#AVIFAVIR for #Treatment of Patients with #Moderate #COVID19: Interim #Results of a Phase II/III Multicenter #RCT (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial

Andrey A Ivashchenko, Kirill A Dmitriev, Natalia V Vostokova, Valeria N Azarova, Andrew A Blinow, Alina N Egorova, Ivan G Gordeev, Alexey P Ilin, Ruben N Karapetian, Dmitry V Kravchenko, Nikita V Lomakin, Elena A Merkulova, Natalia A Papazova, Elena P Pavlikova, Nikolay P Savchuk, Elena N Simakina, Tagir A Sitdekov, Elena A Smolyarchuk, Elena G Tikhomolova, Elena V Yakubova, Alexandre V Ivachtchenko

Clinical Infectious Diseases, ciaa1176, https://doi.org/10.1093/cid/ciaa1176

Published: 09 August 2020

 

Abstract

In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the pilot stage of Phase II/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days, and was safe and well-tolerated.

AVIFAVIR, favipiravir, COVID-19, SARS-CoV-2

Issue Section: Brief Report

This content is only available as a PDF.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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Effect of #favipiravir and an anti-inflammatory strategy for #COVID19 (Crit Care, summary)

[Source: Critical Care, full page: (LINK). Summary, edited.]

Effect of favipiravir and an anti-inflammatory strategy for COVID-19

Hitoshi Yamamura, Hiroshi Matsuura, Junichiro Nakagawa, Hiroshi Fukuoka, Hisaya Domi & Satoru Chujoh

Critical Care volume 24, Article number: 413 (2020)

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Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the ribonucleic acid (RNA)-dependent RNA polymerase of RNA viruses [1]. In Japan, it is approved for use with novel influenza virus and is thought to be an effective drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus disease 2019 (COVID-19) presents a complex pathology including inflammation, endothelial damage, thrombus formation, and acute respiratory failure [2,3,4] This syndrome requires complex treatment to reduce viral genome amounts, anti-inflammatory drugs, and anticoagulation. We attempted the cocktail treatment of favipiravir, steroid, and heparin for COVID-19. This study aimed to evaluate the effect of cocktail therapy for severe COVID-19.

(…)

Keywords: SARS-CoV-2; COVID-19; Cytokines; Antivirals; Favipiravir.

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#Nafamostat mesylate #treatment in combination with #favipiravir for patients critically ill with #Covid19: a case series (Crit Care, summary)

[Source: Critical Care, full page: (LINK). Summary, edited.]

Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series

Kent Doi, Mahoko Ikeda, Naoki Hayase, Kyoji Moriya, Naoto Morimura & the COVID-UTH Study Group

Critical Care volume 24, Article number: 392 (2020)

___

Development of specific therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently required. Several drugs such as antimalarial and anti-Ebola virus drugs are under investigation for coronavirus disease 2019 (Covid-19). Transmembrane protease serine 2 (TMPRSS2) plays a crucial role for SARS-CoV-2 entry into the cytoplasm [1]. Inhibition of TMPRSS2 protease activity is assumed to prohibit viral entry of SARS-CoV-2. Through high-throughput screening of 1017 existing drugs, a clinically available serine protease inhibitor nafamostat mesylate was identified as a potent inhibitor of Middle East respiratory syndrome coronavirus entry into human epithelial cells [2]. More recently, nafamostat mesylate was shown to inhibit the entry of SARS-CoV-2 into the human epithelial cells at EC50 of ~ 10 nM [3, 4]. Nafamostat mesylate has been clinically used for the treatment of acute pancreatitis and disseminated intravascular coagulation in Japan. By intravenous administration, its blood concentrations are maintained at 30–240 nM, which are sufficient to block the virus entry [3]. An anti-influenza A H1N1 virus drug favipiravir exhibits antiviral activity against other RNA viruses and therefore is expected to have antiviral action against SARS-CoV-2. This drug has been approved in Japan for novel influenza virus disease.

(…)

Keywords: SARS-CoV-2; COVID-19; Antivirals; Nafamostat; Favipiravir; Japan.

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#Clinical #trials of repurposed #antivirals for #SARS-CoV-2 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Clinical trials of repurposed antivirals for SARS-CoV-2

Miguel Angel Martinez

DOI: 10.1128/AAC.01101-20

 

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir/ritonavir, ribavirin, interferons, and hydroxychloroquine. Unfortunately, the first open-label, randomized controlled trials are showing the poor efficacy of these repurposed drugs. These results highlight the necessity of identifying and characterizing specific and potent SARS-CoV-2 antivirals.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Chloroquine; Lopinavir/Ritonavir; Ribavirin; Favipiravir; Remdesivir.

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In vitro inhibition of #mumps virus #replication by #Favipiravir (T-705) (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 14 June 2020, 104849 | In Press, Journal Pre-proof

In vitro inhibition of mumps virus replication by Favipiravir (T-705)

Benton Lawson, Suganthi Suppiah, Paul A. Rota, Carole J. Hickman, Donald R. Latner, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases,  Centers for Disease Control and Prevention, Atlanta, GA, USA

Received 10 March 2020, Revised 21 May 2020, Accepted 4 June 2020, Available online 14 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104849

 

Highlights

  • Favipiravir inhibits the growth of wildtype and vaccine strains of mumps virus in vitro at low micro-molar concentration.
  • Favipiravir inhibits viral growth by significantly reducing viral ribonucleic acid (RNA) and protein production.
  • We did not observe the development of resistance.

 

Abstract

During the last decade multiple mumps outbreaks have occurred in the U.S. despite high two dose MMR coverage with most cases detected among two dose MMR vaccine recipients. Waning immunity, the evolution of wild-type virus strains, and settings with intense exposure have contributed to the resurgence of mumps. Typically, mumps virus infections resolve without serious clinical sequelae; however, serious complications may occur among unvaccinated or severely immunocompromised individuals. Favipiravir (T-705) has been shown to have in vitro anti-viral activity against a broad range of positive and negative strand RNA viruses. Here, we demonstrate that T-705 inhibits the growth of wildtype and vaccine strains of mumps virus in vitro at low micro-molar concentrations (EC50 8-10μM). We did not observe the development of resistance after five subsequent passages at low concentrations of drug. Both viral RNA and protein synthesis were selectively reduced compared to host mRNA and protein synthesis. Antiviral treatment options for mumps virus infection may be valuable, especially for areas with a high disease burden or for cases with severe complications. These results presented here suggest that further studies are warranted.

Keywords: Favipiravir – T-705 – mumps – paramyxovirus –  anti-viral – MMR

© 2020 Elsevier B.V. All rights reserved.

Keywords: Mumps; Antivirals; Favipiravir.

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The #Mechanism and #Clinical #Outcome of Patients With #COVID19 Whose Nucleic Acid Test Has Changed From Negative to Positive, and the Therapeutic Efficacy of #Favipiravir: … (Trials, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Trials. 2020 Jun 5;21(1):488. doi: 10.1186/s13063-020-04430-y.

The Mechanism and Clinical Outcome of Patients With Corona Virus Disease 2019 Whose Nucleic Acid Test Has Changed From Negative to Positive, and the Therapeutic Efficacy of Favipiravir: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Jiawen Li 1, Chi Zhang 1, Zhao Wu 1, Guiqiang Wang 2, Hong Zhao 3

Affiliations: 1 Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, China. 2 Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, China. john131212@126.com.  3 Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, China.  haohong_pufh@bjmu.edu.cn.

PMID: 32503657 DOI: 10.1186/s13063-020-04430-y

 

Abstract

Objectives:

A variety of possible mechanisms can make the nucleic acid test of patients who meet the discharge conditions positive again, including reinfection, reactivation of the original virus, lack of strict discharge criteria, new infection, and so on. Different reasons will correspond to different prevention and control measures. We will enroll patients who are discharged after treatment, whose nucleic acid test has changed from negative to positive during the screening visit, regardless of the severity of the symptoms, to investigate the mechanism, clinical outcome and therapeutic efficacy with Favipiravir patients with Corona virus Disease 2019. Favipiravir is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase, it has been used for treatment of some life-threatening infections such as Ebola virus, Lassa virus and rabies. Its therapeutic efficacy has been proven in these diseases.

Trial design:

This is a multi-center, two arm, open label, parallel group, randomized controlled trial.

Participants:

Eligibility criteria:

Inclusion criteria:

1.Adults 18 to 80 years, male or female.

2.After the first diagnosis and treatment of COVID-19, the nucleic acid test of respiratory specimens such as sputum or nasopharyngeal swabs, has been negative for two consecutive times (sampling time interval of at least 24 hours), in accordance with the COVID-19’s diagnosis and treatment Plan (7th Edition), discharged.

3.During screening visit (follow-up after discharge), The nucleic acid test of COVID-19 is positive in any one of the following samples: sputum, throat swabs, blood, feces or other specimens. Regardless of whether or not they had symptoms and the severity of symptoms.

4.Volunteer to participate in the research and sign the Informed Consent Form.

Exclusion criteria:

1.Allergic to Favipiravjr;

2.Pregnant or lactating women

3.Uncontrolled diseases of the blood and cardiovascular system, liver or kidney.

4.History of mental disorders, drug abuse or dependence;

5.Researchers consider it inappropriate for adults to participate;

6.Participating in other clinical studies.

Loss to Follow up:

Cases that do not complete the clinical trial program will be regarded as lost to follow up. Including the withdrawal of patients by themselves (such as poor compliance, etc.), or the withdrawal of patients ordered by the researcher (those who need other drugs which affect the judgment of the curative effect, and those who need to stop taking drugs for severe adverse events)

Study setting: The participating hospitals are some of the designated hospitals that have been or may be admitting patients who meet the eligibility criteria, mainly in Hubei, Shenzhen, Anhui and Beijing. Participants will be recruited from these 15 hospitals: Wuhan Pulmonary Hospital, Hubei; Jinyintan Hospital of Wuhan, Hubei; Ezhou Central Hospital, Hubei; The Second People’s Hospital of Fuyang, Anhui; The First Affiliated Hospital of USTC, Anhui; Beijing Youan Hospital, Beijing; Capital Medical University Beijing Institute of Hepatology, Beijing; Ezhou Hospital of Traditional Chinese Medicine, Hubei; Zhongnan Hospital of Wuhan University, Hubei; The Fifth Hospital of ShiJiazhuang, Hebei; Jinan Infectious Diseases Hospital, Shandong; Public Health Clinical Center of Chengdu, Sichuan; Wuxi No.5 People’s Hospital, Jiangsu; The Third People’s Hospital of Shenzhen, Guangdong; The First Affiliated Hospital of Bengfu Medical College, AnHui.

Intervention and comparator:

Favipiravir group (experimental): Favipiravir 1600mg each dose, twice a day on the 1st day; 600mg each dose, twice a day from the 2nd to the 7th day, Oral administration, the maximum number of days taken will be no more than 14 days plus routine treatment for COVID-19. Regular treatment group (control): Treatments other than Antiviral drugs can be given. Routine treatment for patients with the corona virus will be administered, this includes oxygen therapy, drugs that reduced phlegm and relieve cough, including thymosin, proprietary Chinese medicine, etc.

MAIN OUTCOMES:

Primary Outcome Measures:

Viral nucleic acid test negative [Time Frame: 5 months]: Subjects who tested negative for nucleic acid from sputum or nasopharyngeal swabs for two consecutive times (sampling time interval of at least 24 hours).

Secondary outcome measures:

Clinical cure [Time Frame: 5 months]:

1.Body temperature returned to normal for more than 3 days;

2.Lung image improved.

3.Clinical manifestation improved;

4.The viral nucleic acid test of respiratory specimens was negative for two consecutive times (sampling time interval of at least 24 hours).

Randomization:

The central randomization system (Interactive Web Response Management System), will be used to randomly divide the subjects into the experimental group and the control group according to the ratio of 2:1. In this study, block randomization will be used, in blocks of 6.

Blinding (masking):

This is an open label trial. Trial participants, investigators, care givers, outcome assessors, and date analysts are not blinded to group assignment.

Numbers to be randomised:

210 patients are expected to be enrolled and allocated according to the ratio of 2 (Favipiravir group, n=140): 1(regular treatment group, n=70).

Trial status:

Protocol version number 3.0, 10th April 2020 First Patient, first visit 17th March 2020; recruitment end date anticipated June 1, 2020.

Trial registration: ClinicalTrials.gov, NCT04333589, April 3, 2020. Registered April 3, 2020.

Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Keywords: COVID-19; Favipiravir; Randomised controlled trial; protocol.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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#Pharmacokinetics of #Favipiravir in Critically Ill Patients With #COVID19 (Clin Transl Sci., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Clin Transl Sci. 2020 May 31. doi: 10.1111/cts.12827. Online ahead of print.

Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID-19

Kei Irie 1 2, Atsushi Nakagawa 3, Hirotoshi Fujita 1, Ryo Tamura 1, Masaaki Eto 4, Hiroaki Ikesue 1, Nobuyuki Muroi 1, Keisuke Tomii 3, Tohru Hashida 1

Affiliations: 1 Department of Pharmacy, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan. 2 Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Kobe, 650-8586, Japan. 3 Department of Respiratory Medicine, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan. 4 Department of Clinical laboratory, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan.

PMID: 32475019 DOI: 10.1111/cts.12827

 

Abstract

Since December 2019, a novel coronavirus (SARS-CoV-2) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID-19). The anti-retroviral drug favipiravir (FPV) has been experimentally used for COVID-19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high-performance liquid chromatography in patients with severe COVID-19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1600 mg of FPV twice daily on Day 1, followed by 600 mg twice daily from Day 2 to Day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty-nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8-12 h) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and EC50 (9.7 µg/mL) against SARS-CoV-2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID-19.

Keywords: COVID-19; Favipiravir; SARS-CoV-2.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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#Favipiravir, an #antiviral for #COVID19? (J Antimicrob Chemother., summary)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Favipiravir, an antiviral for COVID-19?

Eric A Coomes, Hourmazd Haghbayan

Journal of Antimicrobial Chemotherapy, dkaa171, https://doi.org/10.1093/jac/dkaa171

Published: 17 May 2020

Issue Section: Research letter

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Sir, A novel coronavirus, SARS-CoV-2, emerged in December 2019 in Wuhan, China, which is spreading far more rapidly than its predecessors, having already infected millions of patients worldwide as of 19 April 2020.1 As the scale of the ongoing COVID-19 outbreak has reached pandemic proportions, intensive worldwide public health efforts are underway to control the outbreak. However, as definitive therapies for established COVID-19 remain to be defined, significant interest exists in repurposing existing antiviral agents for use against COVID-19.

(…)

Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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Rapid #repurposing of #drugs for #COVID19 (Science, summary)

[Source: Science, full page: (LINK). Summary, edited.]

Rapid repurposing of drugs for COVID-19

R. Kiplin Guy1, Robert S. DiPaola2, Frank Romanelli1, Rebecca E. Dutch2

1 College of Pharmacy, University of Kentucky, Lexington, KY, USA. 2 College of Medicine, University of Kentucky, Lexington, KY, USA. Email: kip.guy@uky.edu

Science  08 May 2020: eabb9332 | DOI: 10.1126/science.abb9332

 

Abstract

The emergence of a new coronaviral respiratory disease calls for repurposing existing drugs

___

In late fall 2019, a novel acute respiratory disease, called coronavirus disease 2019 (COVID-19) emerged in Wuhan, China. COVID-19 is caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) (1, 2). COVID-19 has been declared a pandemic by the World Health Organization and continues to spread across the globe. Most patients recover within 1 to 3 weeks. However, a small proportion (~5%) develop severe illness that can progress to acute respiratory distress syndrome (ARDS), which can lead to death. Currently, only supportive care is available; patients would greatly benefit from the availability of direct therapeutic approaches. One approach to identifying therapeutics is to repurpose approved drugs developed for other uses, which takes advantage of existing detailed information on human pharmacology and toxicology to enable rapid clinical trials and regulatory review.

(…)

Keywords: SARS-CoV-2; COVID-19; Antivirals.

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#Candidate #drugs against #SARS-CoV-2 and #COVID19 (Pharmacol Res., abstract)

[Source: Pharmacological Research, full page: (LINK). Abstract, edited.]

Pharmacological Research | Volume 157, July 2020, 104859 | Review

Candidate drugs against SARS-CoV-2 and COVID-19

Dwight L. McKee a, Ariane Sternberg b, Ulrike Stange b, Stefan Laufer c, Cord Naujokat d

a Integrative Cancer Consulting, Aptos, CA, USA; b Center and Network for Targeted Oncology, Muehlackerweg 8, D-69239, Heidelberg, Germany; c Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen and Tuebingen Center for Academic Drug Discovery, Auf Der Morgenstelle 8, 72076, Tuebingen, Germany; d Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120, Heidelberg, Germany

Received 27 March 2020, Revised 20 April 2020, Accepted 22 April 2020, Available online 29 April 2020.

DOI: https://doi.org/10.1016/j.phrs.2020.104859

 

Abstract

Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

Keywords: COVID-19  – SARS-CoV-2 – Drugs – Camostat – Chloroquine – Remdesivir – Lopinavir  – Ritonavir  – Favipiravir – Arbidol – Phytochemicals

Keywords: SARS-CoV-2; COVID-19; Antivirals; Cytokines; Chloroquine; Remdesivir; Favipiravir; Lopinavir; Ritonavir.

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