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      Repurposed Therapeutic Agents Targeting the Ebola Virus: A Systematic Review

      research-article
      , MD, MSc, FACS 1 , 2 , * , , MSc, PhD 3 , 4 , , MHE 5 , , MPP, MSc, PhD 1 , 3 , 6
      Current Therapeutic Research, Clinical and Experimental
      Elsevier
      chemoembolization, hepatic tumor, liver abscess

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          Abstract

          Background

          The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD.

          Objective

          We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy.

          Methods

          We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial.

          Results

          We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence.

          Conclusions

          Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.

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          Most cited references67

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          SYRCLE’s risk of bias tool for animal studies

          Background Systematic Reviews (SRs) of experimental animal studies are not yet common practice, but awareness of the merits of conducting such SRs is steadily increasing. As animal intervention studies differ from randomized clinical trials (RCT) in many aspects, the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies. The Cochrane Collaboration developed a Risk of Bias (RoB) tool to establish consistency and avoid discrepancies in assessing the methodological quality of RCTs. A similar initiative is warranted in the field of animal experimentation. Methods We provide an RoB tool for animal intervention studies (SYRCLE’s RoB tool). This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies. To enhance transparency and applicability, we formulated signalling questions to facilitate judgment. Results The resulting RoB tool for animal studies contains 10 entries. These entries are related to selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. Half these items are in agreement with the items in the Cochrane RoB tool. Most of the variations between the two tools are due to differences in design between RCTs and animal studies. Shortcomings in, or unfamiliarity with, specific aspects of experimental design of animal studies compared to clinical studies also play a role. Conclusions SYRCLE’s RoB tool is an adapted version of the Cochrane RoB tool. Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies. This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the methodological quality of animal studies.
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            Are animal models predictive for humans?

            It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics.
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              Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.

              Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are associated with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide derivative T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4log units with an IC90 of 110μM. Mice lacking the type I interferon receptor (IFNAR(-)(/)(-)) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochemical parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Curr Ther Res Clin Exp
                Curr Ther Res Clin Exp
                Current Therapeutic Research, Clinical and Experimental
                Elsevier
                0011-393X
                1879-0313
                02 February 2017
                2017
                02 February 2017
                : 84
                : 10-21
                Affiliations
                [1 ]Institute of Health Services Research and Health Economics, School of Medicine, Heinrich-Heine University Dû¥sseldorf, Dû¥sseldorf, Germany
                [2 ]Surgical Department, Klinikum Frankfurt HûÑchst, Frankfurt, Germany
                [3 ]Cooperative Research Group for Evidence-Based Public Health, Department of Prevention and Evaluation, Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany
                [4 ]Department of Clinical Pharmacy and Pharmacy Management, Nnamdi Azikiwe University, Awka, Nigeria
                [5 ]Department for Evidence-based Health Services Research, Institute for Research in Operative Medicine, Witten/Herdecke University, Witten, Germany
                [6 ]Institute for Public Health, Health Sciences Bremen, University of Bremen, Bremen, Germany
                Author notes
                [* ]Address correspondence to: Hussein Sweiti, Heinrich-Heine University Du¨sseldorf, Institute of Health Services Research and Health Economics, School of Medicine, Moorenstr 5, Du¨sseldorf 40225, Germany.Heinrich-Heine University Du¨sseldorf, Institute of Health Services Research and Health Economics, School of Medicine, Moorenstr 5Du¨sseldorf40225Germany hussein.sweiti@ 123456uni-duesseldorf.de
                Article
                S0011-393X(16)30122-9
                10.1016/j.curtheres.2017.01.007
                5522984
                28761574
                b1ea0887-bf67-4b72-ab04-4fceec61a8e7
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 30 January 2017
                Categories
                Article

                chemoembolization,hepatic tumor,liver abscess
                chemoembolization, hepatic tumor, liver abscess

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