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Ivermectin: Potential Role as Repurposed Drug for COVID-19

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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.
Malays J Med Sci. Jul–Aug 2020; 27(4): 154–158
www.mjms.usm.my © Penerbit Universiti Sains Malaysia, 2020
This work is licensed under the terms of the Creative Commons Attribution (CC BY)
(http://creativecommons.org/licenses/by/4.0/).
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
www.mjms.usm.my 155
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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156
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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4. Gautret P, Lagier JC, Parola P, Hoang VT,
Meddeb L, Sevestre J, et al. Clinical and
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j.tmaid.2020.101663
5. Molina JM, Delaugerre C, Go J Le, Mela-
Lima B, Ponscarme D, Goldwirt L, et al.
No evidence of rapid antiviral clearance
or clinical benet with the combination of
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2020;50(4):384. https://doi.org/10.1016/
j.medmal.2020.03.006
6. Philippidis A. COVID-19: top 60 drug treatments
in development: the biopharma industry is
ramping up the development of dozens of
potential drug therapies and clinical testing in an
all-hands eort to combat the pandemic. Genet
Eng Biotechn N. 2020;40(4):10–13.
7. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan
G, et al. A trial of lopinavir–ritonavir in adults
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NEJMoa2001282
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al. Remdesivir and chloroquine eectively inhibit
the recently emerged novel coronavirus (2019-
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10. Pariser DM, Meinking TL, Bell M, Ryan WG.
Topical 0.5% ivermectin lotion for treatment of
head lice. N Engl J Med. 2012;367(18):1687–
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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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... Adaptado de Panoutsopoulos, 2020 (21) La ivermectina se usa en una dosis de 0,15 mg/kg a 0,2 mg/kg de peso corporal para la mayoría de las parasitosis como tableta oral y es bien tolerada. Sería razonable utilizar una dosis similar empíricamente en pacientes con COVID-19 con síntomas leves a moderados, mientras se obtiene evidencia contundente en ensayos clínicos controlados y aleatorizados (24) . La estructura molecular de la ivermectina es compleja y está formada por un conjunto de isómeros de lactona macrocíclicos (Figura 3). ...
... Los efectos adversos que rara vez se observan con la ivermectina son convulsiones, hipotensión y empeoramiento del asma, por lo que el uso del fármaco debe evitarse en pacientes con antecedentes de alergia, enfermedad hepática y asma (24) . ...
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Desde su aparición en diciembre de 2019, la infección por SARS-CoV-2 se expandió rápidamente a todo el mundo. Aproximadamente, el 80 % de pacientes con COVID-19 presentan síntomas leves a moderados, el 20 % desarrolla cuadros respiratorios graves, y alrededor del 6 % pueden requerir ventilación mecánica. En ausencia de pautas terapéuticas comprobadas, varios medicamentos ya conocidos empezaron a ser evaluados por sus probables beneficios en el tratamiento de COVID-19. Entre ellos, está el fármaco antiparasitario ivermectina, una de las avermactinas producidas por la bacteria Streptomyces avermitilis, que fue descubierta en los años setenta por el grupo del profesor Omura, en colaboración con la industria farmacéutica. Se ha demostrado que la ivermectina inhibe la interacción entre la proteína viral y el heterodímero de importina α/β1, lo que provoca la inhibición de la replicación del virus. Recientemente, este mecanismo de acción de la ivermectina frente al SARS-CoV-2 fue demostrado en células Vero/hSLAM. A la fecha, se conocen los resultados de un ensayo clínico en Argentina que comprueba la utilidad de la ivermectina en las etapas tempranas de la enfermedad; asimismo, en el mundo se registran alrededor de 40 estudios clínicos que buscan confirmar su importancia como un tratamiento costo-efectivo para COVID-19. Respecto a la seguridad, en estos años la ivermectina ha demostrado ser un fármaco bien tolerado.
... It was originally targeted for the treatment of animals; however, it has now been shown to be safe in humans for the treatment of parasitic infections [50]. In addition to its anti-parasitic mode of action, ivermectin has been shown to inhibit α/β mediated nuclear import of viral particles by the inhibition of the interaction between integrase and importin [51]. This is an important mechanism, which subsequently reduces viral replication. ...
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The capacity for social media to influence the utilization of re-purposed medicines to manage COVID-19, despite limited availability of safety and efficacy data, is a cause for concern within health care systems. This study sought to ascertain links between social media reports and utilization for three re-purposed medicines: hydroxychloroquine (HCQ), ivermectin and colchicine. A combined retrospective analysis of social media posts for these three re-purposed medicines was undertaken, along with utilization and clinical trials data, in South Africa, between January 2020 and June 2021. In total, 77,257 posts were collected across key social media platforms, of which 6884 were relevant. Ivermectin had the highest number of posts (55%) followed by HCQ (44%). The spike in ivermectin use was closely correlated to social media posts. Similarly, regarding chloroquine (as HCQ is not available in South Africa), social media interest was enhanced by local politicians. Sentiment analysis revealed that posts regarding the effectiveness of these repurposed medicines were positive. This was different for colchicine, which contributed only a small number of mentions (1%). Of concern is that the majority of reporters in social media (85%) were unidentifiable. This study provides evidence of social media as a driver of re-purposed medicines. Healthcare professionals have a key role in providing evidence-based advice especially with unidentifiable posts.
... It has been an approved drug for human use for >30 years to treat a broad spectrum of parasitic infections. (11) It has demonstrated in vitro antiviral activity against several types of viruses in addition to SARS-CoV-2, such as dengue, Venezuelan equine encephalitis, and avian influenza A virus. (12) The concern with using ivermectin orally or by injection as a therapy for COVID-19 is that achieving the concentrations of ivermectin demonstrated to inhibit SARS-CoV-2 in vitro would likely result in dose-limiting side-effects. ...
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Background: Ivermectin has received worldwide attention as a potential COVID-19 treatment after showing antiviral activity against SARS-CoV-2 in vitro. However, the pharmacokinetic limitations associated with oral administration have been postulated as limiting factors to its bioavailability and efficacy. These limitations can be overcome by targeted delivery to the lungs. In this study, inhalable dry powders of ivermectin and lactose crystals were prepared and characterized for the potential treatment of COVID-19. Methods: Ivermectin was co-spray dried with lactose monohydrate crystals and conditioned by storage at two different relative humidity points (43% and 58% RH) for a week. The in vitro dispersion performance of the stored powders was examined using a medium-high resistance Osmohaler connecting to a next-generation impactor at 60 L/min flow rate. The solid-state characteristics including particle size distribution and morphology, crystallinity, and moisture sorption profiles of raw and spray-dried ivermectin samples were assessed by laser diffraction, scanning electron microscopy, Raman spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption. Results: All the freshly spray-dried formulation (T0) and the conditioned samples could achieve the anticipated therapeutic dose with fine particle dose of 300 μg, FPFrecovered of 70%, and FPFemitted of 83%. In addition, the formulations showed a similar volume median diameter of 4.3 μm and span of 1.9. The spray-dried formulations were stable even after conditioning and exposing to different RH points as ivermectin remained amorphous with predominantly crystalline lactose. Conclusion: An inhalable and stable dry powder of ivermectin and lactose crystals was successfully formulated. This powder inhaler ivermectin candidate therapy appears to be able to deliver doses that could be safe and effective to treat the SARS-COV-2 infection. Further development of this therapy is warranted.
... Ivermectin's anti-parasitic mode of action is to enhance inhibitory neurotransmission by binding to glutamate-gated chloride channels. It has been shown to be effective against several positivesense single-strand RNA viruses including SARS-CoV-2, and has been proposed as a strong COVID-19 drug candidate [15][16][17]. It inhibits replication of SARS-CoV-2 in monkey kidney cell culture with an IC 50 of 2.2-2.8 ...
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Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.
... Ivermectin have also antiviral activity against both RNA and DNA viruses [40]. Recently in April 2020, the in-vitro activity of Ivermectin against SARS-CoV-2 was reported [41]. Ivermectin's antiviral mechanism of action in COVID-19 may be block the activity of α/β1 receptors, which inhibiting viral protein transport in and out of the host nucleus [42]. ...
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In the present study, we have described how by using molecular docking and molecular dynamics (MD) simulation studies the combination drug of ivermectin and doxycycline can be used as a potential inhibitor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) virus. In lieu of unavailability of specific cure of coronavirus disease of 2019 (COVID-19) till now various possibilities for individual and combination drugs have been explored by the medical practitioners/scientists for the remedial purpose of CoV-2 infections. 3C-like protease (3CL pro ) is the main protease of SARS-CoV-2 virus which plays an essential role in mediating viral replication in the human body. 3CL pro protein can serve as an attractive drug target. In this work, we have studied drug: 3CL pro interactions by in-silico molecular docking and MD simulation approaches. Common and easily available antiviral drugs ivermectin, doxycycline and their combination can regulate 3CL pro protein's function due to its easy inhibition.
... The antiviral activity of IVM had been reported previously, wherein IVM was found to have in-vitro activity against both RNA and DNA viruses including human immunodeficiency virus type 1, influenza virus, Venezuelan equine encephalitis virus, dengue virus, yellow fever virus and Zika virus [7,8]. In April 2020, the in-vitro activity of IVM against SARS-CoV-2 was reported: a single dose of the drug administered after 2 h of infecting cultured Vero/hSLAM cells reduced the viral load up to 5000 times within 48 h [9]. ...
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Introduction and Objective Ivermectin (IVM) and doxycycline (DOXY) have demonstrated in-vitro activity against SARS-CoV-2, and have a reasonable safety profile. The objective of this systematic review was to explore the evidence in the literature on the safety and efficacy of their use as monotherapy and combination therapy in COVID-19 management.Methods After prospectively registering the study protocol with the Open Science Framework, we searched PubMed, Google Scholar, clinicaltrials.gov, various pre-print servers and reference lists for relevant records published until 16 February, 2021 using appropriate search strategies. Baseline features and data pertaining to efficacy and safety outcomes were extracted separately for IVM monotherapy, DOXY monotherapy, and IVM + DOXY combination therapy. Methodological quality was assessed based on the study design.ResultsOut of 200 articles screened, 19 studies (six retrospective cohort studies, seven randomised controlled trials, five non-randomised trials, one case series) with 8754 unique patients with multiple stages of COVID-19 were included; four were pre-prints and one was an unpublished clinicaltrials.gov document. The comparator was standard care and ‘hydroxychloroquine + azithromycin’ in seven and three studies respectively, and two studies were placebo controlled; six studies did not have a comparator. IVM monotherapy, DOXY monotherapy and IVM + DOXY were explored in eight, five and five studies, respectively; one study compared IVM monotherapy and IVM + DOXY with placebo. While all studies described efficacy, the safety profile was described in only six studies. Efficacy outcomes were mixed with some studies concluding in favour of the intervention and some studies displaying no significant benefit; barring one study that described 9/183 patients with erosive esophagitis and non-ulcer dyspepsia with IVM + DOXY (without causality assessment details), there were no new safety signals of concern with any of the three interventions considered. The quality of studies varied widely, with five studies having a ‘good’ methodological quality.Conclusions Evidence is not sufficiently strong to either promote or refute the efficacy of IVM, DOXY, or their combination in COVID-19 management.Systematic Review Protocol Registration DetailsOpen Science Framework: https://osf.io/n7r2j.
... It was suggested that IVM might be used for the treatment of COVID-19 patients in the early phase with mild to moderate symptoms, PCR positive for SARS-CoV-2 virus, and those without comorbidities such as chronic obstructive pulmonary disease, diabetes, hypertension, obesity, acute or chronic renal failure, and coronary diseases. IVM suggested anti-CoV-2 effects are based on in vitro studies, showing that this compound inhibits the importin alpha/beta-1 nuclear transporter, and thus, in cell cultures, reduces the replication of various viruses including SARS-CoV-2 (Bray et al. 2020;Caly et al. 2020;Rizzo 2020;Sharun et al. 2020;Heidary and Gharebaghi 2020;Dixit et al. 2020;Chaccour et al. 2020a, b;Formiga et al.2020). In addition, in a silico-based analysis of Ivermectin's molecular interaction indicates positive interaction of Ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain) (Kaur et al. 2021). ...
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The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl- hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC50 values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 ( P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug-drug or drug-toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.
... Ivermectin is a semisynthetic anthelmintic agent that selectively binds to glutamate-gated chloride ion channels found in nerve and muscle cells of invertebrates (3). However, an antiviral activity in RNA and DNA viruses has also been reported (4). ...
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Background: To assess the outcomes of ivermectin in ambulatory and hospitalized patients with COVID-19. Methods: Five databases and websites for preprints were searched until January 2021 for randomized controlled trials (RCTs) and retrospective cohorts assessing ivermectin versus control in ambulatorys or hospitalized participants. The primary outcome was overall mortality. Secondary outcome was the recovered patients. For meta-analysis, random-effects and inverse variance meta-analyses with logarithmic transformation were performed. ROBINS-I for cohort studies, and the Cochrane Risk of Bias 2.0 tool for trials were used. The strength of evidence was assessed using GRADE. Results. After the selection, twelve studies (five retrospective cohort studies, six randomized clinical trials and one case series), were included. In total, 7412 participants were reported, the mean age was 47.5 (SD 9.5) years, and 4283 (58%) were male. Ivermectin is not associated with reduced mortality (logRR: 0.89, 95% CI 0.09 to 1.70, p = 0.04, I2= 84.7%), and it was not associated with reduced patient recovery (logRR 5.52 , 95% CI -24.36 to 35.4, p = 0.51, I2 = 92.6%). All studies had a high risk of bias, and showed a very low certainty of the evidence. Conclusions: There insufficient certainty and quality of evidence to recommend the use of ivermectin to prevent or treat ambulatory or hospitalized patients with COVID-19.
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Purpose The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). Method Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. Results Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. Conclusion In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.
Article
COVID-19 is an emerging, rapidly evolving situation worldwide. It is a contagious respiratory disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) which spreads through air (droplet infection) when an infected person sneezes or coughs. The SARS CoV-2 is a 50 nm, positive sense single stranded RNA virus and it is diagnosed from a nasopharyngeal swab by real-time Reverse Transcriptase Polymerase Chain Reaction test (RT-PCR). It produces symptoms like fever, fatigue, dry cough, breathing difficulties and loss of smell and taste. It can cause both Upper and Lower Respiratory tract infections. Although there are many clinical trials going on worldwide to test possible therapies there are a few older, FDA approved drugs that can fight COVID-19. One of these drugs is Ivermectin, used to treat parasitic infections. It has in vitro antiviral effects and has shown to inhibit replication in SARS CoV-2. Ivermectin is a safe, FDA approved drug which has high efficacy. Therefore, it could serve as potential treatment for mild to moderate SARS CoV-2 infections.
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Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
Article
Background We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration. Methods We conducted an uncontrolled non-comparative observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU). Results All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care. A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5. Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days. Conclusion We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease. Furthermore, the cost of treatment is negligible.
Article
Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
Article
Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously provisionally named 2019 novel coronavirus or 2019-nCoV) disease (COVID-19) in China at the end of 2019, has caused a large global outbreak and a major public health issue. As of February 11, 2020, data from the WHO has shown that more than 43,000 confirmed cases have been identified in 28 countries/regions, with more than 99% of the cases being detected in China. On January 30, 2020, WHO has declared COVID-19 as the sixth public health emergency of international concern. The SARS-CoV-2 is closely related to two bat-derived severe acute respiratory syndrome-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. It is spread by human-to-human transmission via droplets or direct contact, and infection has been estimated to have mean incubation period of 6.4 days and a basic reproduction number of 2.24-3.58. Among the patients with pneumonia caused by the SARS-CoV-2 (novel coronavirus pneumonia or Wuhan pneumonia), fever was the most common symptom, followed by cough. Bilateral lung involvement with ground glass opacity was the most common finding from computerized tomography images of the chest. Although the one case of SARS-CoV-2 pneumonia in the United States responding well to remdesivir, which is now undergoing a clinical trial in China. Currently, controlling infection to prevent the spread of the SARS-CoV-2 is the primary intervention being used. However, public health authorities should keep monitoring the situation closely, as the more we can learn about this novel virus and its associated outbreak, the better we can respond.
Article
Pseudorabies virus (PRV) is an important viral pathogen of pigs that causes huge losses in pig herds worldwide. Ivermectin is a specific inhibitor of importin-α/β-dependent nuclear transport and shows antiviral potential against several RNA viruses by blocking the nuclear localization of viral proteins. Since the replication of DNA viruses is in the nucleus, ivermectin may be functional against DNA virus infections if the DNA polymerase or other important viral proteins enter the nucleus via the importin-α/β-mediated pathway. Here, we determined whether ivermectin suppresses PRV replication in hamster kidney BHK-21 cells and investigated the effect of ivermectin on the subcellular localization of the PRV UL42 protein, the accessory subunit of PRV DNA polymerase. Also, an in vivo anti-PRV assay was conducted in mice. Our data demonstrate that ivermectin treatment inhibits PRV infection in cells in a dose-dependent manner. Treatment of PRV-infected cells with ivermectin significantly suppressed viral DNA synthesis and progeny virus production. Ivermectin disrupted the nuclear localization of UL42 by targeting the nuclear localization signal of the protein in transfected cells. Ivermectin treatment increased the survival rates of mice infected with PRV and relieved infection as indicated by lower clinical scores and fewer gross lesions in the brain. Together, our results suggest that ivermectin may be a therapeutic or preventative agent against PRV infection.