Antiviral Activity of Ivermectin Against SARS-CoV-2: An Old-Fashioned Dog with a New Trick - A Literature Review

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is a major global threat. With no effective antiviral drugs, the repurposing of many currently available drugs has been considered. One such drug is ivermectin, an FDA-approved antiparasitic agent that has been shown to exhibit antiviral activity against a broad range of viruses. Recent studies have suggested that ivermectin inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus suggesting its potential for use against COVID-19. This review has summarized the evidence derived from docking and modeling analysis, in vitro and in vivo studies, and results from new investigational drug protocols, as well as clinical trials, if available, which will be effective in supporting the prospective use of ivermectin as an alternative treatment for COVID-19.

Full text

Scientia
Pharmaceutica
Review
Antiviral Activity of Ivermectin Against SARS-CoV-2:
An Old-Fashioned Dog with a New Trick—
A Literature Review
Mudatsir Mudatsir 1,2,3,* , Amanda Yufika 2,4 , Firzan Nainu 5, Andri Frediansyah 6,7 ,
Dewi Megawati 8,9, Agung Pranata 2, 3, 10 , Wilda Mahdani 1,2,3, Ichsan Ichsan 1,2,3,
Kuldeep Dhama 11 and Harapan Harapan 1,2,3,*
1Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh 2311,
Indonesia; wildamahdani@unsyiah.ac.id (W.M.); ichsan@unsyiah.ac.id (I.I.)
2Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh 23111, Indonesia;
amandayufika@gmail.com (A.Y.); agungp11@unsyiah.ac.id (A.P.)
3Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh 23111, Indonesia
4Department of Family Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh,
Aceh 23111, Indonesia
5Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; firzannainu@unhas.ac.id
6Research Division for Natural Product Technology (BPTBA), Indonesian Institute of Sciences (LIPI),
Wonosari 55861, Indonesia; andri.frediansyah@lipi.go.id
7Department of Pharmaceutical Biology, Pharmaceutical Institute, University of Tübingen,
72076 Tübingen, Germany
8Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences,
Warmadewa University, Denpasar 80239, Indonesia; amegawati@ucdavis.edu
9
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis,
California, CA 95616, USA
10
Department of Parasitology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh 23111, Indonesia
11
Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122,
India; kdhama@rediffmail.com
*Correspondence: mudatsir@unsyiah.ac.id (M.M.); harapan@unsyiah.ac.id (H.H.)
Received: 20 July 2020; Accepted: 10 August 2020; Published: 17 August 2020


Abstract:
The coronavirus disease 2019 (COVID-19) pandemic is a major global threat. With no
effective antiviral drugs, the repurposing of many currently available drugs has been considered.
One such drug is ivermectin, an FDA-approved antiparasitic agent that has been shown to
exhibit antiviral activity against a broad range of viruses. Recent studies have suggested that
ivermectin inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
thus suggesting its potential for use against COVID-19. This review has summarized the evidence
derived from docking and modeling analysis,
in vitro
and
in vivo
studies, and results from new
investigational drug protocols, as well as clinical trials, if available, which will be effective in
supporting the prospective use of ivermectin as an alternative treatment for COVID-19.
Keywords: SARS-CoV-2; COVID-19; ivermectin; treatment; antiviral
1. Introduction
In December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in central China [
1
,
2
]. As of 30 July 2020,
more than 16 million confirmed cases and more than 600,000 deaths have been reported in 188 countries
based on the COVID-19 Dashboard database [
3
]. Most SARS-CoV-2 infections are asymptomatic or
Sci. Pharm. 2020,88, 36; doi:10.3390/scipharm88030036 www.mdpi.com/journal/scipharm

Sci. Pharm. 2020,88, 36 2 of 8
result in mild symptoms, such as cough, fatigue, and myalgia [
4
]; however, up to 20.3% of hospitalized
patients require admission to the intensive care unit (ICU) [
5
]. The data suggest that dysregulation of
the host immune response contributes to disease progression and severity [6].
COVID-19 is a global threat to public health and no effective vaccines or pharmaceutical agents
against SARS-CoV-2 are available [
1
,
4
]. To respond to the pandemic, a long list of potential drugs has
been proposed as potential treatments for COVID-19; some of these have been selected for clinical trials
in many countries [
7
,
8
]. In accordance with the concept of drug repurposing, these prospective drugs,
which are either already marketed as antivirals or have been chosen from different pharmacological
classes, have been suggested to provide antiviral activity against SARS-CoV-2 infection and/or to
improve the pathological symptoms of COVID-19 [
7
,
8
]. The drugs span from current antivirals
to antiparasitic agents, such as protease inhibitors [
9
–
12
], nucleoside analogs [
13
,
14
], chloroquine,
and hydroxychloroquine [14–17].
Among the drugs repurposed for COVID-19 is ivermectin, an FDA-approved antiparasitic agent
with antiviral activity against a broad range of viruses, such as influenza [
18
], human immunodeficiency
virus (HIV) [
19
], dengue virus [
20
], West Nile virus [
21
], and Venezuelan equine encephalitis virus [
22
].
An initial
in vitro
study suggested that ivermectin could inhibit SARS-CoV-2 [
23
]. In this review,
we have summarized the evidence from docking and modeling studies,
in vitro
and
in vivo
studies,
new investigational drug protocols, and, where available, clinical trials; from this evidence, we aim to
evaluate the potency of ivermectin for use as a treatment option for COVID-19.
2. Materials and Methods
We searched for relevant articles on PubMed and Google Scholar using the search terms
“coronavirus”, OR “SARS-CoV”, OR “MERS-CoV”, OR “SARS-CoV-2” AND “ivermectin” in the title
or abstract. Available clinical trials assessing the efficacy of ivermectin were searched for on the
ClinicalTrials.gov database. Available publications were discussed based on the study types (
in vitro
,
in vivo
, emergency use in hospitals, and clinical trials). All available articles until 10 May 2020were
considerate eligible. All studies were discussed narratively. To build our discussion, previous studies
assessing the antiviral effect of ivermectin against other viruses and its action mechanisms were also
searched and discussed.
3. Ivermectin: An Introduction
Ivermectin is an antiparasitic agent with broad spectrum activity, high efficacy, and a wide safety
margin. It has been in common use in veterinary medicine since 1981 for the treatment of onchocerciasis
and filariasis [
24
]. Ivermectin was first used in humans in 1987 for the treatment of onchocerciasis;
currently, it is approved in many countries for the treatment of onchocerciasis, filariasis, strongyloidiasis,
and scabies [
25
]. Over the past three decades, approximately 3.7 billion doses of ivermectin have been
distributed worldwide through mass drug administration (MDA) campaigns [26].
Ivermectin isavailable in multiple forms, including tablets, capsules, and an oral solution; however, it is
only approved for administration via the oral route for humans. Studies of the metabolism of ivermectin
in humans are limited; however, it was suggested that the drug is extensively metabolized in the liver [
25
].
The elimination half-life of ivermectin is approximately 24 h, although a previous study suggested that the
drug persisted for several months after a single dose of ivermectin [
27
]. Ivermectin is distributed widely
throughout the body, owing to its high lipid solubility, and binds strongly to plasma proteins, particularly
serum albumin, and is notably excreted in feces [25].
A previous study suggested an antagonistic effect of ivermectin on vitamin K after hematomatous
swellings were reported in two out of 28 ivermectin-treated patients, along with a significantly increased
prothrombin time of between 1 week and 1 month after drug administration [
28
]. Notably, even though
the reduction of factor II and factor VII levels was reported to occur in most of the patients, bleeding
complications were not observed in any patients [28].

Sci. Pharm. 2020,88, 36 3 of 8
Despite being approved as an antiparasitic agent, ivermectin has also been shown to exert antiviral
activity against a broad range of viruses
in vitro
. It was suggested that ivermectin inhibited the
action of the integrase of HIV [
19
] and non-structural protein 5, a polymerase, in dengue virus [
20
].
In addition, ivermectin exerted inhibitory activities against several RNA viruses, such as West Nile
virus [
21
], Venezuelan equine encephalitis virus (VEEV) [
22
], and influenza [
18
]. This antiviral effect
was not only demonstrated against RNA viruses, but was also shown to be effective against a DNA
virus, pseudorabies virus (PRV), both in vitro and in vivo [29].
Ivermectin binds importin (IMP)
α
armadillo (ARM) repeat domain, which causes IMP
α
thermal
instability and
α
-helicity that prevents IMP
α
-IMP
β
1 interaction [
30
]. Ivermectin is also able to dissociate
the IMP
α
/
β
1 heterodimer, which further inhibits NS5-IMP
α
interaction within cells [
30
]. A significant
increase in the ratio of free IMP
α
to IMP
α
/
β
1 was observed when the IMP
α
/
β
1 heterodimer was
incubated with 12.5
µ
M ivermectin, suggesting that ivermectin binds IMP
α
directly to impact the IMP
α
structure, most likely within the ARM repeat domain [
30
]. In short, ivermectin affects the IMP
α
/
β
1
recognition of viral and other proteins by preventing its formation or dissociating the heterodimer,
which is crucial in the nuclear transport of viral proteins. As the replication cycle of the virus and
the inhibition of the host’s antiviral response occur in a manner dependent on the nuclear transport
of viral proteins, targeting the transport process may be a feasible pharmacological approach for
dealing with RNA viral infections [
21
,
30
,
31
]. In PRV, ivermectin inhibited viral entrance into the
cell nucleus,
as well as
viral proliferation, in a dose-dependent manner [
29
]. The drug significantly
reduced viral DNA synthesis, inhibited virus production, and blocked DNA polymerase accessory
subunit UL42 entrance into the nucleus by targeting the nuclear localization signal in the transfected
cells [
29
]. Moreover, the administration of ivermectin increased the survival rates of Ross River virus
(RRV)-infected mice, most likely by relieving the infection of the infected host [
29
]. The broad-spectrum
antiviral activity of ivermectin is believed to be due to its nuclear inhibitory activity [31,32].
4. Ivermectin and SARS-CoV-2 Infection
There are no antiviral drugs available to treat SARS-CoV-2 infection. However, several clinical
trials are in progress to explore the potential antiviral activities of some drugs. Although most of these
drugs were initially designed for other pathogens, they appear to have the potential to treat COVID-19,
either by acting directly on the virus or modulating the human immune system [
30
]. One of the drugs
with the potential for COVID-19 treatment is ivermectin. This antiparasitic drug has shown potential
antiviral activity by inhibiting the nuclear transport of viral proteins [18–22].
Previous studies on SARS-CoV proteins have shown the potential role of IMP
α
/
β
1 during infection
in the signal-dependent nucleocytoplasmic shuttling of the SARS-CoV nucleocapsid protein, which may
affect host cell division [
21
,
33
]. Moreover, open reading frame (ORF) 6, as the accessory protein of
SARS-CoV, has been shown to have an antagonistic effect against the antiviral activity of the STAT1
transcription factor [
34
]. As ivermectin has shown a potential inhibitory effect on nuclear transport,
particularly by preventing IMPα/β1 binding, it may also act on SARS-CoV-2. As SARS-CoV-2 is very
similar to SARS-CoV, it is suggested that ivermectin may also be effective against SARS-CoV-2 by
inhibiting its nuclear transport [
25
]. A proposed schematic figure of the antiviral action of ivermectin
against SARS-CoV 2 is depicted in Figure 1.

Sci. Pharm. 2020,88, 36 4 of 8
Sci. Pharm. 2020, 88, x FOR PEER REVIEW 4 of 8
Figure 1. Ivermectin inhibits SARS-CoV-2 protein transport to the nucleus.
4.1. In Vitro and In Vivo Studies
An in vitro study demonstrated that a single dose of ivermectin was able to limit SARS-CoV-2
replication within 24–48 h, very likely through the inhibition of the IMPαβ1-mediated nuclear import
of viral proteins [23]. In that study, the levels of viral RNA released from the infected cells and cell-
associated viral RNA were significantly reduced by more than 90% and 99%, respectively, at 24 h
post infection. Furthermore, the treatment of SARS-CoV-2-infected cells with ivermectin for 48 h was
shown to result in a dramatic reduction of viral RNA (by ~5000-fold) compared with the control
group. However, no further reduction in viral RNA was observed at 72 h [23]. Lastly, the study
suggested that no toxicity of ivermectin was observed in either group at any time point, which agreed
with previous studies [19,20,22]. There was no clear explanation of how ivermectin achieved its
antiviral properties against SARS-CoV-2, but it was believed to function in same way as it did against
other viruses.
SARS-CoV-2 protein is translocated into the nucleus through the nuclear pore complex (NPC)
via binding to the importin-α (IMP-α) and importin-β (IMP-β) heterodimer. Once in the nucleus, the
SARS-CoV-2 protein is released by the importin-α/β complex. The SARS-CoV-2 protein then
promotes host shut-off, which results in the reduction of the host immune response, thereby allowing
the virus to replicate. Ivermectin inhibits SARS-CoV-2 protein translocation into the nucleus by
binding to the importin-/β complex and destabilizing the importin-/β heterodimer. The ivermectin
treatment most likely promotes host immune responses to occur in an efficient manner.
There has been increased public interest in ivermectin after the study showed the effect of the
drug on SARS-CoV-2 in vitro. The Food and Drug Administration (FDA) even responded to this
study by issuing an official letter to emphasize that research was still at the very early stage and to
highlight the need to conduct further phases of clinical trials to determine if ivermectin is effective in
the treatment of COVID-19. This is important, as the study may lead to the high-risk practice of self-
medication by consumers [35]. Regardless of the controversy, this study is an important milestone
for further research on the effect of ivermectin on SARS-CoV-2 infection.
4.2. Results from Patients
The drug combination of ivermectin and hydroxychloroquine was proposed as a combination
therapy for the prophylaxis or treatment of COVID-19. This combination may produce a synergistic
Figure 1. Ivermectin inhibits SARS-CoV-2 protein transport to the nucleus.
4.1. In Vitro and In Vivo Studies
An
in vitro
study demonstrated that a single dose of ivermectin was able to limit SARS-CoV-2
replication within 24–48 h, very likely through the inhibition of the IMP
αβ
1-mediated nuclear import
of viral proteins [
23
]. In that study, the levels of viral RNA released from the infected cells and
cell-associated viral RNA were significantly reduced by more than 90% and 99%, respectively, at 24 h
post infection. Furthermore, the treatment of SARS-CoV-2-infected cells with ivermectin for 48 h was
shown to result in a dramatic reduction of viral RNA (by ~5000-fold) compared with the control group.
However, no further reduction in viral RNA was observed at 72 h [
23
]. Lastly, the study suggested that
no toxicity of ivermectin was observed in either group at any time point, which agreed with previous
studies [
19
,
20
,
22
]. There was no clear explanation of how ivermectin achieved its antiviral properties
against SARS-CoV-2, but it was believed to function in same way as it did against other viruses.
SARS-CoV-2 protein is translocated into the nucleus through the nuclear pore complex (NPC)
via binding to the importin-
α
(IMP-
α
) and importin-
β
(IMP-
β
) heterodimer. Once in the nucleus,
the SARS-CoV-2 protein is released by the importin-
α
/
β
complex. The SARS-CoV-2 protein then
promotes host shut-off, which results in the reduction of the host immune response, thereby allowing
the virus to replicate. Ivermectin inhibits SARS-CoV-2 protein translocation into the nucleus by binding
to the importin-
α
/
β
complex and destabilizing the importin-
α
/
β
heterodimer. The ivermectin treatment
most likely promotes host immune responses to occur in an efficient manner.
There has been increased public interest in ivermectin after the study showed the effect of the drug
on SARS-CoV-2
in vitro
. The Food and Drug Administration (FDA) even responded to this study by
issuing an official letter to emphasize that research was still at the very early stage and to highlight the
need to conduct further phases of clinical trials to determine if ivermectin is effective in the treatment
of COVID-19. This is important, as the study may lead to the high-risk practice of self-medication by
consumers [
35
]. Regardless of the controversy, this study is an important milestone for further research
on the effect of ivermectin on SARS-CoV-2 infection.

Sci. Pharm. 2020,88, 36 5 of 8
4.2. Results from Patients
The drug combination of ivermectin and hydroxychloroquine was proposed as a combination therapy
for the prophylaxis or treatment of COVID-19. This combination may produce a synergistic effect with the
inhibition of both viral entry and viral replication [
36
]. However, pharmacokinetic analysis indicated that
a higher dosage was required to replicate the antiviral activity. Therefore, the recommended inhibitory
concentration is very difficult to reach in humans [
37
]. In addition, although hydroxychloroquine has
been approved by the FDA as an Emergency Use Authorization (EUA) against COVID-19, its efficacy is
questioned [
38
] and its usage against SARS-CoV-2 is still highly controversial [
39
,
40
]. Further randomized
clinical controlled studies are required to come to a conclusion about the efficacy of ivermectin in patients
with SARS-CoV-2.
4.3. Ongoing Clinical Trials
Several clinical trials are ongoing in various countries, including India, the USA, Egypt, and Iraq,
to assess the efficacy of ivermectin for COVID-19. The list of the current ongoing clinical trials is
presented in Table 1. The results of these clinical trials will provide robust information on the efficacy
of ivermectin for COVID-19 treatment.
Table 1. A list of ongoing registered clinical trials of ivermectin to treat COVID-19.
Identifier
Number Title Expected
Participants
Length of
Treatment Ivermectin Dose Location
NCT04373824
Max ivermectin-COVID 19
study versus standard of
care treatment for COVID
19 cases. A pilot study
50 2 days 200–400 µg per kg body weight +
standard treatment India
NCT04374279
Trial to promote recovery
from COVID-19 with
ivermectin or endocrine
therapy
60
3 days (with
possible extension
up to 6 days)
600
µ
g/kg (up to a maximum dose
of 60 mg) USA
NCT04360356
Ivermectin and
nitazoxanide combination
therapy for COVID-19
100 6 days
200 µg/kg once orally on empty
stomach plus nitazoxanide 500
mg twice daily orally with meal
Egypt
NCT04343092
Ivermectin adjuvant to
hydroxychloroquine and
azithromycin in COVID19
patients
50 No information
12 mg/week +hydroxychloroquine
400 mg/day +azithromycin 500
mg daily
Iraq
NCT04351347
The efficacy of ivermectin
and nitazoxanide in
COVID-19 treatment
60 No information Combined with chloroquine (no
information about dose) Egypt
NCT04374019
Novel agents for treatment
of high-risk COVID-19
positive patients
240
2 days for
ivermectin +14
days for
hydroxychloroquine
First 2 days: Weight <75 kg: four
tablets (12 mg total daily dose).
Days 1–2: Weight >75 kg: five
tablets (15 mg total daily dose) in
combination with
hydroxychloroquine. Days 1–14:
three tablets (600 mg total daily
dose)
USA
NCT04345419
A real-life experience on
treatment of patients with
COVID 19
120 No information As a single dose (no information) Egypt
5. Conclusions
Ivermectin is an antiparasitic drug with potential use as a broad-spectrum antimicrobial agent for
the treatment of viral infections. Initial evidence indicated that ivermectin, an importin
α
/
β
1-mediated
nuclear import inhibitor, inhibited SARS-CoV-2
in vitro
. In a small clinical study, the administration of
ivermectin (150
µ
g/kg) in hospitalized patients with COVID-19 was associated with a lower mortality
rate and a shorter hospital stay. Several randomized controlled trials are ongoing to investigate the
efficacy of ivermectin against COVID-19. In addition to ivermectin, several drugs either currently
classified as an antiviral or alternative class of drug, have been the subject of clinical trials as a part

Sci. Pharm. 2020,88, 36 6 of 8
of the drug repurposing effort in the fight against COVID-19. The results of these clinical trials are
required to confirm the efficacy of these drugs for the treatment of patients with COVID-19.
Author Contributions:
Conceptualization, H.H.; validation, M.M., A.Y., F.N., A.F., D.M., A.P., W.M., I.I., K.D.,
and H.H.; writing—original draft preparation, M.M., A.Y., F.N., D.M., and H.H.; writing—review and editing,
M.M., A.Y., F.N., A.F., D.M., A.P., W.M., I.I., K.D., and H.H. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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