Is ivermectin–Azithromycin combination the next step for COVID-19?

Hayder Mutter Al-Kuraishy; Nawar Raad Hussien; Marwa Salih Al-Naimi; Ali Kadhem Al-Buhadily; Ali Ismail Al-Gareeb; Claire Lungnier

doi:10.4103/bbrj.bbrj_109_20

BRIEF REPORT

Year : 2020 | Volume : 4 | Issue : 5 | Page : 101-103

Is ivermectin–Azithromycin combination the next step for COVID-19?

Hayder Mutter Al-Kuraishy¹, Nawar Raad Hussien¹, Marwa Salih Al-Naimi¹, Ali Kadhem Al-Buhadily¹, Ali Ismail Al-Gareeb¹, Claire Lungnier²
¹ Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
² Department EA 3072 “Mitochondria, Oxidative Stress and Muscular Protection”, Institute of Physiology, Faculty of Medicine, Strasbourg Cedex, France

Date of Submission	28-Jun-2020
Date of Acceptance	10-Jul-2020
Date of Web Publication	13-Aug-2020

Correspondence Address:
Prof. Hayder Mutter Al-Kuraishy
Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty College of Medicine, Al-Mustansiriya University, P.O. Box 14132, Baghdad
Iraq

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_109_20

Abstract

Different experimental and approved drugs were tested for coronavirus infection disease (COVID-19) to detect effective one that attenuates or prevents the pathogenesis of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Repurposing of old approved drugs with the potential arrhythmogenic effect such as chloroquine in COVID-19 may increase the risk of sudden cardiac death due to torsadogenic potential. The Food and Drug Administration approved the drugs, such as ivermectin, which can kill SARS-CoV-2 within 48 h. Azithromycin augments the antiviral activity of chloroquine in COVID-19 with a high risk of morbidity and mortality through torsadogenic potential. There were no obvious interactions between ivermectin and azithromycin and without risk of torsadogenic effect despite the prolongation of QT by azithromycin. Therefore, azithromycin–ivermectin is regarded as an effectual combo for COVID-19 in elderly patients with underlying cardiac abnormalities.

Keywords: Azithromycin, chloroquine, COVID-19, ivermectin, severe acute respiratory syndrome coronavirus type 2, torsadogenic potential

How to cite this article:
Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Is ivermectin–Azithromycin combination the next step for COVID-19?. Biomed Biotechnol Res J 2020;4, Suppl S1:101-3

How to cite this URL:
Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Is ivermectin–Azithromycin combination the next step for COVID-19?. Biomed Biotechnol Res J [serial online] 2020 [cited 2023 Mar 27];4, Suppl S1:101-3. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/101/292072

Introduction

Coronavirus infection disease (COVID-19) is an infectious disease caused by a novel coronavirus (nCoV-19), which also called severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).^[1] Coronavirus (CoV) is an enveloped positive-sense, single-strand RNA virus. The imperative proteins in the structure of CoV are membrane protein, spike protein, and nucleocapsid protein, which involved in the viral pathogenesis, and development of COVID-19 [Figure 1].^[2] The SARS-CoV-2 genome is 96% similar to that of bat CoV; hence, spike glycoprotein (S protein) and receptor-binding domain of both SARS-CoV-2 and bat CoV bind angiotensin-converting enzyme 2 (ACE2), which might explain the cross-species transmission.^[3]

Figure 1: Structure of severe acute respiratory syndrome coronavirus type 2

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Different experimental and approved drugs were tested for COVID-19 to detect an effective one which may attenuates or prevents the pathogenesis of SARS-CoV-2. Chloroquine is an antimalarial drug that has been recently approved with precautions by the Food and Drug Administration (FDA).^[4] However, chloroquine may cause potentially severe adverse effects, including allergic reactions, ocular and labyrinth disorders, and immunological complications. Giudicessi et al. found that repurposing of old approved drugs with a potential arrhythmogenic effect such as chloroquine or ritonavir in COVID-19 may increase the risk of sudden cardiac death due to torsadogenic potential.^[5] As well, SARS-CoV-2 itself or SARS-CoV-2-induced inflammatory changes may cause cardiac damages with prolongation of QT interval.^[6] Hence, uses of chloroquine in COVID-19 mainly in elderly or younger patients with underlying inherited or acquired arrhythmogenic causes may increase the morbidity and mortality through torsadogenic potential. Therefore, other clinical trials are in a continuous way like China Clinical Trial Registry, which has 218 clinical trials registered on the platform since March 9, 2020 (http://www.chictr.org.cn).^[7] Thereby, it is from wise to find an effective and marginally safe drug, with little cardiac adverse effects in the management of COVID-19 mainly in elderly patients.

Recently, an Australian Scientist from Monash University in Melbourn has shown that FDA-approved drugs, such as ivermectin [Figure 2], can kill SARS-CoV-2 within 48 h and reduces viral RNA-polymerase and DNA by 99.8% within 24 h in cell lines.^[8]

Figure 2: Chemical structure of ivermectin

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Ivermectin is an antiparasitic drug used in humans and animals since 1988 and has the capability to target exophilic and exophagic vectors, with different modes of actions.^[9] Ivermectin has antiviral activity for both RNA and DNA viruses, so it is effective against dengue fever, influenza, yellow fever, and flaviviruses.^[10]

It has been shown that the anti-SARS-CoV-2 of ivermectin is likely through inhibition of viral IMPα/β1-mediated nuclear import, which reduces viral replication and load in the infected cells. Thereby, a single dose of ivermectin is able to limit person–person transmission of SARS-CoV-2.^[8] As well, ivermectin inhibits nuclear transporter protein called cargo transporter, which is essential for the transport of SARS-CoV-2 from the cytoplasm to the nucleus. Besides, ivermectin can dissociate the performed IMPα/β1 heterodimer and prevent its production via binding of IMPα armadillo repeat domain, which prevents the stability of α-helicity [Figure 3].^[8],[11]

Figure 3: Anti-severe acute respiratory syndrome coronavirus type 2 effect of ivermectin

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In general, the antiviral potential of ivermectin therapy is related to different cellular pathways, including the suppression of viral RNA synthesis, viral protein expression, and progeny of virus production, which might be the applicable mechanisms for ivermectin against SARS-CoV-2 [Figure 4].^[12]

Figure 4: Anti-severe acute respiratory syndrome coronavirus type 2 effect of azithromycin

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On the other hand, Yan et al. found that ivermectin had a potent anti-inflammatory effect in allergic asthma,^[13] so it may play an integral role in the attenuation of COVID-19-induced cytokine storm and hyperinflammation.^[14] Apart from neurotoxicity and central nervous system depression, ivermectin is a safe drug and does not affect cardiac conductivity even in elder patients.^[15]

Alongside, azithromycin is a broad-spectrum antibiotic with noteworthy anti-inflammatory and immune modulator effects.^[16] Different preclinical and clinical studies have shown that azithromycin inhibits cytokine release, attenuating the inflammatory response, and improves immunoglobulin response.^[17] Gautret et al. established that azithromycin augments the activity of chloroquine in COVID-19.^[18] However, azithromycin alone may be an effective drug in the management of initial COVID-19 due to its antiviral and anti-inflammatory activity.^[19]

The antiviral activity of azithromycin is linked to diverse mechanisms, including structural and functional lysosomal damage of the infected cells, inhibition of lysosomal protease, which mediates the binding of SARS-CoV-2, and modulation of ACE2 receptors (entry point of SARS-Cov2).^{[20],[21],[22]}

Regarding the cardiac safety of azithromycin, in 2012, the New England Journal of Medicine published a study which found that azithromycin was linked with arrhythmias and cardiac death due to prolongation of QT interval.^[23] However, Mortensen et al.'s study involving 70,000 hospitalized patients with pneumonia showed that treatment with azithromycin lowers 90-day mortality without risk of arrhythmias.^[24]

Therefore, both azithromycin and ivermectin possess significant anti-SARS-CoV-2, anti-inflammatory, and immune modulator effects with no significant arrhythmogenic or torsadogenic potential effects such chloroquine–azithromycin combination. Herein, azithromycin–ivermectin is regarded as an effectual combo for COVID-19 in elderly patients with underlying cardiac abnormalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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