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Therapeutic potential of ivermectin for COVID-19 · PDF file 2020. 5. 26. · The literature suggests the use of ivermectin as a potential drug for combatting COVID-19. Ivermectin

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    Therapeutic potential of ivermectin for COVID-19

    Kalyne Gonçalves1, Amanda Vasconcelos2, Davi Barbirato1, César Vasconcelos2, and Belmiro Vasconcelos1

    1University of Pernambuco 2Federal University of Pernambuco

    May 26, 2020

    Abstract

    Background The aim of the present theoretical essay is to evaluate evidence published on the characteristics of the transcription of SARS-CoV-2 and explain the mechanism of action of ivermectin that may justify its therapeutic use in clinical practice for the treatment of COVID-19. Methods Laboratory studies, narratives, editorials and expert opinions on the subject were identified through a systematic search of the literature in the Medline/PubMed, Cochrane Library, Web of Science and Embase databases. Two blinded, independent reviewers selected studies published up to May 17, 2020 based on the eligibility criteria. Results The search of the databases led to the retrieval of 25 articles. After the different phases of the selection process, eight articles were included in the present review for the extraction of relevant data. The results suggest that ivermectin inhibits the viral replication of SARS-CoV-2 through the action of the hypoxia-inducible factor (HIF-1α) and consequent destabilization of importin α/β1 proteins. Conclusions Ivermectin inhibits the viral replication of SARS-CoV-2. Laboratory and clinical studies

    are needed to provide more evidence in terms of the best posology and possible associations with other drugs for combatting

    COVID-19.

    Therapeutic potential of ivermectin for COVID-19

    Kalyne Kelly Negromonte Gonçalvesa (D.D.S.), Amanda Freire de Melo Vasconcelosb (D.D.S.), Davi da Silva Barbiratoa (Ph.D.), César Freire de Melo Vasconcelosc (M.Sc.), Belmiro Cavalcanti do Egito Vasconcelosa

    (Ph.D.).

    aDivision of Oral and Maxillofacial Surgery, University of Pernambuco, Recife–PE, Brazil.

    bDepartment of Clinical and Preventive Dentistry, Federal University of Pernambuco, Recife–PE, Brazil.

    cPostgraduate Department in Surgery, Federal University of Pernambuco, Recife–PE, Brazil.

    dDepartment of Clinical and Preventive Dentistry, Federal University of Pernambuco, Recife–PE, Brazil.

    Corresponding author:

    Dr. Belmiro Cavalcanti do Egito Vasconcelos.

    Division of Oral and Maxillofacial Surgery, Dental School, University of Pernambuco, Arnóbio Marques St., 310, Recife, PE, Zip code 50100-130, Phone number +55 81 3184-1468, E-mail: [email protected]

    BRIEF DESCRIPTION

    What is already known about this subject

    We already know how some viruses replicate, as well as the mechanism of action of drugs with antiviral potential, such as ivermectin. Its therapeutic potential against SARS-CoV-2 is related to the inhibition or under-regulation of importin α/β1 complex, which results in the control of replication of single-stranded viral

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    RNA in the cell nucleus. The antiviral potential of ivermectin can be enhanced by micronutrients, especially zinc.

    What this study adds

    This study adds the participation of the hypoxia-inducible factor (HIF-1α) in the antiviral mechanism of ac- tion of ivermectin, in addition to responding to reductions in the oxygen available in the cellular environment (common in cases of severe acute respiratory syndrome such as COVID-19). Its modulation can affect viral replication and the cytokine-mediated proinflammatory response, through genetic underexpression in the host cell nucleus. In addition to contributing to a better antiviral response to ivermectin by modulating the importin α/β1-HIF-1α complex, zinc promotes a beneficial immunomodulation for the patient, by reducing the regulation of pro-inflammatory cytokines; Ivermectin + zinc represents a potential therapeutic protocol against COVID-19 to be tested at different stages of the disease.

    ABSTRACT

    Background

    The aim of the present theoretical essay is to evaluate evidence published on the characteristics of the tran- scription of SARS-CoV-2 and explain the mechanism of action of ivermectin that may justify its therapeutic use in clinical practice for the treatment of COVID-19.

    Methods

    Laboratory studies, narratives, editorials and expert opinions on the subject were identified through a sys- tematic search of the literature in the Medline/PubMed, Cochrane Library, Web of Science and Embase databases. Two blinded, independent reviewers selected studies published up to May 17, 2020 based on the eligibility criteria.

    Results

    The search of the databases led to the retrieval of 25 articles. After the different phases of the selection process, eight articles were included in the present review for the extraction of relevant data. The results suggest that ivermectin inhibits the viral replication of SARS-CoV-2 through the action of the hypoxia- inducible factor (HIF-1α) and consequent destabilization of importin α/β1 proteins.

    Conclusions

    Ivermectin inhibits the viral replication of SARS-CoV-2. Laboratory and clinical studies are needed to provide more evidence in terms of the best posology and possible associations with other drugs for combatting COVID-19.

    Keywords: Ivermectin; Coronavirus Infection; Drug Treatment.

    INTRODUCTION

    The new coronavirus (COVID-19), which is also denominated SARS-CoV-2, causes a novel respiratory disease of a viral origin. On December 8th, 2019, the first reports came out of China of patients with severe cases of pneumonia of an unknown origin, but it was only on January 7th, 2020 that COVID-19 was identified by the Chinese Center of Disease Prevention and Control. According to the World Health Organization (WHO), COVID-19 is a public health emergency affecting hundreds of thousands of people throughout the world [1,2].

    No vaccine or specific treatment is yet defined for this new coronavirus and there is an urgent need to find a therapeutic resource that can impede or at least control the replication of this virus [3]. Antiviral drugs are being studied to assist in combatting COVID-19, as antivirals inactivate enzymes that activate glycoproteins, thereby impeding the penetration of the virus in human cells [4].

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    The literature suggests the use of ivermectin as a potential drug for combatting COVID-19. Ivermectin is a broad-spectrum antiparasitic agent used in veterinary medicine and approved by the Food and Drug Administration (FDA) for use in humans [5]. This drug is used for the control of onchocerciasis and filariasis as well as the treatment of mange and lice [6]. Ivermectin has also been evaluated in clinical trials for the control of malaria as well as in vitro studies for the control of dengue, yellow fever and the zika virus. Ivermectin has also been demonstrated to inhibit the replication of HIV-1 [7,8]

    However, more in-depth knowledge on the mechanism of action of ivermectin is needed to gain a better understanding of its capacity for viral inhibition. SARS-CoV-2 is a positive-chain RNA virus. Due to its pharmacokinetic properties, ivermectin has the capacity to inhibit the bond between a virus and the nuclea