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

Authors:
  • School of Medicine, Universitas Syiah Kuala

Abstract and Figures

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.
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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@redimail.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
eective 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 eective 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 eective 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 dierent 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 [1417].
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 ecacy 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 eect 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 eect 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 eect
was not only demonstrated against RNA viruses, but was also shown to be eective 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 aects 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 [1822].
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
aect 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 eect against the antiviral activity of the STAT1
transcription factor [
34
]. As ivermectin has shown a potential inhibitory eect 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 eective 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-o, 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 ecient manner.
There has been increased public interest in ivermectin after the study showed the eect of the drug
on SARS-CoV-2
in vitro
. The Food and Drug Administration (FDA) even responded to this study by
issuing an ocial 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 eective 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 eect 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 ecacy 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 ecacy
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 ecacy 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
ecacy 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 eort in the fight against COVID-19. The results of these clinical trials are
required to confirm the ecacy 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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... It has also been observed through both in vitro and in vivo studies that ivermectin has some effects on several viruses. Several studies have shown that ivermectin might be helpful in treating COVID-19 patients at both mild-moderate and severe phases of the disease, and also as a potential prophylaxis [38][39][40]. ...
... It is proposed that ivermectin might have anti-viral and immunomodulatory properties [16,39,40]. There are several biologically plausible reasons for the activity of ivermectin against SARS-cov2 in the treatment of COVID-19: ...
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The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for ster-oids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.
... To date, the most accepted mechanism of action for ivermectin against SARS-CoV-2 is inhibition of the nuclear import of viral proteins and RNA, as has been found for HIV-1 and dengue [9]. However, it has also been reported that ivermectin has a potentially inhibitory effect against other viruses such as flaviviruses by blocking the NS3 helicase [10]. ...
... This corresponds to existing data reported between these structures and HB1a using ADV [4,46]. This result could perhaps be related to the proportion of the HB1a in the ivermectin mixture and to the described mechanism of action of inhibition of import [9]. The binding energy shown by HB1a and HB1b towards M pro , which in this study exceeds that predicted for Importins by up to ~5 kcal/mol depending on the type of sampling method, allows us to infer the possibility of a more probable docking of this mixture of homologs against M pro from a statisticalthermodynamic point of view (between − 8 kcal/mol and − 10 kcal/ mol). ...
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The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.
... As the pandemic continues, the availability of numerous efficient and safe vaccines has provided some relief [144][145][146]. A long list of potential COVID-19 drug candidates, each with their own mechanism of action, has been proposed [7,[147][148][149]. Nevertheless, the US Food and Drug Administration has only approved two antiviral drugs for SARS-CoV-2, including remdesivir, a protease inhibitor, and baricitinib, a Janus kinase inhibitor that inhibits immune system overstimulation [150]. ...
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The SARS-CoV-2 virus, which caused the COVID-19 infection, was discovered two and a half years ago. It caused a global pandemic, resulting in millions of deaths and substantial damage to the worldwide economy. Currently, only a few vaccines and antiviral drugs are available to combat SARS-CoV-2. However, there has been an increase in virus-related research, including exploring new drugs and their repurposing. Since discovering penicillin, natural products, particularly those derived from microbes, have been viewed as an abundant source of lead compounds for drug discovery. These compounds treat bacterial, fungal, parasitic, and viral infections. This review incorporates evidence from the available research publications on isolated and identified natural products derived from microbes with anti-hepatitis, anti-herpes simplex, anti-HIV, anti-influenza, anti-respiratory syncytial virus, and anti-SARS-CoV-2 properties. About 131 compounds with in vitro antiviral activity and 1 compound with both in vitro and in vivo activity have been isolated from microorganisms, and the mechanism of action for some of these compounds has been described. Recent reports have shown that natural products produced by the microbes, such as aurasperone A, neochinulin A and B, and aspulvinone D, M, and R, have potent in vitro anti-SARS-CoV-2 activity, targeting the main protease (Mpro). In the near and distant future, these molecules could be used to develop antiviral drugs for treating infections and preventing the spread of disease.
... Ivermectin has been shown to be effective against a variety of RNA viruses [16]. The antiviral activity is likely due to the inhibition of importin α/β1 integrase, which leads to the nuclear import and spread of RNA virus infection [17][18][19]. Based on this, researchers have suggested the use of ivermectin as a therapy for the treatment of COVID-19 [20]. ...
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Background: : To investigate the efficacy and safety of ivermectin compared to hydroxychloroquine and placebo in hospitalized moderate to severe COVID-19 patients. Research design and methods: : The study was an adaptive, randomized, double-blinded, controlled, single-center trial. The study was a series of 3-arm comparisons between two different investigational therapeutic agents (ivermectin and hydroxychloroquine) and a placebo. There was interim monitoring to allow early stopping for futility, efficacy, or safety. Results: : Ivermectin decreased survival time from 29 to 18.3 days (HR, 9.8, 95%CI, 3.7-26.2), while it did not shorten the recovery time (HR, 1.02, 95%CI, 0.69-1.5). Subgroup analysis showed an association between ivermectin-related mortality and baseline oxygen saturation level. Moreover, stratified groups showed higher risk among patients on high flow O2. Hydroxychloroquine delayed recovery from 10.1 to 12.5 days (HR, 0.62, 95%CI, 0.4-0.95) and non-significantly decreased survival time from 29 to 26.8 days (HR, 1.47, 95%CI, 0.73-2.9). However, 3 months-mortality rates were increased with hydroxychloroquine (RR, 2.05, 95%CI, 1.33-3.16). Neither ivermectin nor hydroxychloroquine increased adverse events and demonstrated safety profile compared to placebo. Conclusions: : The study recommends against using either ivermectin or hydroxychloroquine for treatment of COVID-19 in hospitalized patients with any degree of severity. Clinical trial registration: www.clinicaltrials.gov identifier is: NCT04746365.
... Even though these data showed the potential usage of IVM as an antiviral medication in the battle against COVID-19; the dose employed was 200 times higher than that typically being used in clinical applications 111 . Moreover, a few observational studies and a real-world clinical practice demonstrated that IVM seems effective in treating COVID-19 patients at both mild-moderate and severe stages of the disease, suggesting that IVM may have antiviral but also immunomodulatory activities [112][113][114][115] . ...
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The SARS-CoV-2 virus, accountable for the COVID-19 pandemic, is now sweeping the globe. As a result, as this disease resists testing and adoption of new treatments, repositioning existing medications may provide a quick and appealing method with established safety, features, and dose used. They are not, however, specific or focused. However, numerous medications have been studied for their efficacy and safety in treatment of COVID-19, with the majority currently undergoing clinical trials. The goal is to rapidly expand novel preventative and therapeutic medications, as well as to apply preventive methods such as early patient identification, isolation, and treatment. Moreover, reducing transmission through physical contact is also important. In the fight against this dangerous disease, finding the proper treatment is crucial. This article summarizes several anti-malarial, anti-parasitic, monoclonal antibodies, immunosuppressant, and immunomodulating agents in clinical trials for COVID-19. The purpose of this article is to evaluate and explore the potential roles of several medications now utilized in COVID-19.
... Not only the healthcare system [5][6][7][8] but the global economy and education [9,10] have also been hit equally hard [11][12][13], particularly by the lockdown policies [9,14]. Although numerous proposed treatments have been investigated [15][16][17][18][19] many failed to provide good efficacy to treat severe COVID-19. ...
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Human civilization is now facing the biggest pandemic of coronavirus disease 2019 (COVID-19) of this century caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Absence of any suitable vaccines makes this virus much more detrimental; various drugs (antiviral drugs and drugs used for other diseases also) are repurposed to cope up with urgent requirements during this emergency period. This chapter will discuss about some of the important small-molecule drug activities and the mechanism of actions used to tackle COVID-19.
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The broad-spectrum antiparasitic agent ivermectin has been very recently found to inhibit SARS-CoV-2 in vitro and proposed as a candidate for drug repurposing in COVID-19. In the present report the in vitro antiviral activity end-points are analyzed from the pharmacokinetic perspective. The available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations are not likely to be attainable in humans. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).
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The technology-driven world of the 21 st century is currently confronted with a major threat to humankind, represented by the coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2). As of now, COVID-19 has affected more than 6 million confirmed cases and took 0.39 million human lives. SARS-CoV-2 spreads much faster than its two ancestors, SARS-CoV and Middle East respiratory syndrome-CoV (MERS-CoV), but Pathogens 2020, 9, 519 2 of 31 has low fatality rates. Our analyses speculate that the efficient replication and transmission of SARS-CoV-2 might be due to the high-density basic amino acid residues, preferably positioned in close proximity at both the furin-like cleavage sites (S1/S2 and S2') within the spike protein. Given the high genomic similarities of SARS-CoV-2 to bat SARS-like CoVs, it is likely that bats serve as a reservoir host for its progenitor. Women and children are less susceptible to SARS-CoV-2 infection, while the elderly and people with comorbidities are more prone to serious clinical outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. The cohesive approach amongst researchers across the globe has delivered high-end viral diagnostics. However, home-based point-of-care diagnostics are still under development, which may prove transformative in current COVID-19 pandemic containment. Similarly, vaccines and therapeutics against COVID-19 are currently in the pipeline for clinical trials. In this review, we discuss the noteworthy advancements, focusing on the etiological viral agent, comparative genomic analysis, population susceptibility, disease epidemiology and diagnosis, animal reservoirs, laboratory animal models, disease transmission, therapeutics, vaccine challenges, and disease mitigation measures.
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The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. The virus causing COVID-19 is SARS-Cov-2. Taking the advantage of a recently released crystal structure of SARS-Cov-2 main protease in complex with a covalently-bonded inhibitor, N3,1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS (Molecular Mechanics-Poisson Boltzmann Surface Area-Weighted Solvent-Accessible Surface Area).2-4 Several promising known drugs stand out as potential inhibitors of SARS-Cov-2 main protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including SARS-Cov, SARS-Cov-2, MERS-Cov, and HCV. The findings of this study can facilitate rational drug design targeting the SARS-Cov-2 main protease.
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Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.