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      Repurposed Therapeutic Agents Targeting the Ebola Virus: A Systematic Review

      , 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 references 67

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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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            Drug development for neglected diseases: a deficient market and a public-health policy failure.

            There is a lack of effective, safe, and affordable pharmaceuticals to control infectious diseases that cause high mortality and morbidity among poor people in the developing world. We analysed outcomes of pharmaceutical research and development over the past 25 years, and reviewed current public and private initiatives aimed at correcting the imbalance in research and development that leaves diseases that occur predominantly in the developing world largely unaddressed. We compiled data by searches of Medline and databases of the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, and reviewed current public and private initiatives through an analysis of recently published studies. We found that, of 1393 new chemical entities marketed between 1975 and 1999, only 16 were for tropical diseases and tuberculosis. There is a 13-fold greater chance of a drug being brought to market for central-nervous-system disorders or cancer than for a neglected disease. The pharmaceutical industry argues that research and development is too costly and risky to invest in low-return neglected diseases, and public and private initiatives have tried to overcome this market limitation through incentive packages and public-private partnerships. The lack of drug research and development for "non-profitable" infectious diseases will require new strategies. No sustainable solution will result for diseases that predominantly affect poor people in the South without the establishment of an international pharmaceutical policy for all neglected diseases. Private-sector research obligations should be explored, and a public-sector not-for-profit research and development capacity promoted.
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              Passive antibody therapy for infectious diseases.

              Antibody-based therapies are currently undergoing a renaissance. After being developed and then largely abandoned in the twentieth century, many antibody preparations are now in clinical use. However, most of the reagents that are available target non-infectious diseases. Interest in using antibodies to treat infectious diseases is now being fuelled by the wide dissemination of drug-resistant microorganisms, the emergence of new microorganisms, the relative inefficacy of antimicrobial drugs in immunocompromised hosts and the fact that antibody-based therapies are the only means to provide immediate immunity against biological weapons. Given the need for new antimicrobial therapies and many recent technological advances in the field of immunoglobulin research, there is considerable optimism regarding renewed applications of antibody-based therapy for the prevention and treatment of infectious diseases.
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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
                © 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/).

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                chemoembolization, hepatic tumor, liver abscess

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