![An approved regimen of IVM for treating COVID-19 as per the health department of the Republic of Peru [46]](https://www.researchgate.net/publication/343742900/figure/tbl2/AS:926246057811976@1597845677772/An-approved-regimen-of-IVM-for-treating-COVID-19-as-per-the-health-department-of-the_Q320.jpg)
Available via license: CC BY 4.0
Content may be subject to copyright.
Vol 13, Issue 8, 2020
Online - 2455-3891
Print - 0974-2441
A REVIEW ON THE ANTIPARASITIC DRUG IVERMECTIN FOR VARIOUS VIRAL INFECTIONS
AND POSSIBILITIES OF USING IT FOR NOVEL SEVERE ACUTE RESPIRATORY SYNDROME
TALHA JABEEN*, MOHD ABDUL KHADER, SHAYESTHA JABEEN2
Department of Pharmacy Practice, Bhaskar Pharmacy College, Jawaharlal Nehru Technological University, Hyderabad, Telangana, India.
2Department of Pharmacy Practice, MRM College of Pharmacy, Jawaharlal Nehru Technological University, Bongloor, Telangana, India.
Received: 17 May 2020, Revised and Accepted: 20 June 2020
ABSTRACT
The novel coronavirus infection has spread all over the world. With no specific drug or vaccine, the process of “drug repurposing” becomes a feasible
solution. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has 80% sequence similarity with the SARS-CoV, the nuclear import
inhibitor “Ivermectin” (IVM) has recently been studied as a possible treatment option for coronavirus disease-2019 (COVID-19). The article aims to
provide a review on structure and immunogenicity of SARS-CoV-2, indications of IVM for viral diseases, its possible mechanism on COVID-19 with
a brief discussion on IVM structure, pharmacokinetics, adverse drug reactions, drug interactions, and contraindications. Further, we made possible
comparisons of IVM with solidarity trial drugs and analyzed its major advantages, limitations and gave necessary recommendations for its use in
future in vivo studies in the treatment of COVID-19.
Keywords: Severe acute respiratory syndrome coronavirus 2, Coronavirus disease-2019, Ivermectin, Drug repurposing, Solidarity trial.
INTRODUCTION
In December 2019, multiple cases of pneumonia with unknown cause
were detected in Wuhan, Hubei Province of China. Soon, the health
authorities have found links to these cases with South China seafood
market. With the doubt of the origin of a similar outbreak in China
in the year 2002 (severe acute respiratory syndrome coronavirus
2 [SARS-CoV]) and 2012 (Middle East Respiratory Syndrome,
[MERS-CoV]) and a new zoonosis transmission, the investigation was
undertaken that have since identified a novel coronavirus, SARS-COV-2
(Formerly 2019-nCoV) [1]. This novel SARS-CoV-2 has taken the world
by storm through the current outbreak of coronavirus disease-2019
(COVID-19) and continues to spread in every continent except
Antarctica. As of May 17, 2020, there have been 4,736,104 confirmed
cases and 313,498 deaths with World Health Organization (WHO)
calling the outbreak “global health emergency” in January 2020 and
have now declared COVID-19 a “global pandemic” because of the
unusually fast rate in which the virus is spreading. China as of now in
May has controlled its peak and Europe has now emerged as the new
epicenter of COVID-19 pandemic [2,3].
As it is a newly emerged virus, researchers have taken quick actions
to isolate the viruses and perform gene sequencing, making identifying
treatments possible. As an urgent need for pharmacological therapies
is on exponential demand due to high infection and mortality rates,
developing now, a new drug or vaccine seems to be a difficult and time-
consuming task. With time requiring to explore their biotherapeutics
and to achieve global immunization, millions of people already could
have infected or dead. Therefore, the idea of “Drug repositioning”
(also called repurposing), i.e., the investigation of existing approved
drugs for new therapeutic purposes, seems to be logical to provide
treatment as fast as possible to the millions of COVID-19 survivors
most safely and cost-effectively [4,5]. Ivermectin (IVM), one such drug
which is originally used to treat parasitic infections, has recently been
found to inhibit the replication of novel SARS-CoV-2 within 48 h in
laboratory settings [6]. The very recent observational registry-based
study from 169 hospitals across different countries revealed that IVM
treated group of COVID-19 critically ill patients requiring mechanical
ventilation has lower mortality and healthcare resource used [7]. IVM
is an Food and Drug Administration (FDA)-approved anti-parasitic drug
that has also been shown to be effective in vitro against a broad range
of viruses, including human immunodeficiency virus (HIV), dengue, and
influenza [8,9].
This article reviews the structure and immunogenicity of SARS-CoV-2,
uses of IVM for various viral diseases, its possible role for SARS-CoV-2, and
briefly explaining its structure, pharmacokinetics (PK’s), adverse drug
reactions (ADR’s), drug interactions (DI’s), contraindications (CI’s), and
finally its comparison over safety, efficacy, and ease of administration to
the drugs in the solidarity trial.
SARS-CoV-2 belongs to beta-coronavirus lineage β, sarbecovirus,
where SARS-CoV and MERS-CoV are included. By forming a new clade
different from SARS-CoV and MERS-CoV, it became the seventh member
of the coronavirus family to infect humans. This novel virus was initially
identified through the next gene sequencing and suggested to have a
possible zoonotic origin [10].
The whole-genome sequencing of the novel coronavirus reveals that it
shares a 40% sequence similarity with MERS-CoV and 80% sequence
similarity with SARS–CoV, indicating that SARS- CoV-2 is much more
comparable with SARS-CoV [11].
The novel coronavirus is an envelope, single, and positive-stranded RNA
virus. The virus particles are round or oval, with an average diameter
of about 60–140 nm.
The transmission electron microscopy imaging of SARS CoV-2 from
Indian researchers indicated their relatively shorter size and a possible
multi-aggregate of the peplomer [12]. A peplomer is a glycoprotein
spike on a viral capsid or viral envelope binding to certain receptors
on the host cells and is essential for both host specificity and viral
© 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2020.v13i8.38357
Review Article
22
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
infectivity. With immunogenicity much closer to SARS-CoV, it has been
found that SARS-CoV-2 uses the SARS-CoV receptors angiotensin-
converting enzyme 2 for entry and serine protease TMPRSS2 for S
protein priming [13]. Further, SARS-CoV proteins have revealed a
potential role for IMP α/β1 during infection in the single-dependent
nucleocytoplasmic shutting of the SARS-CoV nucleocapsid protein that
may impact host cell division [14].
SARS-CoV-2 has the typical beta-coronavirus organization: 5’
untranslated region (UTR), replication enzyme coding region, S gene, E
gene, M gene, N gene, 3’ UTR, and several unidentified non-structural
open reading frames (ORFs). It was revealed before that the accessory
ORFs of SARS-CoV are unique to each different strain of CoV and are
predicted to encode functions important in pathogenesis. Among the
SARS-CoV accessory ORFs-ORF3a, ORF6, ORF7a, and ORF7b are not
essential for in vitro or in vivo replication or release of infectious viruses,
but each one of them is reported to be incorporated into the virion [15].
IVM
The labeled “Wonder drugs,” avermectins were discovered by Omura
and Campbell from the bacterium Streptomyces avermitilis. After
purifying avermectins from a culture obtained from Omura by Campbell
and led efforts leading to the discovery of IVM in 1975, a derivative of
greater potency and lower toxicity. IVM, the first avermectin drug, was
introduced as a veterinary drug by Merck and Co. in 1981, and new
formulations were released every year. At that time, the human use of
IVM was not much established. It was in 1987, IVM was first registered
as human drug under the brand name Mectizan® after its efficacy
against filarial nematodes were shown.
In 1988, IVM was first used to treat onchocerciasis in humans. As the
years passed, its efficacy for an expanding number of other parasitic
diseases was established. Interest has mainly grown on IVM as it
showed greater potency and lower toxicity for treating parasitic
infections. It is worth noting that half of the 2015 Noble Prize in
Physiology and Medicine was awarded jointly to Campbell and Omura
for their discovery of IVM. Since its discovery, the anti-parasitic uses of
IVM have increased and its promising role in non-parasitic infections
continues to accumulate. The drug is approved by FDA and is on the
WHO’s list of essential medicine.
Today IVM is one of the most used and best known antiparasitic drugs
in human and veterinary medicine. IVM currently uses for the treatment
of lymphatic filariasis, onchocerciasis, strongyloidiasis, trichinellosis,
ectoparasite infestations, pediculosis, scabies, myiasis, and malaria.
The antiparasitic activity of IVM is through the activation of glutamate-
gated chloride channels, γ-aminobutyric acid (GABA) transmission in
worms, and thereby resulting in their paralysis and death [14,16].
IVM FOR VIRAL DISEASES
IVM has shown a promising treatment option for certain viral
pathogens. We conducted a literature search of Google Scholar,
PubMed, and Scopus databases regardless of the publication dates of
the articles. All search protocols were in accordance with Preferred
Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA)
guidelines for systemic reviews. The keywords such as “IVM” and
“VIRAL INFECTIONS” were used. The titles of the top 200 articles from
1960 to 2020 were then read. After screening for their appropriateness
and removing duplicates, a total of 11 articles met the inclusion criteria
revealing the potential anti-viral efficacy of IVM for 12 viral pathogens
which are summarized in Table 1.
From all these studies mentioned in Table 1, it can be concluded that
IVM exerts its antiviral activity mainly through inhibition of nuclear
import activity. Most of the mentioned studies concluded that IVM
possesses a dose-dependent antiviral activity. However, at higher
doses, cytotoxicity can also occur [22]. These studies were primarily
performed in in vitro settings.
As the immunogenicity of SARS-CoV-2 is much closer to that of SARS-
CoV, studies on SARS- CoV protein have revealed a potential role for
IMPα/β during infection in signal-dependent nucleocytoplasmic
shuttings of the SARS-CoV nucleocapsid proteins that may disrupt
the host cell division [28]. In another study by Mathew Frieman, it
was found that accessory SARS ORF6 antagonizes STAT1 function
by sequestering nuclear import factors on the rough endoplasmic-
reticulum/Golgi membrane [15].
As IVM has been an effective anti-viral agent through nuclear transport
inhibitory activity (observed from the Table 1), it can inhibit importin
α/β mediated transport of SARS-CoV-2 viral proteins into the nucleus
resulting in the inhibition of SARS-CoV-2 RNA replication process. The
mechanism of action of IVM against SARS-CoV-2 is shown in Fig. 1.
The recent study by Caly et al. [6] from Australia has evaluated the
above promising mechanisms of IVM for SARS-CoV-2. The study reveals
that IVM at a dose of 5 µM inhibits the replication of SARS-CoV-2 in vitro
with an IC50 of 2.2–2.8 µM, which is similar to the efficacy of IVM in
dengue virus (IC50: 2.2µM for DENVI). Further, a single addition of
IVM 2-h post-infection with SARS-CoV-2 was able to effect ≈5000 fold
reduction in viral RNA at 48 h. At 24th h, there was a 93% reduction in
viral RNA and a 99.98% reduction at 48th h. In an observational registry-
based study [7] from 169 hospitals with 1970 COVID-19 patient’s
with lung injury requiring mechanical ventilation across Asia, Europe,
Africa, North, and South America, the IVM, 150 mcg/kg treatment group
(n=52) has lesser mortality rate, length of stay in intensive care unit and
hospital compared to that of n=1918 conventionally treated patients
(mortality rate=7.7% vs. 18.6%; hospital length of stay=10.9±6.1
days vs. 15.7±8.1 days, and intensive care unit length of stay=6.0±3.9
days vs. 8.2±6.2 days for IVM, and conventional treatment group resp,
all at p<0.001 resp). This study was first of its kind for evaluating the
significance of IVM in the treatment of COVID-19 in in vivo.
These results make IVM a possible candidate for COVID-19 drug
repurposing research.
STRUCTURE, PK’S, ADR’S, DI’S, AND CI’S TO IVM
Structure
The avermectins are a class of macrocyclic lactones with nematocidal,
acaricidal, and insecticidal activities. IVM is a derivative of naturally occurring
avermectin B1, composed of approximately 80% of 22,23-dihydro-
avermectin B1a ( molecular weight, 875.10 g/mol) and approximately 20%
22,23-dihydro-avermectin B1b ( molecular weight, 861.07 g/mol) [14].
The structural components of IVM are shown in Fig. 2. The structure is
downloaded from (https://dailymed.nlm.nih.gov) [29].
PK’s
The IVM has favorable PK characteristics. IVM can be given orally,
topically, or through injection. However, only oral IVM is a licensed
route of administration for human use. It has rapid oral absorption,
and higher lipid solubility and is widely distributed in the body. It
reaches peak plasma levels in 3.5–5 h after an std. oral dose in healthy
humans and plasma half-life has been reported to be 12–66 h. Oral IVM
is available in different forms, i.e., solution, tablet, and capsules with
solutions having approximately twice systemic availability compared
with solid forms (tablets and capsules). Its bioavailability gets increased
post-high-fat meal intake due to its higher lipid solubility. For healthy
adults, the volume of distribution is approximately 46.9 l. It has 93%
protein binding and elimination half-life of 18 h. It is metabolized in the
liver microsomes by a cytochrome p450 enzyme system with at least
ten metabolites, mostly hydroxylated and demethylated derivatives.
Excretion mainly occurs in feces in about 12 days. Less than 1% of
the drug is excreted in the urine. It does not readily cross the blood–
brain barrier due to the presence of p-glycoprotein, but crossing can be
significant at higher doses [14].
23
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
Virus Disease Study design Mechanism of action of IVM Reference
Dengue virus (DENV1-4) Dengue In vitro 0.4–45 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[17]
Pseudorabies virus (PRV) Pseudorabies In vitro+In vivo 2.5, 5 By inhibiting nuclear import of PRV
UL42
[18]
Porcine reproductive and
respiratory syndrome
virus (PRRS)
Porcine reproductive
and respiratory
syndrome
In vitro 1–15 Inhibits PRRSV infection in PAM-
PCD 16 3 cells
[19]
Chikungunya virus
(CHIKV)
Chikungunya In vitro 0.1–10 Inhibiting intracellular viral RNA
synthesis
[20]
Human immunodeficiency
virus-1 (HIV-1)
Acquired
immunodeficiency
syndrome
In vitro 25, 50 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[21]
Newcastle disease virus
(NDV)
Virulent Newcastle
disease
In vitro 0.25, 12.5, 25, 50 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[22]
West Nile virus (WNV) West Nile fever In vitro 0.1–100 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[23]
Zika virus (ZIKV) Zika virus disease In vitro 0.1–100 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[23]
Bovine herpes virus (BHV) Rhinotracheitis,
vaginitis,
balanoposthitis,
abortion,
conjunctivitis, enteritis
In vitro 5, 12.5, 25 By inhibiting nuclear import
of UL42 and reducing BOHV-1
replication
[24]
Venezuelan Equine
encephalitis virus (VEEV)
Venezuelan equine
encephalitis
In vitro 1By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[25]
Yellow fever virus (YFV) Yellow fever In vitro 0.78, 1.56, 3.13,
6.25, 12.5, 25, 50,
100
By inhibiting N S3 helicase [26]
Influenza A virus Influenza In vitro 10 By inhibiting importin α/β
mediated transport of viral proteins
into the nucleus
[27]
Mechanism of action of Ivermectin against severe acute respiratory syndrome coronavirus 2
General dose and administration: IVM is administered as a single dose
of 150 mg/kg given annually for its antifilarial activity.
3 mg PO (15–24 kg): Doses can be given according to body weight and
incorporated as 6 mg (35 kg), 9 mg (50 kg), 12 mg (65 kg), and 15 mg,
150 mcg/kg ,and 200 mcg per kg (≥80 kg).
IVM should be taken on an empty stomach (1 h before a meal) or 2-h
post-meal.
ADR’s
IVM is a generally well-tolerated drug with a good safety profile. The
drug is used approximately 250 million people for parasitic diseases
24
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
because of its greater potency and lower toxicity. The most common
adverse effects reported include myalgia, rashes, node tenderness,
swelling, itching, fever and chills, limb, joints, and facial swelling. The
effects are usually mild to moderate and respond well with analgesics
or anti-histamines. They almost always appear during the first 3 days
following treatment and subside thereafter with a reduction in parasitic
load. Further, these ADR’s effects are mainly linked to an immune
mechanism with parasitic involvement.
An uncommon severe potentially dangerous symptomatic postural
hypotension occurred in 37 of approximately 14,000 patients treated
in Ghana and was associated with fainting, sweating, tachycardia, and
rarely confusion. Systemic corticosteroids instituted in such patients,
but their requirement was not established [30].
Neurotoxicity has also been the main concern, but reviews of the cases
with the extensive post-marketing experience show that several such
events are likely to be rare, with controversial mechanisms mostly
suggesting the role of concomitant infections such as Loa-Loa allowing
IVM penetration into the central nervous system (CNS) due to Mdr-1
gene in humans.
In a large scale study from eight community trials with 50,929 patients
given IVM and monitored for 72 h, 9% reported with ADRs, 2.4% with
moderate reactions, and 0.24% with severe reactions, three cases
of life-threatening dyspnea apart from postural hypotension were
reported. The investigation suggested that IVM is sufficiently safe
for large scale treatment and monitoring for at least 36 h by resident
nurses is recommended [31]
No significant changes in electrocardiographic parameters were
observed in IVM treated patients.
In a study by Plaque et al. with 200 pregnant women’s treated with IVM,
the risk of fetal damage was not greater than in control women’s. The
investigation recommends most of the pregnant women treated with
IVM should continue its use [32].
The Mazzotti reaction can occur during the treatment of filariasis.
However, the reaction is more common with Diethylcarbamazine and
less likely with IVM, manifesting as complex of multiple infections and
respond well with I.V. therapy of methylprednisolone.
Regarding blood-related disorders, hamatomatous swelling was
reported in 2 out of 28 onchocerciasis patients treated with IVM
(50 µg/kg) with increment in prothrombotic time above baseline by
1 week to 1 month after drug ingestion.
Interactions
Since IVM is metabolized by the CYP450 enzyme system, the inhibition
and induction of the enzyme can influence the IVM metabolic activity.
Doxycycline enhances IVM induced suppression of microfilariae virus
and has beneficiary effects. Information about the influence of food
in Pk’s of IVM is scarce. Coadministration of alcohol with IVM is not
recommended because IVM is associated with GABA receptors and
the effect of alcohol in the CNS. The plasma concentration of IVM was
significantly greater in patients who drank 750 ml beer (66.37, 109, and
97.2 ng/ml at 1, 3, and 4 h resp) versus those who drank 750 ml water
(44.0, 67.5, and 58.7 ng/ml, resp, p<0.01 at each time point).
IVM administration with orange juice or water resulted in a decreased
area under the curve with orange juice (15.7 ng/ml) and Cmax
(20.7 ng/ml) compared to water (33.8 ng/ml, and 24.3 ng/ml) possibly
because fruit juice and constituents are potent inhibitors of certain
drugs transporters [33].
COMPARISON OF IVM WITH SOLIDARITY TRIAL BY THE WHO
The WHO has initiated a solidarity trial of four most promising COVID-19
treatments, to find out whether any of these can treat infections from
the novel coronavirus, causing dangerous respiratory disease.
The drugs that solidarity will test are:
1. Remdesivir
2. Chloroquine and hydroxychloroquine (HCQ).
3. Ritonavir and lopinavir
4. Ritonavir, lopinavir, and interferon β.
The efficacy of all the above drugs for novel SARS-CoV-2 has been
proposed by the researchers extensively.
Remdesivir
Originally developed as a treatment option for Ebola virus disease
and Marburg virus infection and did not make to come in the market
yet and is not licensed nor approved by the FDA. The drug had shown
promising results for the previous coronavirus SARS-CoV and MERS-
CoV and is currently hoping to provide treatment for SARS-CoV-2.
However, the data on its safety profile are lacking. As a typical antiviral
drug, it has shown side effects such as nausea and vomiting. In the Ebola
trial, researchers detected increased liver enzymes in their patients.
Similar adverse effects of remdesivir in increasing liver enzymes are
documented by 23% of COVID-19 patients [34]. Further, many ADR’s of
drugs are mainly documented during its post-marketing surveillance.
As the drug is soon to come to patients because of the unmet patient
needs from COVID-19, a longer time may be needed to establish its
safety. Remdesivir can only be administered through intravenous
injection, which makes difficulty for its production, requiring sterile
drug product manufacturing and administration to COVID-19 patients
as the presence of doctor or nurse to administer the medicine is must,
regarding their safety and protection and in case if there is a shortage
of healthcare workers. Further, it is an expensive drug. As IVM is in the
market for four decades and is used annually by 250 million people, it
has good oral bioavailability and affordable price, IVM, if it shows good
efficacy for SARS CoV-2 in large trials, could be much a patient-friendly
treatment option.
Chloroquine and HCQ
Chloroquine and HCQ have taken the pharma industry to storm with
a rush in its requirement since the studies published its efficacy for
SARS-CoV-2. The drug primarily used for Malaria was discovered back
in 1934. Chloroquine has a variety of side effects, and, in some cases,
can cause more harm than good [35]. Both chloroquine and HCQ can
cause cardiac electrocardiogram QT-prolongation and subsequent
arrhythmias, including torsade de points. The drugs have several drug
interactions, and there is also not enough data to determine whether
chloroquine is safe to be given to patients aged 65 and older. As the old
age is more at risk for illness with SARS-CoV-2 and deaths, chloroquine,
if given to them, should additionally be a monitor for its toxicity on
kidney function. Since IVM has very few adverse effects, it could provide
better safety over chloroquine and HCQ under large study trials.
Ritonavir/lopinavir
Is a fixed-dose combination medicine used for the treatment and
prevention of HIV/AIDS. The combination is an effective treatment
Fig. 2: Structural components of ivermectin
25
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
option for the COVID-19 with trials going on. As an antiviral drug, they
have an adverse effect of causing nausea and vomiting, diarrhea has
been observed in 27% of patients in the clinical trials. Elevation in liver
enzymes is commonly observed during ritonavir/lopinavir treatment.
It has varying degrees of interactions with other medications that are
also CYP3A or P-glycoprotein substrates. FDA has issued safety labels
in patients with heart patients [36]. Further, the drug is high in cost.
Therefore, IVM with lesser adverse effects and cost could be a better
option if it gets satisfied with clinical trial results.
Ritonavir/lopinavir+interferon-β
Solidarity is also having an arm that combines the two antivirals
with interferon-β, molecules used for communication between cells
to trigger the protective defense of the immune system that helps
to eradicate the pathogens. Interferons are mostly administered by
intramuscular injections. Interferon therapy in addition to side effects
of flu-like symptoms, ill feel, analgesia, and convulsions can cause
immunosuppression [37]. The decreasing efficacy of the immune
system could worsen the COVID-19 patient’s condition instead of
helping them. The cost of interferons is also much higher. Therefore,
IVM with less adverse events and cost affordability could be a better
option for patients if larger trials get success.
LIMITATIONS AND RECOMMENDATIONS FOR IVM IN THE
The major limitation of all these previous studies (mentioned in
Table 1) is the efficacy of IVM as an antiviral agent has been performed
in-vitro only with the exception of pseudorabies virus done both
in vivo (mice) and in vitro. Recently published report of IVM efficacy
against novel SARS-CoV-2 by Australian researchers has also been
performed in in vitro laboratory settings. We found only a single
study indicating IVM use for COVID-19 patient’s in humans. Further,
we also think that the dosage adjustment of IVM when treating
COVID-19 is particularly important as cytotoxicity was observed at
higher doses. Schmith et al. [38] stated that the drug concentration
required to kill SARS-CoV-2 (IC50, 2Μm) as reported by Caly et al., and
was >35× higher than maximum plasma concentration (Cmax) after
oral administration of an approved dose of IVM when given fasting,
though, the usual dose of IVM 150 mcg/kg used by Patel et al. and
was found satisfactory in treating COVID-19 patients. Therefore, the
possible safety and efficacy of IVM use for viral infections in humans
need much validation. Large scale studies on animals and humans
are needed to determine whether IVM might be safe and effective to
prevent or treat COVID-19.
We also suggest that people should be made aware to not self-medicate
by taking IVM intended for animals, as it was witnessed with an elderly
couple taking chloroquine phosphate, an additive use to clean fish tanks
as a prophylactic measure for COVID-19 resulted in the death of a man and
his wife needing critical care. There could be a rush in the market for IVM
by people, so pharmacists must not dispense IVM without prescription
by licensed health-care providers. The authorities should be watchful for
the selling of IVM in the market in comparison to the previous years and
make sure that the drug should be available for the ones who need it.
CLINICAL TRIALS DESIGNED TO STUDY THE EFFECTIVENESS OF
A total of seven clinical trials have been registered under Clinical
Trials.gov aim to evaluate the efficacy of IVM in treating COVID-19
(Table 2) [39-45].
Table 2: Different clinical trials registered under clinical trials.gov to evaluate the efficacy of IVM against SARS-CoV-2
S. no. Study title Intervention/treatment Phase Estimated
enrollment
Actual/
Estimated
study start date
Actual/Estimated
study completion
date and References
1. Ivermectin Adjuvant to
Hydroxychloroquine and
Azithromycine in COVID19
Patients (ClinicalTrials.gov
Identifier: NCT04343092)
Drug: Ivermectin
Drug: Hydroxychloroquine
Sulfate
Drug: Placebos
Drug: Azithromycin 500 mg
Phase 1 50
participants
April 18, 2020 August 1, 2020 [39]
2. Max Ivermectin- COVID 19
Study versus Standard of Care
Treatment for COVID-19 Cases.
A Pilot Study (ClinicalTrials.gov
Identifier: NCT04373824)
Drug: Ivermectin Not
Applicable
50
participants
April 25, 2020 July 25, 2020 [40]
3. Ivermectin and Nitazoxanide
Combination Therapy for
COVID-19 (ClinicalTrials.gov
Identifier: NCT04360356)
Combination Product:
Ivermectin plus Nitazoxanide
Other: Standard Care
Phase 2
Phase 3
100
participants
May 2020 December 202 [41]
4. Ivermectin Effect on SARS-
CoV-2 Replication in Patients
with COVID-19(ClinicalTrials.
gov Identifier: NCT04381884)
Drug: Ivermectin (IVER P®)
arm will receive IVM 600 µg/
kg once daily plus standard
care. The control arm will
receive standard care.
Phase 2 45
participants
May 7, 2020 June 30, 202 [42]
5. Sars-CoV-2/COVID-19
Ivermectin Navarra-ISGlobal
Trial (SAINT) (ClinicalTrials.
gov Identifier: NCT04390022)
Drug: Ivermectin
Drug: Placebo
Phase 2 24
participants
May 14, 2020 August 30, 2020 [43]
6. Trial to Promote Recovery from
COVID-19 With Ivermectin or
Endocrine Therapy (RECOVER)
(ClinicalTrials.gov Identifier:
NCT04374279)
Drug:
Bicalutamide 150 Mg Oral
Tablet
Drug: Ivermectin 3Mg Tab
Phase 2 60
participants
June 2020 June 2021 [44]
7. The Efficacy of Ivermectin
and Nitazoxanide in COVID-19
Treatment (ClinicalTrials.gov
Identifier: NCT04351347)
Drug: Chloroquine
Drug: Nitazoxanide
Drug: Ivermectin
Phase 2
Phase 3
60
participants
April 17, 2020 December 1, 2030
[45]
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, NCT: National Clinical Trial Identifier
26
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
Research Institute in Spain-Clínica Universidad de Navarra and the
Barcelona Institute for Global Health (ISGlobal), have launched a
clinical trial to investigate the effectiveness of IVM against COVID-19.
On May 8, 2020, the Health Department of the Republic of Peru
approved IVM for the treatment of COVID-19 in humans [Table 3] [46].
CONCLUSION
With the exception of rare serious reactions, IVM is generally well
tolerated. It has the clear advantages of ease of administration and
better tolerability compared with the other possible options for
COVID-19. As a nuclear import inhibitor, it has been shown promising
antiviral activities for many viral infections. However, there is a lack of
data establishing its antiviral activity in vivo. The recent studies of IVM
efficacy on novel SARS-CoV2 have been performed in in vitro and in vivo
settings each. Therefore, additional studies are required to establish
its safety and efficacy for COVID-19. With results from an in vitro
study revealing 99.8% reduction in viral RNA at 48 h and satisfactory
results in critically ill patient’s, the wonder drug IVM could be tried as a
possible option for COVID-19 treatment in in vivo settings with animals,
smaller number of human population shifting to larger clinical trials
as soon as its efficacy gets established. We, therefore, hope that this
wonder drug with in vivo studies could meet the unmet medical needs
in the outbreak of COVID-19.
FUNDING
This work is not supported by any institution or organization.
ACKNOWLEDGMENT
The authors would like to thank Ramanachary namoju, Dr. A.V
Kishore Babu, Dr. A. Srinivasa Rao, and other faculty members at
Bhaskar Pharmacy College, Hyderabad, for their help in reviewing the
manuscript.
AUTHORS’ CONTRIBUTIONS
Talha Jabeen and Mohd Abdul Khader conceptualized all the research
data and contributed to the preparation of this review and editing of
the manuscript. Shayestha Jabeen contributed for literature search and
manuscript editing.
POTENTIAL CONFLICT OF INTERESTS
All authors declare that they have no conflicts of interest.
REFERENCES
1. Lu H, Stratton CW, Tang Y. Outbreak of pneumonia of unknown
etiology in Wuhan, China: The mystery and the miracle. J Med Virol
2020;92:401-2.
2. Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J
Pediatr 2020;87:281-6.
3. Ayoub MD. Carvedilol as a potential addition to the covid-19
therapeutic arsenal. Int J Pharm Pharm Sci 2020;12:87-9.
4. Zhou Y, Hou Y, Shen J, Huang Y. Network-based drug repurposing for
novel coronavirus 2019 nCoV/SARS-CoV-2. Cell Discov 2020;6:14.
5. Hudu SA, Shinkafi SH, Umar S. An overview of recombinant vaccine
technology, adjuvants and vaccine delivery methods. Int J Pharm Pharm
Sci 2016;8:19-4.
6. Tayade MR, Shinkar DM, Patil PB, Saudagar RB. Emerging therapy for
dengue. Int J Curr Pharm Sci 2018;10:1-4.
7. Yanuar A, Syahdi RR, Aryati WD. Parameter optimization and virtual
screening Indonesian herbal database as human immunodeficiency
virus-1 integrase inhibitor using autodock and vina. Int J App Pharm
2017;90:90-3.
8. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-
approved drug ivermectin inhibits the replication of SARS-CoV-2
in vitro. Antivir Res 2020;178:104787.
9. Patel AN, David WG, Mandeep RM. Ivermectin in COVID-19 related
critical illness. SSRN Electron J 2020; Available from: https://www.
ssrn.com/abstract=3570270.
10. Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of
potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2)
based on SARS-CoV immunological studies. Viruses 2020;12:254.
11. Morse JS, Lalonde T, Xu S, Liu WR. Learning from the past: Possible
urgent prevention and treatment options for severe acute respiratory
infections caused by 2019-nCoV. ChemBioChem 2020;21:730-8.
12. Prasad S, Cherian S, Abraham P. Transmission electron microscopy
imaging of SARS-CoV-2. Indian J Med Res 2020;151:241-3.
13. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen
S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is
blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.
14. Ashour DS. Ivermectin: From theory to clinical application. Int J
Antimicrob Agents 2019;54:134-42.
15. Laing R, Gillan V, Devaney E. Ivermectin-old drug, new tricks? Trends
Parasitol 2017;33:463-72.
16. Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS.
Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1
function by sequestering nuclear import factors on the rough endoplasmic
reticulum/golgi membrane. J Virol 2007;81:9812-24.
17. DailyMed-STROMECTOL-ivermectin tablet. Available from: http://
dailymed.nlm.nih.gov.
18. Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al.
Nuclear localization of dengue virus (DENV) 1-4 non-structural protein
5; protection against all 4 DENV serotypes by the inhibitor ivermectin.
Antivir Res 2013;99:301-6.
19. Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J. Ivermectin inhibits DNA
polymerase UL42 of pseudorabies virus entrance into the nucleus and
proliferation of the virus in vitro and vivo. Antivir Res 2018;159:55-62.
20. Lee YJ, Lee C. Ivermectin inhibits porcine reproductive and respiratory
syndrome virus in cultured porcine alveolar macrophages. Arch Virol
2016;161:257-68.
21. Varghese FS, Kaukinen P, Gläsker S, Bespalov M, Hanski L,
Wennerberg K, et al. Discovery of berberine, abamectin and ivermectin
as antivirals against chikungunya and other alphaviruses. Antivir Res
2016;126:117-24.
22. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA.
Ivermectin is a specific inhibitor of importin α/β-mediated nuclear
import able to inhibit replication of HIV-1 and dengue virus. Biochem J
2012;443:851-6.
23. Azeem S, Ashraf M, Rasheed MA, Anjum AA, Hameed R. Evaluation
of cytotoxicity and antiviral activity of ivermectin against Newcastle
disease virus. Pak J Pharm Sci 2015;28:597-602.
24. Yang SN, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA,
et al. The broad spectrum antiviral ivermectin targets the host nuclear
transport importin α/β1 heterodimer. Antivir Res 2020;177:104760.
25. Raza S, Shahin F, Zhai W, Li H, Alvisi G, Yang K, et al. Ivermectin
inhibits bovine herpesvirus 1 DNA polymerase nuclear import and
interferes with viral replication. Microorganisms 2020;8:409.
26. Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM.
Nuclear import and export inhibitors alter capsid protein distribution
in mammalian cells and reduce venezuelan equine encephalitis virus
replication. Antivir Res 2013;100:662-72.
27. Mastrangelo E, Pezzullo M, Burghgraeve TD, Kaptein S. Ivermectin
is a potent inhibitor of flavivirus replication specifically targeting
NS3 helicase activity: New prospects for an old drug. J Antimicrob
2012;67:1884-94.
28. Gotz V, Magar L, Dornfeld D, Giese S. Influenza a viruses escape
from MxA restriction at the expense of efficient nuclear vRNP import.
Nature 2016;6:23138.
29. Rowland RR, Chauhan V, Fang Y, Pekosz A, Kerrigan M, Burton MD.
Intracellular localization of the severe acute respiratory syndrome
coronavirus nucleocapsid protein: Absence of nucleolar accumulation
during infection and after expression as a recombinant protein in vero
cells. J Virol 2005;79:11507-12.
30. Remme J, Baker RH, Sole GD, Dadzie KY. A community trial of
ivermectin in the onchocerciasis focus of Asubende, Ghana. I. Effect on
the microfilarial reservoir and the transmission of Onchocerca volvulus.
Trop Med Parasitol 1989;40:367-74.
per the health department of the Republic of Peru [46]
Medicine Dose Duration Route
Ivermectin
(solution oral 6 mg/ml)
200 mcg/kg Single dose Oral
27
Asian J Pharm Clin Res, Vol 13, Issue 8, 2020, 21-27
Jabeen et al.
31. Sole GD, Remme J, Awadzi K, Accorsi S, Alley ES, Ba O, et al.
Adverse reactions after large-scale treatment of onchocerciasis with
ivermectin: Combined results from eight community trials. Bull WHO
1989;67:707-20.
32. Pacqué M, Muñoz B, Poetscke G, Foose J, Taylor HR, Greene BM.
Pregnancy outcome after inadvertent ivermectin treatment during
community-based distribution. Lancet 1990;336:1486-9.
33. Canga AZ, Prietp AM. The pharmacokinetics and interactions of
ivermectin in humans-a mini-review. AAPS J 2008;10:42-6.
34. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A.
Compassionate use of remdesivir for patients with severe covid-19. N
Engl J Med 2020;382:2327-36.
35. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A
systematic review on the efficacy and safety of chloroquine for the
treatment of COVID-19. J Crit Care 2020;57:279-83.
36. Human Prescription Drug Label. KALETRA-lopinavir and Ritonavir
Tablet, Film Coated Kaletra-lopinavir and Ritonavir Solution. United
States: AbbVie Inc. [Last accessed on 2019 Dec 26].
37. Abdolvahab MH, Mofrad MR, Schellekens H. Interferon beta:
From molecular level to therapeutic effects. Int Rev Cell Mol Biol
2016;326:343-72.
38. Schmith VD. The approved dose of ivermectin alone is not the ideal dose
for the treatment of COVID-19. Clin Pharmacol Ther 2020;2020:1889.
39. Gorial F. Efficacy of Ivermectin as Add on Therapy in COVID19 Patients:
A Pilot Randomized Study. Report No: NCT04343092. Avaialable from:
http://www.clinicaltrials.gov. [Last accessed on 2020 Jun 10].
40. Max Healthcare Insititute Limited. To Study the Effectiveness of
Ivermectin With Standard of Care Treatment Versus Standard of
Care Treatment for COVID 19 Cases. A Pilot Study. Report No:
NCT04373824. Available from: http://www.clinicaltrials.gov. [Last
accessed on 2020 May 10].
41. Okasha PD. Clinical Trial Evaluating Safety and Efficacy of Ivermectin
and Nitazoxanide Combination as Adjuvant Therapy in COVID-19
Newly Diagnosed Egyptian Patients: A Tanta University Hope. Report
No: NCT04360356. Available from: http://www.clinicaltrials.gov.
[Last accessed on 2020 Apr 28].
42. Ivermectin Effect on SARS-CoV-2 Replication in Patients. Available
from: http://www.COVID-19-fullTextView-ClinicalTrials.gov.
43. Sars-CoV-2/COVID-19 Ivermectin Navarra-ISGlobal. Available from:
http://www.Trial-FullTextView-ClinicalTrials.gov.
44. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. A
Phase II Trial to Promote Recovery From COVID-19 With Ivermectin
or Endocrine Therapy. Report No: NCT04374279. Available from:
http://www.clinicaltrials.gov. [Last accessed on 2020 May 10].
45. Abd-Elsalam S. Clinical Study Evaluating the Efficacy of Ivermectin
and Nitazoxanide in COVID-19 Treatment. Report No: NCT04351347.
Available from: http://www.clinicaltrials.gov. [Last accessed on 2020
Apr 28].
46. How a Grass Roots Health Movement Led to Acceptance of Ivermectin
as a COVID-19 Therapy in Peru. Available from: http://www.
trialsitenews.com.
