Ivermectin: Potential Role as Repurposed Drug for COVID-19

Abstract

Severe acute respiratory illness caused by 2019 novel coronavirus (2019-nCoV), officially named severe acute respiratory syndrome coronavirus (SARS-CoV-2) in late December 2019 is an extremely communicable disease. World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a pandemic as it has spread to at least 200 countries in a short span of time. Being a new disease there is lack of information about pathogenesis and proliferation pathways of this new coronavirus. Currently there is no effective treatment for coronavirus infection; major effort is to develop vaccine against the virus and development of therapeutic drugs for the disease. The development of genome-based vaccine and therapeutic antibodies require thorough testing for safety and will be available after some time. In the meanwhile, the available practical approach is to repurpose existing therapeutic agents, with proven safety record as a rapid response measure for the current pandemic. Here we discuss the presently used repurposed drugs for COVID-19 and the potential for ivermectin (IVM) to be used as a therapeutic option in COVID-19.

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154
Introduction
The severe acute respiratory syndrome
caused by coronavirus 2 (SARS-CoV-2) has been
detected as the pathogenic virus in the current
outbreak which started in the city of Wuhan,
Hubei Province of China in early December 2019.
The Centre of Disease Control and Prevention
in China, detected a new type of corona virus on
7th January 2020 causing coronavirus disease
of 2019 (COVID-19), provisionally named as
2019 novel coronavirus (2019-nCoV) by World
Health Organization (WHO) and later renamed
as SARS-CoV-2 by International Committee on
Taxonomy of Virus (1). SARS-CoV-2 is highly
pathogenic virus, possesses mutative behaviour
and causes rapid human to human spread.
Specic treatment for COVID-19 has not been
established yet, and the management of patients
is primarily symptomatic or supportive care
treatment. Anticipating that vaccine will take
time and there is critical need of an eective
treatment against COVID-19, many drugs
are being repurposed for use among patients
and healthcare workers for the purpose of
prophylaxis and treatment of severe cases.
These repurposed drugs include chloroquine
phosphate, hydroxychloroquine (HCQ),
lopinavir/ritonavir, umifenovir, remdesivir,
favipiravir and monoclonal antibody tocilizumab.
Repurposed Drugs for COVID-19
Chloroquine phosphate conventionally
used for prophylaxis/treatment of malaria,
and extraintestinal amoebiasis whereas
hydroxychloroquine approved for suppressive
treatment/treatment of acute attacks of malaria
and rheumatoid arthritis are the two most
commonly used drugs for COVID-19 worldwide.
To cite this article: Dixit A, Yadav R, Singh AV. Ivermectin: potential role as repurposed drug for COVID-19.
Malays J Med Sci. 2020;27(4):154–158. https://doi.org/10.21315/mjms2020.27.4.15
To link to this article: https://doi.org/10.21315/mjms2020.27.4.15
Abstract
Severe acute respiratory illness caused by 2019 novel coronavirus (2019-nCoV), ocially
named severe acute respiratory syndrome coronavirus (SARS-CoV-2) in late December 2019 is an
extremely communicable disease. World Health Organization (WHO) declared coronavirus disease
2019 (COVID-19) as a pandemic as it has spread to at least 200 countries in a short span of time.
Being a new disease there is lack of information about pathogenesis and proliferation pathways
of this new coronavirus. Currently there is no eective treatment for coronavirus infection; major
eort is to develop vaccine against the virus and development of therapeutic drugs for the disease.
The development of genome-based vaccine and therapeutic antibodies require thorough testing for
safety and will be available after some time. In the meanwhile, the available practical approach is
to repurpose existing therapeutic agents, with proven safety record as a rapid response measure
for the current pandemic. Here we discuss the presently used repurposed drugs for COVID-19 and
the potential for ivermectin (IVM) to be used as a therapeutic option in COVID-19.
Keywords: ivermectin, coronavirus disease 2019, SARS-CoV-2, drug repurposing, antiparasitic
Ivermectin: Potential Role as Repurposed
Drug for COVID-19
Alok Dixit1, Ramakant YaDav2, Amit Vikram Singh1
1 Department of Pharmacology, Uttar Pradesh University of Medical Sciences,
Uttar Pradesh, India
2 Department of Neurology, Uttar Pradesh University of Medical Sciences,
Uttar Pradesh, India
Submitted: 13 May 2020
Accepted: 21 Jun 2020
Online: 19 Aug 2020
Brief
Communications

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Brief Communications | Ivermectin in COVID-19
Favipiravir is a prodrug of a purine
nucleotide, favipiravir ribofuranosyl-5′
triphosphate and approved for therapeutic use
in resistant cases of inuenza. The active agent
inhibits the ribonucleic acid (RNA) polymerase,
inhibiting viral replication. In vitro, the EC50 of
favipiravir against SARS-CoV-2 was 61.88 μM/L
in Vero E6 cells (9).
Ivermectin: An Antiparasitic Drug
Apart from above discussed drugs, an
additional drug which has property to inhibit
the replication of RNA viruses found in
several studies is ivermectin (IVM). IVM, an
anthelminthic drug is used to treat various
parasitic infestations. This includes river
blindness (onchocerchiasis), head lice, scabies,
lymphatic lariasis, ascariasis, entrobiasis,
strongyloidiasis and trichuriasis (10). IVM
was discovered by Satoshi Omura of Kitasato
University, Tokyo in 1975 and came to use in
1981. IVM was chemically derived from the
avermectin family of compound, identied
by William C. Omura from the bacterium
Streptomyces avermitilis and puried by
Campbell, has greater potency and lower toxicity
(11). They act via binding to glutamate-activated
chloride channels found in nematode nerve or
muscle cells and causes hyperpolarisation by
increasing intracellular chloride concentration,
resulting in paralysis (12). The peak plasma
concentration of IVM is achieved within 4 h–5 h
after oral ingestion and is about 93% bound
to plasma proteins. The drug is metabolised
by hepatic microsomal enzymes CYP3A4 and
adverse eect includes fever, pruritus, arthralgia,
postural hypertension, tachycardia, oedema,
lymphadenopathy, sore throat, cough and
headache. IVM should be avoided in pregnancy
and children below 5 years of age (13).
IVM for Viral Diseases
Independent of its antiparasitic action,
IVM has demonstrated broad spectrum antiviral
property in vitro. IVM is shown to be eective
in vitro against RNA and deoxyribonucleic
acid (DNA) viruses, including human
immunodeciency virus-1 (HIV-1), dengue
virus (DENV), inuenza, Venezuelan equine
encephalitis virus (VEEV) and Zika virus (14).
Nuclear import of viral proteins plays important
role in life cycle of many viruses, including RNA
They predominantly act by increasing endosomal
pH and interfere with the glycosylation of
cellular receptor of SARS-CoV and thus it
has the potential to block viral infection.
Additionaly, chloroquine also inhibits the
quinone reductase-2, which is involved in sialic
acid biosynthesis (an acidic monosaccharides
of cell transmembrane proteins required for
ligand recognition) that makes this agent a
broad antiviral agent (2). The mechanism of
action of chloroquine and hydroxychloroquine
are same, both act as a weak base that can
change the pH of acidic intracellular organelles
including endosomes/lysosomes, essential for
the membrane fusion. Besides chloroquine also
possesses immune-modulating properties which
may augment the antiviral activity in vivo. It is
believed that both the agents could be eective
tools against SARS-CoV-1 and SARS-CoV-2 (3).
Though they have shown promising activity
against SARS-CoV-2, still there is a risk of
arrhythmia associated with their administration
at higher cumulative dosages; hence, vigilance
is required with prior electrocardiogram for
corrected QT (QTc) interval in vulnerable cases.
Recent studies have reported contrasting results
for the combination of hydroxychloroquine and
azithromycin in COVID patients as regards viral
load, positivity at day 7 and culture (4, 5).
Combination of lopinavir/ritonavir is
used for the treatment of HIV and is a potential
candidate for the treatment of COVID-19.
The antiretroviral drug lopinavir, a protease
inhibitor is formulated in combination with
ritonavir which inhibits the metabolising enzyme
cytochrome P450 3A and therefore increases
the half-life of lopinavir (6). A randomised
open labelled clinical trial of lopinavir/ritonavir
400 mg/100 mg, twice daily for 14 days
(n = 99) has concluded that the combination was
not more eective than standard care treatment
and had similar recovery process in severe
COVID-19 (7).
Remdesivir is a monophosphate prodrug
that undergoes metabolism to an active
C-adenosine nucleoside triphosphate analogue.
Currently, remdesivir is a promising potential
therapy for COVID-19 due to its broad-spectrum
and potent in vitro activity against several novel
coronavirus (nCoVs), including SARS-CoV-2
with EC50 (half maximal eective concentration)
and EC90 (concentration to induce 90% maximal
response) values of 0.77 μM and 1.76 μM,
respectively (8).

Malays J Med Sci. Jul–Aug 2020; 27(4): 154–158
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used to improve the pharmacological availability
of IVM. IVM, when delivered through liposomes,
reduced cytotoxicity up to ve times, improves its
activity and eectively inhibit DENV replication
(20). Recently, the joint work of Biomedicine
Discovery Institute, Monash University and
the Peter Doherty Institute of Infection and
Immunity has found that a single dose treatment
eectively removed all SARS-CoV-2 viral RNA
in a cell culture by 48 h. It is hypothesised that
its action is likely through inhibiting IMP alfa/
beta1-mediated nuclear import of viral proteins.
Development of an eective antiviral for SARS-
CoV-2, if given to patients early in infection,
could help to limit the viral load, prevent severe
disease progression and limit person-person
transmission (18).
IVM is used in a dose of 0.15 mg/kg–
0.2 mg/kg body weight for most of the parasitic
infestations as oral tablet and is well tolerated. It
will be reasonable to use similar dose empirically
in COVID-19 patients with mild to moderate
symptoms, PCR positive for SARS-CoV-2 virus,
and without comorbidities on rst encounter, till
there is conclusive evidence from randomised
controlled trials. Rarely adverse eects such as
seizure, hypotension and worsening of asthma
are observed with IVM and should be avoided
in patients with history of allergy, liver disease
and asthma. A combination of IVM (200 mcg/
day once stat) with doxycycline (200 mg/day
for 5 days) can also be attempted empirically as
it has been administered previously for parasitic
infections too.
COVID-19 pandemic has aected over
200 countries in a span of less than 4 months
burdening the entire health care system with
no viable drug which can inhibit the viral
transmission or infectivity. Most of the drugs
which are being used to treat this novel disease
are not so eective and the development of
vaccines is distant in near future, thus there
is enormous requirement to repurpose the
available drugs using concrete evidences. Present
circumstances demand a therapeutically eective
option against SARS-CoV-2 without delay. IVM
which is a widely used as antiparasitic drug has
shown to have antiviral activity in in vitro studies
against HIV, dengue, inuenza, VEEV and Zika
virus. The broad-spectrum antiviral activity of
IVM against both RNA and DNA viruses oers an
added advantage to its potential use over other
antiviral drugs. Studies are available for its use
against RNA virus and have also been tested for
its eectiveness against SARS-CoV-2 in vitro.
viruses that replicate in the cytoplasm such as
DENV, respiratory syncytial virus (RSV) and
rabies. IVM inhibits the interaction between
integrase protein and importin α/β1-mediated
nuclear import essential for HIV infection and
was the earliest demonstration that inhibitors of
nuclear import can have potent antiviral activity
(15).
Pseudorabies virus (PRV) is the causative
agent for pseudorabies (PR), which is an
important swine disease. Virus can cause lifelong
infection in pigs by residing in the trigeminal
ganglia. Vaccines are used widely but are unable
to provide absolute protection. Use of IVM,
blocked the nuclear/nucleolar translocation of
the accessory subunit of the DNA polymerase
UL42 and reduced the lesions in mice caused
by PRV infection in vitro and in vivo (16). This
implies that IVM, a small-molecule inhibitor,
can be a potential antiviral drug candidate
against PRV infection. Likewise, VEEV, from the
genus Alphavirus and family Togaviridae, can
cause a fatal neurological disease in equines and
humans. Endemic to northern South America
and ranging into Mexico and the southern United
States, the virus is transmitted between hosts
and mosquitoes (11). Mifepristone and IVM were
identied as importin alfa/beta1 inhibitors and
useful in the treatment of VEEV (17).
IVM has been shown to inhibit nuclear
import of host and viral proteins, including
simian virus SV40 large tumour antigen
(T-ag) and DENV nonstructural (NS1) protein
5. In DENV, a single daily oral dose of IVM has
resulted in a signicant reduction in serum
level of viral NS1 protein, but no change in viral
load has been observed (18). Infections with
yellow fever virus (YFV), DENV, encephalitic
viruses such as west nile virus (WNV), Japanese
encephalitis (JEV) pathogenic aviviruses create
a serious global public health problem. IVM, by
in-silico docking analysis, has been identied
to inhibit the in vitro replication of dierent
aviviruses, specically targeting NS3 helicase
activity. In a cytopathic eect (CPE) reduction
assay in Vero-B cell culture, the EC50 for
inhibition of YFV replication was between 3.1 nM
and 6.3 nM. IVM proved less active against
DENV in the CPE reduction assay (EC50 0.1 mM),
although inhibition in virus yield reduction
assays was observed (EC50 0.7 mM). IVM has
proved to be most potent against YFV and
inhibit the in vitro replication of DENV, JEV and
WNV, though less eciently (19). Liposomes,
microemulsion and polymeric micelles have been

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Brief Communications | Ivermectin in COVID-19
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Based on evidences it seems prudent to use IVM
empirically and conduct well designed controlled
randomised trials to prove its ecacy in vivo.
Acknowledgements
None.
Conflicts of Interest
None.
Funds
None.
Authors’ Contributions
Conception and design: AD
Analysis and interpretation of the data: AD
Drafting of the article: AVS
Critical revision of the article for important
intellectual content: AD, RY
Final approval of the article: AD, RY
Collection and assembly of data: AVS
Correspondence
Professor Dr Alok Dixit
MD (HNB Garhwal University)
Department of Pharmacology,
Uttar Pradesh University of Medical Sciences,
Saifai, Etawah, Uttar Pradesh 206130, India.
Tel: +91 9639523852
E-mail: alkdxt@yahoo.co.in
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