMC8078467 DOI: 10.1097/md.0000000000025532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) has spread almost all regions of the world and caused great loss to the whole body of mankind. Thus, numerous clinical trials were conducted to find specific medicine for COVID-19 recently. However, it remains unanswered whether they are beneficial. OBJECTIVE This study aimed to evaluate the efficiency and safety of the COVID-19 medicine. METHODS Studies were determined through searching PubMed, Embase, Cochrane Library, and Medline. The studies of COVID-19 medicine were involved with eligible end points containing mortality, discharge rate, rate of clinical improvement, and rate of serious adverse events. RESULTS A total of 33 studies involving 37,879 patients were included in our study, whose intervening measures contained three major types of COVID-19 medicine, ACEI/ARB, antiviral medicine, and chloroquine/hydroxychloroquine. Compared to control group, COVID-19 drugs have no distinct effect on mortality (RR, 0.93; 95% CI, 0.79-1.11, P = .43) and discharge rate (RR, 1.06; 95% CI, 0.98-1.14, P = .13). However, antiviral medicine presents the obvious advantage in clinical improvement (RR, 1.11; 95% CI, 1.01-1.23, P < .05). In addition, the serious adverse events rate (RR, 0.75; 95% CI, 0.63-0.88, P < .05) of COVID-19 medicine is lower than control group. CONCLUSION The results indicated antiviral medicine was potential specific medicine for COVID-19 treatment by improving clinical symptoms, but it failed to increase the discharge rate and reduce mortality. Chloroquine/hydroxychloroquine and ACEI/ARB had no significant effect on treatment of COVID-19, thus they were not recommended for routine medication. Moreover, more trials are needed to find effective drugs to lower the mortality of COVID-19 patients.
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Affiliation(s)
- Rong Qiu
- Department of Respiratory and Critical Care Medicine
| | - Jingwei Li
- Department of Respiratory and Critical Care Medicine
- West China Medical School/West China Hospital
| | | | - Ziyi Gao
- West China Medical School/West China Hospital
| | | | - Qiran Zhang
- West China Medical School/West China Hospital
| | - Chengdi Wang
- Department of Respiratory and Critical Care Medicine
| | - Hanlin Gong
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine
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