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 Table of Contents  
BRIEF REPORT
Year : 2020  |  Volume : 4  |  Issue : 5  |  Page : 101-103

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


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 Submission28-Jun-2020
Date of Acceptance10-Jul-2020
Date of Web Publication13-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
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_109_20

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  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 2020 Nov 27];4, Suppl S1:101-3. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/101/292072




  Introduction Top


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.



 
  References Top

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Al-Kuraishy H M, Al-Gareeb A I. From SARS-CoV to nCoV-2019: Ruction and Argument, Arch Clin Infect Dis 2020;15(2):e102624. (In Press) [doi: 10.5812/archcid.102624].  Back to cited text no. 1
    
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Al-Kuraishy HM, Al-Niemi MS, Hussain NR, Al-Gareeb AI, Al-Harchan NA, Al-Kurashi AH. The Potential Role of Renin Angiotensin System (RAS) and Dipeptidyl Peptidase-4 (DPP-4) in COVID-19: Navigating the Uncharted. InSelected Chapters from the Renin-Angiotensin System 2020. IntechOpen.  Back to cited text no. 2
    
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Al-kuraishy HM, Al-Maiahy TJ, Al-Gareeb AI, Musa RA, Ali ZH. COVID-19 pneumonia in an Iraqi pregnant woman with preterm delivery. Asian Pacific Journal of Reproduction 2020;9(3):156.  Back to cited text no. 3
    
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Zhu S, Guo X, Geary K, Zhang D. Emerging therapeutic strategies for COVID-19 patients. Discoveries (Craiova) 2020;8:e105.  Back to cited text no. 4
    
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Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020;95:1213-21.  Back to cited text no. 5
    
6.
Wu CI, Postema PG, Arbelo E, Behr ER, Bezzina CR, Napolitano C, et al. SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes. Heart Rhythm 2020;31:112-19.  Back to cited text no. 6
    
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Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-3.  Back to cited text no. 7
    
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Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA approved drug ivermectin inhibits the replication of SARS-CoV-2in vitro. Antiviral Res 2020;33(2):41-9. Available from: https://doi.org/10.1016/j.antiviral.2020.104787.  Back to cited text no. 8
    
9.
Laing R, Gillan V, Devaney E. Ivermectin-Old drug, new tricks? Trends Parasitol 2017;33:463-72.  Back to cited text no. 9
    
10.
Croci R, Bottaro E, Chan KW, Watanabe S, Pezzullo M, Mastrangelo E, et al. Liposomal systems as nanocarriers for the antiviral agent ivermectin. Int J Biomater 2016;2016:8043983.  Back to cited text no. 10
    
11.
Yang SN, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, Jans DA. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res 2020;22:104760.  Back to cited text no. 11
    
12.
Lee YJ, Lee C. Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages. Arch Virol 2016;161:257-68.  Back to cited text no. 12
    
13.
Yan S, Ci X, Chen N, Chen C, Li X, Chu X, et al. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res 2011;60:589-96.  Back to cited text no. 13
    
14.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.  Back to cited text no. 14
    
15.
Levy M, Martin L, Bursztejn AC, Chiaverini C, Miquel J, Mahé E, et al. Ivermectin safety in infants and children under 15 kg treated for scabies: A multicentric observational study. Br J Dermatol 2020;182:1003-6.  Back to cited text no. 15
    
16.
Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020;395:e30-1.  Back to cited text no. 16
    
17.
Lee N, Wong CK, Chan MC, Yeung ES, Tam WW, Tsang OT, et al. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial. Antiviral Res 2017;144:48-56.  Back to cited text no. 17
    
18.
Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label nonrandomized clinical trial. International Journal of Antimicrobial Agents. 2020;73(32):105949.  Back to cited text no. 18
    
19.
Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microbial pathogenesis 2020;25:104228.  Back to cited text no. 19
    
20.
Nujić K, Banjanac M, Munić V, Polančec D, Eraković Haber V. Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. Cell Immunol 2012;279:78-86.  Back to cited text no. 20
    
21.
Liu Y, Kam WR, Ding J, Sullivan DA. Effect of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells. JAMA Ophthalmol 2014;132:226-8.  Back to cited text no. 21
    
22.
Zhang J, Zhou L, Yang Y, Peng W, Wang W, Chen X. Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics. Lancet Respir Med 2020;8:e11-2.  Back to cited text no. 22
    
23.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-90.  Back to cited text no. 23
    
24.
Mortensen EM, Halm EA, Pugh MJ, Copeland LA, Metersky M, Fine MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA 2014;311:2199-208.  Back to cited text no. 24
    


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