pharmaceuticals

Review
Repurposing Potential of the Antiparasitic Agent Ivermectin for
the Treatment and/or Prophylaxis of COVID-19
Hoda Awad 1 , Basmala Hassan 1 , Sara Dweek 1 , Yasmeen Aboelata 1 , Mutasem Rawas-Qalaji 1,2
and Iman Saad Ahmed 1,2, *

1 Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, University of Sharjah,

Sharjah 27272, United Arab Emirates
2 Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
* Correspondence: [email protected]; Tel.: +971-65057403

Abstract: Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019
(COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a
miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for
its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM
resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment
and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the
targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted
literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the
ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a
Citation: Awad, H.; Hassan, B.; treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM
Dweek, S.; Aboelata, Y.; Rawas-Qalaji, efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials,
M.; Ahmed, I.S. Repurposing
novel nasal formulations of IVM were explored with the hope of an improved optimized effect.
Potential of the Antiparasitic Agent
Ivermectin for the Treatment and/or
Keywords: ivermectin; COVID-19; SARS-CoV-2; coronavirus; drug repurposing
Prophylaxis of COVID-19.
Pharmaceuticals 2022, 15, 1068.
https://doi.org/10.3390/
ph15091068
1. Introduction
Academic Editors: Jean
In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic,
Jacques Vanden Eynde and
and a global emergency following its widespread from Wuhan City, China, to the rest of the
Annie Mayence
world [1]. This was the first designation since the H1N1 influenza pandemic in 2009. The
Received: 3 August 2022 identified cause behind the disease is a novel coronavirus called severe acute respiratory
Accepted: 24 August 2022 syndrome coronavirus-2 (SARS-CoV-2). Two years later and as of June 2022, COVID-19
Published: 27 August 2022 has affected more than 500 million people worldwide, costing more than 6 million lives [2].
Publisher’s Note: MDPI stays neutral
Among the highly pathogenic coronaviruses, SARS-CoV-2 was found to be one with the
with regard to jurisdictional claims in most extensive spread in epithelial cells of the upper respiratory tract [3].
published maps and institutional affil- The pathogenesis of SARS-CoV-2 is initiated by viral entry through the angiotensin-
iations. converting enzyme 2 (ACE-2) receptor in the host cell. After entry, RNA is translated
into viral proteins upon its release in the cytoplasm. The resulting symptoms and clinical
manifestations include fever, headache, myalgia, and respiratory symptoms [4]. Some host-
related factors can increase the risk and severity of symptoms, which may include older
Copyright: © 2022 by the authors. age and male gender, as well as co-existing medical conditions and impaired immunity [5].
Licensee MDPI, Basel, Switzerland. Throughout the past two years, several prominent variants have emerged including Alpha,
This article is an open access article Beta, Delta, and the latest and most infectious, Omicron [4].
distributed under the terms and Consequently, several drugs have been and continue to be repurposed for the prophy-
conditions of the Creative Commons
laxis and treatment of COVID-19 [6,7]. These drugs include antimalarials, such as chloro-
Attribution (CC BY) license (https://
quine phosphate, hydroxychloroquine (HCQ), and antivirals such as lopinavir/ritonavir,
creativecommons.org/licenses/by/
umifenovir, remdesivir, and favipiravir. Moreover, monoclonal antibodies, such as tocilizumab,
4.0/).

Pharmaceuticals 2022, 15, 1068. https://doi.org/10.3390/ph15091068 https://www.mdpi.com/journal/pharmaceuticals

s 2022, 15, x FOR PEER REVIEW 2 of 18

chloroquine phosphate, hydroxychloroquine (HCQ), and antivirals such as lopinavir/ri-

Pharmaceuticalstonavir,
2022, 15, 1068
umifenovir,
remdesivir, and favipiravir. Moreover, monoclonal antibodies, such 2 of 18

as tocilizumab, are being investigated as potential COVID-19 treatments [8]. Interestingly,

the antiparasitic macrocyclic lactone ivermectin (IVM), due to its in vitro antiviral activity,
became a research aretarget
being investigated as potential
for its potential againstCOVID-19
COVID-19treatments
[9]. [8]. Interestingly, the antiparasitic
macrocyclic lactone ivermectin (IVM), due to its in vitro antiviral activity, became a research
target for its potential against COVID-19 [9].
2. Background
2. Background
Ever since its discovery in 1975 [10,11], IVM has always attracted attention, starting
with a Nobel Prize and Everending
since itswith what in
discovery could
1975 potentially
[10,11], IVM be hasaalways
solution to theattention,
attracted current starting
world pandemic.with a NobeltoPrize
It belongs and ending
the naturally with what
occurring couldof
family potentially be a produced
avermectins solution tobythe current
the bacterium Streptomyces avermitilis [10]. Its broad antiparasitic spectrum is achievedproduced
world pandemic. It belongs to the naturally occurring family of avermectins
by the bacteriumofStreptomyces
through the hyperpolarization avermitilis
the invertebrate’s [10].
cell Its broad antiparasitic
membrane, spectrum
with subsequent is achieved
par-
through the hyperpolarization of the invertebrate’s cell membrane, with subsequent par-
asite paralysis [9]. In 1981, it came into use for the treatment of multiple indications, in-
asite paralysis [9]. In 1981, it came into use for the treatment of multiple indications, in-
cluding strongyloidiasis, onchocerciasis
cluding strongyloidiasis, (river blindness)
onchocerciasis [9,12], ascariasis
(river blindness) [13], scabies
[9,12], ascariasis [13], scabies [14],
[14], cutaneous larva migrans
cutaneous larva [15], filariasis
migrans [15],[9,16], lice[9,16],
filariasis and myiasis
lice and[17]. Through
myiasis its wide its wide
[17]. Through
applications, affordability,
applications,high efficacy,high
affordability, andefficacy,
safety,and thesafety,
widethe therapeutic usefulness
wide therapeutic of of IVM
usefulness
IVM resulted in its inclusion
resulted in itsininclusion
the 21stinEssential
the 21st Medications List by the
Essential Medications ListWHO.
by the The
WHO.chem-
The chemical
structure
ical structure of IVM of IVMinisFigure
is shown shown 1in[18,19].
Figure 1 [18,19].

Figure 1. ChemicalFigure
structure of Ivermectin
1. Chemical (IVM),
structure consisting(IVM),
of Ivermectin of components H2components
consisting of B1a (C48H74OH
14, B
875.1
2 1a (C48 H74 O14 ,
g/mol) and H2B1b (C H O , 861.1 g/mol). Figure adapted from references [18,19] .
875.1 g/mol) and H2 B1b (C47 H72 O14 , 861.1 g/mol). Figure adapted from references [18,19].
47 72 14

3. Pharmacokinetics of IVM
3. Pharmacokinetics of IVM
Oral, topical, and injectable dosage forms of IVM are available; however, only the oral
Oral, topical, and injectable dosage forms of IVM are available; however, only the
and topical formulations are licensed for administration in humans. Oral IVM is rapidly ab-
oral and topical formulations are licensed
sorbed, with similar for administration
rates of absorption in humans.
for both solid and liquid Oral IVMforms
dosage is rap-
but varying
idly absorbed, with similar
systemic rates of absorption
bioavailability (twice forfor both solid
ethanolic and liquid
solution compared dosage forms but
to capsules/tablets) [20].
varying systemicUponbioavailability
administration(twice
of a for ethanolic
standard solution
oral dose compared
(a single to capsules/tab-
dose of 150–200 µg/kg) [21], maxi-
lets) [20]. Upon administration of a standard
mum plasma concentrations oral dose
are reached (a single
within three todose of 150–200
five hours. μg/kg)
A second peak is often
observedconcentrations
[21], maximum plasma indicating enterohepatic recycling
are reached within occurring
three to[22].
five hours. A second
peak is often observed Due to its highenterohepatic
indicating lipophilicity, IVM has a large
recycling volume
occurring of distribution (Vd ). Its central
[22].
compartment Vd is 3.1 to 3.5 L/kg in healthy adults [20]. The drug is highly distributed in
Due to its high lipophilicity, IVM has a large volume of distribution (Vd). Its central
fats but has low distribution in the subcutaneous fascia [22]. Plasma protein binding was
compartment Vdfoundis 3.1 totobe
3.593%
L/kg in healthy adults [20]. The drug is highly distributed in
with preferential binding to serum albumin, which results in higher levels
fats but has low of
distribution in the subcutaneous
free drug in populations fascia [22]. Plasma
with hypoalbuminemia protein binding
and malnutrition was its wide
[23]. Despite
found to be 93% with preferential
distribution, binding
IVM does to serumto
not distribute albumin, which results
the cerebrospinal in higher levels
fluid [20].
of free drug in populations
The metabolism of IVM is hepatic, with cytochrome P-4503A4 being its
with hypoalbuminemia and malnutrition [23]. Despite thewide
main responsi-
distribution, IVMbledoes not distribute
isoform. The drug isto the cerebrospinal
metabolized fluid [20].mostly through hydroxylation and
into 10 compounds
demethylation
The metabolism of IVM is[24]. The elimination
hepatic, half-lifeP-4503A4
with cytochrome of IVM was reported
being to be respon-
the main 18–24 h; however,
its pharmacological antiparasitic activity was reported to
sible isoform. The drug is metabolized into 10 compounds mostly through hydroxylation be sustained for up to months. Its
excretion is primarily fecal with less than 1% excreted in the urine [20].
and demethylation [24]. The elimination half-life of IVM was reported to be 18–24 h; how-
In this review article, the potential use of IVM in the therapy and prophylaxis of
ever, its pharmacological antiparasitic activity was reported to be sustained for up to
COVID-19 will be discussed. Amid the pandemic, many clinical trials and studies were
months. Its excretion is primarily fecal with less than 1% excreted in the urine [20].
 In this review article, the potential use of IVM in the therapy and prophylaxis of
COVID-19 will be discussed. Amid the pandemic, many clinical trials and studies were
conducted across the world to test the efficacy of IVM in the treatment and prophylaxis
Pharmaceuticals 2022, 15, 1068 3 of 18
of COVID-19. Its affordability and global availability could have potentially played a ma-
jor role for its selection in these clinical trials and studies, specifically the ones performed
in developing countries. This was evident, as most of the trials were held in countries such
conducted across the world to test the efficacy of IVM in the treatment and prophylaxis of
as Egypt, India, Argentina,
COVID-19. Its Mexico, Brazil,and
affordability andglobal
Bangladesh. Despite
availability could the
haverise in its investi-
potentially played a major
gative trials, IVM is not yet approved by most of the regulatory authorities forthe
role for its selection in these clinical trials and studies, specifically its ones
use in
performed
COVID-19 patients nor is it added
in developing to hospitals’
countries. This wastreatment
evident, asprotocols.
most of the trials were held in countries
such as Egypt, India, Argentina, Mexico, Brazil, and Bangladesh. Despite the rise in its
4. IVM Potentialinvestigative
Mechanismtrials,
of Action
IVM isagainst COVID-19
not yet approved by most of the regulatory authorities for its
use in COVID-19 patients nor is it added to hospitals’ treatment protocols.
Different hypothesized mechanisms of action were explored in multiple studies to
understand the IVM4. IVMactivity against
Potential COVID-19.
Mechanism In March
of Action 2020,
against Caly et al. introduced IVM
COVID-19
as a potential therapy for thehypothesized
Different pandemic by demonstrating
mechanisms its were
of action antiviral
exploredactivity againststudies to
in multiple
SARS-CoV-2 in understand
Vero E6 cells. The article suggested that the antiviral
the IVM activity against COVID-19. In March 2020, Caly et activity is gained
al. introduced
through the inhibition
IVM as of importin
a potential (IMP)-α/β1-mediated
therapy for the pandemic by nuclear import of
demonstrating its viral proteins
antiviral activity against
of SARS-CoV-2, SARS-CoV-2
resulting in the inhibition
in Vero E6 cells.ofThe
RNA replication
article suggested [25]. This
that thewas further
antiviral illus-is gained
activity
trated by Mudatsirthrough
et al.the inhibition
as shown inof importin
Figure (IMP)-α/β1-mediated
2 [26]. It is important tonuclear
note that import of viralof
the levels proteins of
IVM used that demonstrated inhibitory activity (5 μM) are not achievable in humans, asillustrated
SARS-CoV-2, resulting in the inhibition of RNA replication [25]. This was further
by Mudatsir et al. as shown in Figure 2 [26]. It is important to note that the levels of IVM
they are 100 times more than the standard dose (200 μg/kg). Furthermore, most of the
used that demonstrated inhibitory activity (5 µM) are not achievable in humans, as they are
conducted clinical trials used the standard dose with a higher frequency of administration
100 times more than the standard dose (200 µg/kg). Furthermore, most of the conducted
rather than a higher dose.
clinical trialsCaly’s
used the study wasdose
standard the with
gateway to frequency
a higher the hundreds of IVM-based
of administration rather than a
trials which tookhigher
placedose.
in 2020
Caly’sandstudy
are still ongoing
was the gatewayto to
this
theday. YangofetIVM-based
hundreds al. reported that
trials which took
in addition to theplace
inhibition of IMP-α/β1, IVM can dissociate the previously formed IMP-
in 2020 and are still ongoing to this day. Yang et al. reported that in addition to the
α/β1 heterodimer in Veroofcells
inhibition [27]. Another
IMP-α/β1, IVM canmolecular
dissociate docking studyformed
the previously revealed that IVM
IMP-α/β1 heterodimer
binds as well to in Vero cells
dimeric [27]. protease
3C-like Another molecular docking study
and non-structural revealed
protein that IVM
(NSP19) binds as well to
in addition
to IMP-α [28]. dimeric 3C-like protease and non-structural protein (NSP19) in addition to IMP-α [28].

Figure 2. PotentialFigure
antiviral action ofantiviral
2. Potential IVM inhibiting
action ofIMPα/β1-mediated nuclear import nuclear
IVM inhibiting IMPα/β1-mediated of viral import
pro- of viral
teins of SARS-CoV-2. Figure
proteins adapted from
of SARS-CoV-2. reference
Figure adapted[26] (CC
from BY 4.0).[26] (CC BY 4.0).
reference

On the contrary,OnIVM
the contrary, IVM at a concentration
at a concentration of 10 μM wasof 10 µM was
found found
to fail to fail in inhibiting
in inhibiting
SARS-CoV-2 infection in a study conducted on human airway-derived
SARS-CoV-2 infection in a study conducted on human airway-derived cell models. cellThese
models. These
contradicting results suggest that the previously determined IVM
contradicting results suggest that the previously determined IVM activity conducted activity conducted
in in
Vero cells might not correlate with the results obtained in different models, and thus, should
not be used to interpret IVM activity in humans [29].
Pharmaceuticals 2022, 15, x FOR PEER REVIEW 4 of 18

Pharmaceuticals 2022, 15, 1068 4 of 18

Vero cells might not correlate with the results obtained in different models, and thus,
should not be used to interpret IVM activity in humans [29].
Another
Anothermechanism
mechanismof ofaction
actionforforCOVID-19
COVID-19isisthrough
throughitsitsinteraction
interactionwith
withthe
theACE-2
ACE-
receptor.
2 receptor.AA study
studybyby Lehrer
Lehrerand andRheinstein
Rheinsteinshowed
showedthat thatIVMIVMdocked
dockedleucine
leucine9191ononthe
the
spike
spikeand
anddocked
dockedhistidine
histidine 378378onon
thethe
ACE-2
ACE-2receptor (Figure
receptor 3) [30].
(Figure The IVM
3) [30]. docking
The IVM may
docking
obstruct the spike’s
may obstruct adhesion
the spike’s to the to
adhesion human cell membrane,
the human cell membrane,due todue the drug’s ability ability
to the drug’s to act
as
to act as a bridge between the virus and the receptor. Similar results were reportedand
a bridge between the virus and the receptor. Similar results were reported by Saha by
Raihan,
Saha and which showed
Raihan, which that IVM has
showed thatlarge
IVMbinding affinity
has large bindingthrough hydrogen
affinity throughbonding
hydrogen to
leucin
bonding492,toglutamine
leucin 492, 493, glycine 496
glutamine 493,and tyrosine
glycine 496505
andresidues
tyrosinein505 theresidues
spike protein
in thewhich
spike
favors
proteinbinding
which to ACE-2
favors [31]. Eweas
binding et al.[31].
to ACE-2 found that in
Eweas et addition
al. foundtothatthe spike proteintoand
in addition the
ACE-2 binding, IVM can bind to type II transmembrane serine protease
spike protein and ACE-2 binding, IVM can bind to type II transmembrane serine protease (TMPRSS2), which
plays a role inwhich
(TMPRSS2), the binding
plays aand rolefusion
in theofbinding
the virusand
intofusion
the cellof membrane.
the virus intoFurther, binding
the cell mem-
to main protease (Mpro), papain-like protease (PLpro), nucleocapsid
brane. Further, binding to main protease (Mpro), papain-like protease (PLpro), nucleocap- phosphoprotein
and
sid NSP14 of the SARS-CoV-2
phosphoprotein and NSP14 prevents
of the the post-translation
SARS-CoV-2 prevents processing, replication, and
the post-translation pro-
assembly [32].
cessing, replication, and assembly [32].

Figure3.3. IVM
Figure IVM bridging
bridging between
between SARS-CoV-2
SARS-CoV-2(left)
(left)and
andACE2
ACE2receptor
receptor(right).
(right).Figure
Figureadapted
adaptedfrom
from
reference [30]with
reference[30] withpermission
permissionfrom
fromthe
theInternational
InternationalInstitute
InstituteofofAnticancer
AnticancerResearch.
Research.

The
The immunomodulatory
immunomodulatory impact impact ofof IVM
IVM through
throughthe thecholinergic
cholinergicanti-inflammatory
anti-inflammatory
pathway
pathway activation was also explored in golden hamsters by de Melo etal.
activation was also explored in golden hamsters by de Melo et al.as
asaapotential
potential
mechanism
mechanism of action in COVID-19. The study concluded that the administeredIVM
of action in COVID-19. The study concluded that the administered IVMsingle
single
dose
dose of
of400 μg/kg injected
400µg/kg injected subcutaneously
subcutaneously resulted
resulted inin the
the sex-dependent
sex-dependent prevention
prevention of of
clinical
clinicaldeterioration
deteriorationand andreduction
reduction inin
olfactory
olfactory deficit, which
deficit, whichwaswaslinked with
linked a remarkable
with a remark-
reduction in theininterleukins
able reduction (IL)-6/IL-10
the interleukins (IL)-6/IL-10ratio in in
ratio thethe
lung
lungtissues
tissues[33].
[33].These
Thesefindings
findings
correlate with a significantly lower IL-6/IL-10 plasmatic ratio reported in
correlate with a significantly lower IL-6/IL-10 plasmatic ratio reported in another studyanother study for
patients with mild COVID-19 infection, compared to patients requiring intensive
for patients with mild COVID-19 infection, compared to patients requiring intensive care care unit
(ICU) admission
unit (ICU) [34]. [34].
admission
5. IVM Role in the Treatment of COVID-19
5. IVM Role in the Treatment of COVID-19
5.1. Therapeutic Benefit
5.1. Therapeutic Benefit
Many trials were conducted in different countries with the aim of exploiting the
Many benefit
therapeutic trials were
of IVMconducted in different
in COVID-19 cases. countries with thecontrolled,
In a randomized, aim of exploiting the ther-
double-blinded
apeutic benefit of IVM in COVID-19 cases. In a randomized, controlled,
study between May and November 2020, Babalola et al. selected 62 mild-to-moderate double-blinded
study between
COVID-19 May
patients andLagos
at the November 2020,Teaching
University BabalolaHospital,
et al. selected 62 mild-to-moderate
Lagos, Nigeria, and divided
COVID-19 patients at the Lagos University Teaching Hospital,
them into 3 treatment groups. Over the duration of two weeks, Group A receivedLagos, Nigeria, and di-
6 mg
intravenous IVM twice a week, Group B received 12 mg intravenous IVM twice a week,6
vided them into 3 treatment groups. Over the duration of two weeks, Group A received
mg Group
and intravenous IVM twice
C received a week, Group B received
oral lopinavir/ritonavir daily and12a mg intravenous
placebo (controlIVM twice
group). Alla
week, and Group C received oral lopinavir/ritonavir daily and a placebo
patients showed mild symptoms, such as cough, headache, and fever. No patients were (control group).
Allmechanical
on patients showed mild Group
ventilation. symptoms, such as
A showed cough, headache,
a negative polymerase and fever.
chain No patients
reaction (PCR)
were on
result 3.15mechanical
days priorventilation.
to the controlGroup A showed
group, a negative
while group polymerase
B showed chain
a negative PCRreaction
result
4.5 days prior to the control group (p = 0.0066). In this study, it was concluded that 12 mg of
Pharmaceuticals 2022, 15, 1068 5 of 18

intravenous IVM is significantly effective, as it showed a shortened duration of treatment.

No adverse side effects were documented during this trial despite using a high dose of
IVM [35].
In another study, similar outcomes on PCR negativity were reported. Mohan et al.
conducted a double blinded, randomized controlled study on 125 hospitalized patients
with mild-to-moderate COVID-19 in the All India Institute of Medical Sciences (New Delhi,
India) between July and September 2020. Forty patients received 24 mg IVM, forty patients
received 12 mg IVM, and forty-five patients received a placebo. IVM oral elixir formulation
was used. No serious adverse events were recorded. Although the PCR negativity at the 5th
day was high in both IVM groups (47.5% for 24 mg group, 35.0% for 12 mg group) compared
to the placebo group (31.1%), these results were statistically insignificant (p = 0.30) [36].

5.2. Viral Clearance/Load

The IVM effect on the viral clearance/load of the COVID-19 patients was also studied.
A pilot, randomized, controlled, outcome-assessor blinded trial by Krolewiecki et al. was
conducted in 4 hospitals in Buenos Aires, Argentina, between May and September 2020.
The study included 30 patients receiving 600 µg/kg/day IVM via oral tablet for 5 days
and 15 patients serving as the control group. Both groups also received the standard of
care which at that time included the hospitalization of all symptomatic patients. The viral
load was not found to be different between the two groups; however, patients with higher
IVM plasma levels exhibited significant viral load reduction (72%) compared to the control
group (42%, p = 0.004). The high dose of IVM was well tolerated [37].
Another randomized controlled trial by Samaha et al. conducted between September
and November 2020 involved 100 asymptomatic COVID-19 patients in Lebanon. Fifty
participants received a single oral dose of IVM based on their body weight (participants
with body weight of 45–64 kg, 65–84 kg, and ≥85 kg received 9 mg, 12 mg or 150 µg/kg,
respectively), and fifty participants were in the control group. Both groups also received
zinc and vitamin C supplements. Viral load was measured utilizing the cycle threshold
indicator (Ct-values) in which a value of 30 or higher indicates an insignificant viral load.
At 72 h after starting the regimen, it was found that Ct-values in the IVM group reached
30.14 ± 6.22, compared to the control group, reaching 18.96 ± 3.26 (p < 0.001). Additionally,
the development of clinical symptoms was more evident in the control group [38].
Another study reported an insignificant effect on the viral load, but a significant
impact on the recovery speed. In Barcelona, Spain, a double-blinded randomized control
trial by Chaccour et al. was designed to test the efficacy of a single maximum dose of
IVM in reducing COVID-19 transmission. Patients of Clinica Universidad de Navarra
with non-severe COVID-19 participated in the trial between July and September 2020.
The participants were divided randomly into two equal groups (1:1). One group (n = 12)
received a single oral dose of IVM (400 µg/kg), and the second group (n = 12) received a
placebo within 72 h of fever or cough onset. The viral load, infectivity, as well as the number
of patients with positive PCR on day 7, were the main outcomes compared between the
two groups. On day 7, there was no difference in the proportion of positive PCR patients
between the two groups (12/12 and 12/12). The viral loads of the IVM group for gene
E and gene N on day 4 and day 7 were lower, though the difference was non-significant
compared to the placebo group (p > 0.1 for all). IgG titers in the IVM group were also
non-significantly lower (p = 0.24) compared to the placebo group. However, the IVM group
had a faster recovery from hyposmia/anosmia (76 patient-days) compared to the placebo
group (158 patient-days) (p < 0.001). Patient-days is the unit used to measure the number
of patients occupying beds in a healthcare facility for the period for which an assessment is
being conducted [39].
Earlier viral clearance was also reported by some studies. In November 2020, Ahmed
et al. published a randomized, double-blinded, placebo-controlled trial in Dhaka, Bangladesh,
to study the efficacy and safety of oral IVM in the management of COVID-19. Seventy-two
hospitalized patients were divided equally into three treatment groups. Group 1 received
Pharmaceuticals 2022, 15, 1068 6 of 18

12 mg of oral IVM once daily for the duration of 5 days. Group 2 received 12 mg of oral
IVM as a single dose with 200 mg doxycycline on day 1 followed by doxycycline 100 mg
every 12 h for 4 days. Group 3 was the placebo group. The results of the trial showed
no statistically significant difference between the three groups in the recession of clinical
symptoms, including fever, sore throat, and cough. However, this was not the case with the
viral clearance. Groups 1 and 2 experienced earlier viral clearance (9.7 days and 11.5 days
respectively), compared to Group 3 (12.7 days). The number of days for viral clearance was
significantly lower in Group 1 compared to Group 3 (p = 0.02), unlike Group 2 (p = 0.27).
Overall, the five-day course of IVM showed faster viral clearance, which suggests the
potential role of IVM in the management of COVID-19 [40].

5.3. Symptoms Resolution/Hospitalization Length

On the other hand, some studies concluded that IVM has an insignificant role in
COVID-19 treatment when it comes to clinical manifestations and health state. In Mexico,
Gonzalez et al. conducted a randomized, controlled, double-blinded trial measuring the
length of hospitalization in severe COVID-19 patients between April and August 2020.
This trial involved 106 participants who were divided into 3 groups: IVM, HCQ, and a
placebo group. Group 1 was treated with oral IVM (12 mg in patients weighing <80 kg
and 18 mg in those >80 kg), group 2 received HCQ 400 mg every 12 h on the 1st day,
followed by 200 mg every 12 h for four days, and group 3 received a placebo. This study
concluded that there was no significant difference between the three groups in the duration
of hospitalization, with an average of 7 days for HCQ group, 6 days for IVM group, and
5 days for the placebo. There was also no significant difference between the three groups in
the respiratory deterioration or death [41].
Another trial that took place between March and October 2020 by Abd-Elsalam et al.
tested the antiviral potential of IVM compared to standard care in mild to moderate COVID-
19 patients hosted in Tanta and Assiut University Hospitals, Egypt. The trial used a 1:1
randomized, open-label parallel-group design. The IVM group (82 participants) received a
single oral dose of IVM tablets (12 mg/day) for 3 days, after which the Egyptian standard
protocol care was added, while the control group (82 participants) received the Egyptian
standard protocol care alone for 14 days. The Egyptian standard protocol included an
empiric antibiotic, oseltamivir (if needed), paracetamol, oxygen, and mechanical ventilation
in case of PaO2 (partial pressure of oxygen in arterial blood) less than 60 mmHg. The results
showed a shorter hospital stay for the IVM group (8.82 ± 4.94 days) in comparison with
the control group (10.97 ± 5.28 days). However, these results lacked statistical significance
(p = 0.085). In both groups, three patients needed mechanical ventilation. The mortality
rates in both groups were not significantly different with 3.7% in the IVM group, compared
to 4.9% in the control group (p = 1.00). Overall, despite the outcomes bearing no significant
difference, the study did observe a pattern of shortened hospitalization periods in the IVM
group [42].
Similarly, López-Medina conducted a double-blinded randomized trial in Cali, Colom-
bia, on 400 patients with mild COVID-19 between July and December 2020. One group of
200 patients received 300 µg/kg of oral IVM (as a solution) per day for 5 days, and 200 pa-
tients received a placebo. The difference in time to symptoms resolution was statistically
insignificant between both groups (10 days in the IVM group compared to 12 days in the
placebo group) [43].
Lastly, in Corrientes, Argentina, during the period between August 2020 and February
2021, Vallejos et al. carried out a randomized, double-blinded, placebo-controlled trial to
determine whether the use of IVM can help with hospitalization prevention in patients with
early COVID-19. The study was conducted on 501 patients. Two hundred and fifty of these
patients were randomized into a weight-based dose of oral IVM for 2 days (participants
with body weight of ≤80 kg, >80 to ≤110 kg, and >110 kg received 12 mg, 18 mg, or
24 mg, respectively) and the rest took placebo treatment. The results showed no significant
difference in hospitalization prevention with 14 patients (5.6%) of the IVM group requiring
Pharmaceuticals 2022, 15, 1068 7 of 18

hospitalization compared to 21 patients (8.4%) in the control group. However, hospitalized

patients that used IVM required invasive mechanical ventilation earlier compared to those
on placebo. Therefore, the authors concluded that there was no significant effect of IVM on
hospitalization prevention in COVID-19 patients [44]. A summary of the reviewed studies
on the role of IVM in the COVID-19 treatment is included in Table 1.

Table 1. Summary of the reviewed studies on the potential of IVM in the treatment of COVID-19.

Date Country Study Design IVM Dose # of Patients Main Outcomes References
Randomized,
6 mg IV twice a
May–November controlled, Significant shortened
Nigeria week or 12 mg IV 62 [35]
2020 double-blinded duration of treatment
twice a week
two-groups trial
Randomized,
Insignificant effect on
July–September controlled, Single oral dose,
India 125 time to PCR [36]
2020 double-blinded 24 mg, or 12 mg
negativity
trial
Randomized,
600 µg/kg/day as
May–September controlled, Significant viral load
Argentina oral tablet for 30 [37]
2020 outcome-assessor reduction
5 days
blinded trial
Single oral
weight-based dose
Randomized,
September– (45–64 kg, 65–84 kg,
controlled, Significant viral load
November Lebanon ≥85 kg received 100 [38]
parallel groups reduction
2020 9 mg, 12 mg or
trial
150 µg/kg
respectively)
Significant faster
Randomized,
recovery from
July–September controlled, Single oral dose
Spain 24 hyposmia/anosmia, [39]
2020 double-blinded (400 µg/kg)
insignificant viral
trial
load reduction
Oral 12 mg/day for
5 days, or oral
Randomized,
12 mg as a single Significant earlier
double-blinded,
dose +200 mg viral clearance,
Bangladesh placebo- 72 [40]
doxycycline on day insignificant clinical
controlled
1, then doxycycline symptoms recession
trial
100 mg every 12 h
for 4 days.
Insignificant effect on
Randomized, Single oral
hospitalization
April–August controlled, weight-based dose
Mexico 106 duration, respiratory [41]
2020 double-blinded (12 mg for <80 kg,
deterioration, or
trial 18 mg for >80 kg)
death
Randomized, Insignificant
Single oral dose
March–October open-label reduction of hospital
Egypt (12 mg/day) for 164 [42]
2020 parallel-groups stays and mortality
3 days.
trial rates
Randomized, 300 µg/kg/day Insignificant
July–December
Colombia double-blinded orally (as a solution) 400 reduction of time to [43]
2020
trial for 5 days symptom resolution
Weight-based
(≤80 kg, >80 to
Randomized,
≤110 kg, and
August double-blinded, Insignificant effect on
>110 kg received
2020–February Argentina placebo- 501 hospitalization [44]
12 mg, 18 mg or
2021 controlled prevention
24 mg respectively)
trial
for 2 consecutive
days
Pharmaceuticals 2022, 15, 1068 8 of 18

6. IVM Role in the Prophylaxis against COVID-19

Treating COVID-19 with IVM was not the only question of interest in the conducted
research. Many studies were conducted and continue to investigate the potential role
of IVM as a chemoprophylactic agent in COVID-19. A clinical randomized open label-
controlled trial was conducted by Shoumann et al. at the University of Zagazig, Egypt,
to investigate the use of IVM as prophylactic therapy in COVID-19 during June and July
2020. Three hundred four asymptomatic participants were enrolled in this study. All
the participants were in close contact with confirmed COVID-19 family members. The
participants were divided into two groups. The IVM group included 203 asymptomatic
participants who received the first dose of oral IVM ranging between 200 and 300 µg/kg
on the enrollment day and an equal second dose on the third day. In the non-intervention
group, no treatment was provided to 101 asymptomatic participants. The groups were
followed-up for a 2-week period for the common symptoms, complete blood count (CBC),
and C-reactive protein (CRP). PCR tests were conducted after the follow-up period and
showed that 59 participants (58.4%) tested positive for COVID-19 in the non-intervention
group. On the other hand, only 15 participants (7.4%) tested positive in the IVM group.
This study reported that there was a 2-day delay in symptoms development in the IVM
group, compared to the control group. IVM protection was more noticeable in participants
less than 60 years old. Differences between the two groups in terms of outcomes were
highly significant (p = 0.001) [45].
A protection program in Itajaí, Brazil, reported by Kerr et al., investigated the role of
IVM in COVID-19 prophylaxis during January 2022. This was an observational prospective
study that included 159,561 citizens. They were divided into two major groups: the IVM
group and the control group. The IVM group included 113,845 participants who received a
dose of 200 µg/kg of IVM as a prophylactic treatment for 2 consecutive days. The control
group consisted of 45,716 participants who did not receive any prophylactic agents. After
15 days of taking IVM, only 4311 (3.9%) tested positive for COVID-19, while 3034 (6.6%)
were reported positive from the control group. According to the findings of this study,
there was an observed reduction in the infection rate by 44%, the mortality rate by 68%,
and the hospitalization rate by 67% in the IVM prophylaxis group, compared to the control
group (p < 0.0001 for all). After this study and considering the benefit and risk analysis, the
authors are waiting for the approval of using IVM by agencies throughout the world, such
as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the
Brazilian Health Regulatory Agency (ANVISA) [46].
Apart from the aforementioned trials, studies investigating the prophylactic role of
IVM were mostly conducted in a retrospective manner. A trial was conducted in Africa
investigating COVID-19 infection rates among countries which have either participated
in the earlier African Program for Onchocerciasis Control (APOC) and those which did
not (non-APOC). APOC was a mass onchocerciasis prevention program which began in
1989 and continued until 2015. The program distributed IVM to a total of 19 countries
and treated 90 million individuals annually. The study demonstrated significantly lower
COVID-19 infection rates, as well as significantly lower mortality in APOC countries,
compared to non-APOC [47].
Similarly, in the period between June and July 2020, Morgenstern et al. conducted an
observational retrospective cohort study in Punta Cana, Dominican Republic, to evaluate
the pre-exposure prophylactic effect of IVM in 271 healthcare personnel who adhered to a
weekly oral dose of 200 µg/kg of IVM versus a control group of another 271 healthcare
personnel who did not adhere to such regimen. After 28 days of follow-up, the IVM exposed
group showed statistically significant prophylaxis against the infection with only 1.8% of
the personnel developing COVID-19 compared to 6.6% in the control group (p = 0.006).
The results suggest that the preventive use of a weekly oral IVM dose could be an option
for healthcare workers and as an adjunct to immunization [48].
Additionally, a hospital-based matched case-control study in AIIMS Bhubaneswar,
India, conducted by Behera et al. from September to October 2020 on 372 individuals,
Pharmaceuticals 2022, 15, 1068 9 of 18

showed that two oral doses of 300 µg/kg IVM, 72 h apart, taken as a prophylactic agent
reduced the COVID-19 infection by 73% in healthcare workers within the subsequent
month [49].
Another study by Hellwig and Maia in October 2020 explored the impact on COVID-
19 patients associated with the prophylactic administration of IVM. They gathered data
from countries that utilize IVM as part of their prophylactic chemotherapy (PCT) campaign
and countries which do not include IVM in the PCT and compared both to countries that
do not deploy PCT at all. The incidence of COVID-19 was significantly lower (p < 0.001) in
populations that previously received IVM compared to populations without PCT, while it
showed lower but statistically insignificant incidence in populations receiving PCT without
IVM [50]. A summary of the reviewed studies on the role of IVM in the prophylaxis against
COVID-19 is included in Table 2.

Table 2. Summary of the reviewed studies on the potential of IVM in the prophylaxis against
COVID-19.

Date Country Study Design IVM Dose # of Subjects Main Outcomes References
Randomized, Oral dose of
2-days delay in
open 200–300 µg/kg,
June–July 2020 Egypt 304 symptoms [45]
label-controlled on the 1st and
development
study 3rd days.
Significant
reduction in the
Observational, 200 µg/kg for infection rate (44%),
January 2022 Brazil prospective 2 consecutive 159,561 mortality rate [46]
study days (68%), and
hospitalization rate
(67%)
Significantly lower
54 African Retrospective
October 2020 Not specified 1,336,943,343 COVID-19 infection [47]
countries study
and mortality rates
Weekly oral
Observational Significant
Dominican dose of
June–July 2020 retrospective 542 prophylaxis against [48]
Republic 200 µg/kg for
cohort study the infection
4 weeks
Hospital-based
September– 2 oral doses of Reduced
matched
October India 300 µg/kg, 72 h 372 COVID-19 infection [49]
case-control
2020 apart (73%)
study
Not specified
Significantly lower
Retrospective (all COVID-19
October 2020 Worldwide Not specified incidence of [50]
study incidences as of
COVID-19
5 June 2020)

7. Combined Therapy of IVM against COVID-19

7.1. Therapeutic Benefit
The use of IVM as part of a combination therapy was reported to have a promising
role against COVID-19 in multiple studies. Chowdhury et al. performed a randomized con-
trolled trial between May and June 2020 in Bazar, Bangladesh, comparing the effects of two
possible combination therapies in COVID-19 patients. The first combination was IVM with
doxycycline, while the second was HCQ with azithromycin. Group A included 60 patients
who received IVM 200 µg/kg as a single oral dose on day 1 of the trial with doxycycline
100 mg twice daily for 10 days, while group B included 56 participants who received HCQ
400 mg on the first day then 200 mg twice daily with azithromycin 500 mg/day for 5 days.
All patients in group A showed negative PCR results within an average of 8.93 days, and
Pharmaceuticals 2022, 15, 1068 10 of 18

symptoms relief was achieved within an average of 5.93 days, and 55.1% of the participants
were symptom free by the fifth day of the trial. Out of the patients in group B, 96.36%
showed negative PCR results after an average of 9.33 days, and all patients were symptom
free after an average of 6.99 days. In group A, 31.67% of the patients experienced side
effects of the combined therapy, compared to 46.43% in group B. The study concluded that
the combination of IVM with doxycycline was superior to the combination of HCQ with
azithromycin in patients with mild–moderate COVID-19 [51].
Coinciding but insignificant findings with regards to the time to negative PCR were
established by Pott-Junior et al. in a randomized open-label study conducted at Federal
University of São Carlos, Brazil, in a group of 32 mild COVID-19 patients who received
standard of care (SOC) alone, or SOC and oral IVM (3 different groups received the follow-
ing doses: 100 µg/kg, 200 µg/kg and 400 µg/kg). The study did not report any serious
adverse events in the SOC with IVM group. Patients receiving IVM required a shorter time
to obtain two consecutive negative PCR result in a dose-dependent manner [52].

7.2. Viral Clearance

IVM was also reported to enhance viral clearance when utilized in combination
therapy. A study conducted by Elalfy et al. at Mansoura University Hospital, Egypt, from
May to October 2020 included 113 participants who tested positive for COVID-19. In this
non-randomized clinical trial, the patients were divided into two groups: the white arm
group which included 51 patients, and the yellow arm group which included 62 patients.
The white arm group was treated with paracetamol 3 tablets per day, zinc supplements
twice daily, healthy nutrition and hydration, and azithromycin, case by case. The yellow
arm group was treated with multidrug therapy, including nitazoxanide, ribavirin, and IVM
plus zinc. The patients received 500 mg nitazoxanide every 6 h, ribavirin 400 mg every
6 h, and a weight-based oral IVM dose every 72 h. In patients weighing between 60 and
90 kg, the IVM dose ranged between 200 and 400 µg/kg, patients weighing between 90 and
120 kg received 300–400 µg/kg IVM, while patients weighing above 120 kg received 30 mg
IVM. The white arm group showed a viral clearance rate of 0% in the first week, and 13.7%
on day 15. On the other hand, the yellow arm group showed a viral clearance rate of 58.1%
in the first week, and 73.1% on day 15. The authors concluded that the use of the triple
therapy (nitazoxanide, ribavirin, and IVM in addition to zinc) cleared the COVID-19 virus
within a shorter period compared to supportive or symptomatic treatment alone. There
were no reported drug-related side effects, except for minor ones, such as stomach upset
and diarrhea [53].

7.3. Symptoms Resolution

The impact of IVM combination therapy on the clinical symptoms’ resolution was also
explored. In a randomized, double-blinded clinical trial published by Shahbaznejad et al. in
Mazandaran, Iran, 69 patients were divided and randomized into either an IVM-receiving
group or a standard treatment group containing 35 and 34 patients respectively. The study
was conducted between May and July 2020. Both groups received supportive treatment for
COVID-19, which was decided according to Iranian protocols at the time (HCQ and/or
lopinavir/ritonavir). The intervention group also received 200 µg/kg of IVM as a single
oral dose. Clinical improvement of baseline cough, dyspnea, and oxygen saturation was
the primary outcome. The study showed faster clinical improvement of symptoms in the
intervention group with a mean dyspnea duration of 2.6 days, persistent cough duration of
3.1 days, and mean hospital stay of 7.1 days, compared to 3.8, 4.8, and 8.4 days, respectively,
in the control group. Additionally, the frequency of lymphopenia was significantly reduced
to 3 patients in the IVM group, compared to 13 patients in the standard treatment group.
Based on the results, it was concluded that the single weight-based IVM dose (200 µg/kg)
could improve clinical symptoms in COVID-19 patients [54].
Another trial was conducted by Mahmud et al. between June and August 2020 in
Bangladesh to investigate whether the use of IVM with doxycycline reduced the recovery
Pharmaceuticals 2022, 15, 1068 11 of 18

duration in patients with mild-to-moderate COVID-19. The study design was a blinded,
randomized, placebo-controlled, two-arm study involving 200 patients assigned to 12 mg
of oral IVM with 100 mg of doxycycline combination treatment versus 200 patients assigned
to placebo treatment. Both groups also received standard treatment which included ac-
etaminophen, cough suppressants, antihistamines, vitamins, oxygen therapy if needed, low
molecular weight heparin if needed, other appropriate broad-spectrum antibiotics, remde-
sivir, other antiviral drugs, and other drugs related to pre-existing comorbid conditions.
The median time to recovery was 7 days in the group receiving IVM with doxycycline and
9 days in the placebo group. Sixty-one percent of the participants in the intervention group
recovered within <7 days compared to forty-four percent in the placebo group. Addition-
ally, a significantly lower number of participants in the intervention group remained PCR
positive on day 14 and were less likely to progress to more serious disease compared to the
placebo group [55].

7.4. Mortality Rate

Another positive role of IVM combination therapy was reported with regards to the
reduction in mortality rate. A retrospective observational study was conducted by Rajter
et al. on hospitalized patients with COVID-19 at four Broward Health hospitals in Florida,
United States, between March and May 2020. The study included 280 patients, 173 had
received IVM and 107 had not, with most of the patients receiving HCQ, azithromycin,
or both. The IVM group patients received at least 200 µg/kg orally as a single dose
along with the routine clinical care. Significantly lower mortality rate was observed in
the IVM receiving patient (15.0%) compared to patients who did not receive IVM (25.0%),
p = 0.03. However, no significant difference was observed in the length of stay or rate of
extubating [56].
Similar results for the mortality rate were reported in Tlaxcala, Mexico, by Lima-
Morales et al. who conducted a non-randomized clinical trial to evaluate the effectiveness
of a multidrug-therapy (TNR4 therapy) in COVID-19-positive cases between May and
September 2020. TNR4 therapy consisted of oral IVM (12 mg single dose), montelukast
(60 mg on day 1 and then 10 mg from day 2 to day 21), acetylsalicylic acid (100 mg
daily for one month), and azithromycin (500 mg for four consecutive days). There were
768 participants in this study divided into two groups: the TNR4 group included 481 cases
who received the TNR4 therapy, and the control group included 287 cases who were self-
medicated for cold and flu symptoms or had received other unspecified treatments. The
investigators concluded the study by listing the major benefits of using the TNR4 therapy
against COVID-19. By day 14, a significantly higher number of patients in the TNR4 group
(84.4%) recovered compared to patients in the control group (58.9%). The overall probability
of full patient recovery in the TNR4 group was 3.4 times greater than the control group.
Moreover, the TNR4 group had a 75% lower risk of hospitalization than the control group.
Mortality risk was also reduced significantly as it was 81% less in the TNR4 group. Overall,
the study proved the effectiveness of the TNR4 therapy against COVID-19 [57].
Additionally, in the period between May and September 2020 in Turkey, Okumuş
et al. performed a randomized, controlled, single-blinded prospective study investigating
the effect of IVM addition to the treatment protocol of patients with severe COVID-19. A
group of 30 patients was given oral IVM 200 µg/kg/day for 5 days alongside azithromycin,
favipiravir, and HCQ. The control group consisted of 30 patients who received HCQ,
azithromycin, and favipiravir, only. Following the end of the treatment period, patients
were followed up for 5 days. Results showed a clinical improvement rate of 73.3% in
the intervention group compared with 53.3% in the control group (p = 0.10). Mortality
in the first group developed in six patients (20%) compared to nine patients (30%) in the
control group (p = 0.37). The lymphocyte count in the intervention group (1698 ± 1438) was
higher compared to the control group (1256 ± 710), (p = 0.24). The IVM-receiving group
showed a more obvious reduction in serum CRP, D-dimer, and ferritin levels (p = 0.02,
p = 0.03, and p = 0.005, respectively) compared to the control group. Results showed that
Pharmaceuticals 2022, 15, 1068 12 of 18

clinical recovery was increased, prognostic laboratory parameters improved, and mortality
rate decreased in the IVM group, even in patients with severe COVID-19. The authors
also concluded that IVM should be used either as a substitute for a drug in the treatment
protocol or in combination with the preexisting protocols [58]. A summary of reviewed
studies on the role of IVM as part of combination therapy against COVID-19 is included in
Table 3.

Table 3. Summary of the reviewed studies on the potential of IVM as part of combination therapies
in COVID-19.

IVM Dose/Other
Date Country Study Design # of Patients Main Outcomes References
Therapeutics
200 µg/kg as a single oral
dose on day 1 +
doxycycline 100 mg twice
IVM + Doxycycline
Randomized, daily for 10 days.
May–June 2020 Bangladesh 116 was superior to HCQ [51]
controlled study or HCQ 400 mg on day 1
+ Azithromycin
then 200 mg twice daily +
azithromycin 500 mg/day
for 5 days
Insignificant shorter
Oral IVM (100 µg/kg,
Randomized, time required to
July–December 2020 Brazil 200 µg/kg or 32 [52]
open label study obtain 2 consecutive
400 µg/kg)/SOC
negative PCR result
Weight-based oral dose
every 72 h (60–90 kg,
The use of the triple
90–120 kg, >120 kg
therapy cleared
Non-randomized received 200–400 µg/kg,
May–October 2020 Egypt 113 COVID-19 virus [53]
study 300–400 µg/kg, and 30 mg
within a shorter
respectively), 500 mg
period
nitazoxanide every 6 h,
ribavirin 400 mg every 6 h
Randomized, 200 µg/kg as a single oral Faster clinical
May–July 2020 Iran double-blinded dose/HCQ and/or 69 improvement of [54]
study lopinavir/ritonavir symptoms
Significantly lower
Randomized,
number of
blinded, 12 mg oral
June–August 2020 Bangladesh 400 participants remained [55]
placebo-controlled dose/doxycycline (100 mg)
PCR positive on
study
day 14
Significantly lower
200 µg/kg orally as a mortality rate,
Retrospective,
March–May 2020 United States single dose/HCQ, 280 insignificant reduction [56]
observational study
azithromycin in the length of stay or
rate of extubating
12 mg single oral
dose/montelukast (60 mg
Higher full recovery
on day 1 and then 10 mg
in the TNR4, 75%
May–September Non-randomized from day 2 to day 21),
Mexico 768 lower risk of [57]
2020 study acetylsalicylic acid (100 mg
hospitalization,
daily for one month), and
reduced mortality risk
azithromycin (500 mg for
four consecutive days)
Clinical recovery is
Randomized,
Oral 200 µg/kg/day for increased, prognostic
May–September controlled,
Turkey 5 days/azithromycin, 60 laboratory parameters [58]
2020 single-blinded
favipiravir, and HCQ improved, mortality
study
rate decreased

8. New Formulations of IVM Specifically Developed for COVID-19

The previously reviewed clinical studies demonstrated variable and suboptimal ef-
ficacy levels for orally administered IVM in humans against SARS-CoV-2. As a result,
research scientists investigated the possibility of using other routes of administration and
targeted therapy to achieve higher and optimal levels of IVM, specially through the lungs.
In a study by Albariqi et al. evaluating the safety and pharmacokinetics of inhaled IVM in
mice, the inhaled formulation showed promising results [59]. The improved pharmacoki-
netics of the inhaled formulation might be attributed to the reduction in protein binding in
the systemic circulation, as well as the sustained high exposure in the respiratory tract.
Pharmaceuticals 2022, 15, 1068 13 of 18

Another animal study was conducted in Argentina by Errecalde et al. to assess the
safety and pharmacokinetics of a novel nasal spray formulation of IVM. Since the viral entry
and replication is primarily through the nasopharyngeal site followed by viral colonization
at the oropharynx, the trial was conducted to assess whether a nasal formulation of IVM
can attain high concentrations in the respiratory tract and consequently can be more
effective, compared to oral administration. Forty healthy pigs were divided into two
groups of equal size. The first group received 2 mg of oral IVM tablet. The second group
received methylene blue colored nasal spray with a dose of 1 mg of IVM in 0.1 mL per
puff as micro-droplets. The performance of the device during drug delivery was sufficient
according to this pre-clinical study. The colored spray showed homogeneous distribution
in the nasopharynx of tested pigs. Considering the high lipophilicity of IVM, the study
reported high and persistent concentrations of IVM in the nasopharyngeal tissue and
limited systemic absorption following nasal administration at lower doses as opposed
to the oral route. According to performed safety tests, animals receiving nasal spray of
IVM showed no clinical, hematological, histopathological, and serum biochemical adverse
effects during the study period, compared to some minor side effects reported in the oral
group [60].
Similar results were reported by Chaccour et al., utilizing nebulized ethanol-based
IVM formulation in 14 Sprague-Dawley rats which received either IVM at a low dose
(80–90 mg/kg), high dose (110–140 mg/kg), or ethanol only for the control group. The
study found that IVM was able to achieve pharmacodynamic concentrations in the rats’
lungs without histological changes. However, the investigators highlighted safety concerns
related to the ethanol vehicle and dosing regimen if a similar study was to be conducted in
humans [61].
Studies investigating targeted delivery formulation were also conducted in both an-
imals and humans. Aref et al. studied the efficacy of an IVM mucoadhesive intranasal
nanosuspension spray in reducing the upper respiratory symptoms in mild COVID-19 cases.
The clinical trial took place in Qena University Hospital, Egypt. It included 114 patients
diagnosed with mild COVID-19 that were divided into two groups. Group A consisted
of 57 patients and received the Egyptian protocol for mild COVID-19 with IVM nanosus-
pension twice daily, while Group B consisted of 57 patients who received the Egyptian
protocol for mild COVID-19 alone. Clinical manifestations, hematological, biochemical
parameters as well as two consecutive negative nasopharyngeal swabs for COVID-19 were
used to evaluate the patients. The results showed that 54 patients of group A (94.7%)
achieved 2 consecutive negative PCR nasopharyngeal swabs compared to only 43 patients
(75.4%) from Group B (p = 0.004). The negative PCR results were obtained significantly
faster in group A (8.3 ± 2.8 days) compared to group B (12.9 ± 4.3 days) (p = 0.0001). The
duration of clinical manifestations including fever, anosmia, cough, and dyspnea were also
significantly shorter in group A compared to group B, excluding gastrointestinal symptoms.
In conclusion, the study supports the local use of mucoadhesive IVM nanosuspension in
mild COVID-19 cases [62].
In another observational study conducted in Osaka, Japan, IVM was administered as
a nasal formulation to COVID-19 patients under mechanical ventilation. Eighty-eight ICU
COVID-19 patients, who were on mechanical ventilation, were divided into two groups:
the IVM group and the control group. The IVM group consisted of 39 patients who received
nasal IVM 200 µg/kg within 3 days of ICU admission. The investigated primary outcome
was the ventilation free days (VFD) measured 4 weeks post admission. VFD are days in
which the patients are alive and free from mechanical ventilation. The secondary outcomes
included gastrointestinal complications, diarrhea, and regurgitation that were measured
4 weeks post admission. The study results showed a significantly higher VFD and a
significantly lower recurring frequency of gastrointestinal complications, diarrhea, and
regurgitation in the IVM group compared to the control group. Additionally, the mortality
rate during the ICU stay was significantly lower in the IVM group compared to the control
group, amounting to 0% and 16.03%, respectively. The authors concluded that nasal IVM
Pharmaceuticals 2022, 15, 1068 14 of 18

had a beneficial influence on VFD and gastrointestinal complications, and there is room for
more investigation for IVM use in COVID-19 patients [63].

9. IVM Safety Concerns

With the greater attention and subsequently increased use of IVM since its association
with COVID-19, it is important to consider what implications this might carry in the
future. Although the safety of IVM was one of the highest amongst the newly repurposed
drugs [64], it is still vital to understand how this translates in practice with its current
growing and often misinformed use.
In a study conducted by Dicks et al., the long-term effects of IVM on the gut microbiota
and dysbiosis were investigated. It was reported that prolonged oral use of IVM could lead
to an imbalance in the oral microbiome. The oral microbiome is an essential constituent
in developing the gut microbiota. Gut dysbiosis is linked with irritable bowel syndrome
(IBS), enterocolitis, and diarrhea. Furthermore, an abnormal gut microbiome is associated
with neurological and psychiatric diseases due to the affected gut-brain access [65]. IVM
bacteriostatic activity evidenced by time-kill kinetics was also demonstrated by Ashraf
et al. [66]. Thus, the repurposing of IVM in COVID-19 and its prolonged use could
potentially result in gut dysbiosis.
Gut dysbiosis was not the only concern of IVM toxicity. The Oregon Poison Center
reported patients suffering from episodes of ataxia, confusion, hypotension, and seizures
as well as gastrointestinal tract distress. The resultant toxicity was observed in patients
receiving high frequent doses of IVM up to once every other day [67]. Therefore, the clinical
use of IVM in COVID-19 patients must be investigated further with more focus on its safety
profile at the proposed dosing regimen to fully understand what the future of IVM use in
COVID-19 patients might look like.

10. Discussion and Conclusions

The recent global pandemic of COVID-19 has elicited a wave of studies and research in-
vestigations with the goal of identifying an effective and safe treatment. IVM was one of the
explored drugs, although its exact mechanism of action against SARS-CoV-2 was not fully
understood. The scope of conducted research studies/clinical trials included understand-
ing its mechanism of action, determining its effectiveness in the treatment/prophylaxis
against COVID-19, as well as exploring the advantage of targeted delivery and novel IVM
formulations.
Studies that aimed to explore the mechanism of action of IVM against COVID-19
reported several potential mechanisms, including the inhibitory effect on RNA replication,
obstruction of binding to the receptor sites, and the immunomodulatory effect. However,
all these studies were conducted in either cell lines or animals, but not in humans.
Although reports from several clinical trials do not show that IVM could be the
wonder drug, it was deemed that for the treatment/prophylaxis of COVID-19, there is still
room for its repurposed use. As observed globally and across many studies, IVM showed
moderate benefit in mild COVID-19 cases when utilized alone or as a part of combination
treatment. These benefits include a shorter duration of treatment, faster negative PCR
results, reduction of viral load and earlier viral clearance. On the other hand, it did not
show considerable impact regarding symptom resolution when used alone as opposed to
significant improvements when used as a combination therapy. Additionally, decrease in
mortality rate was reported for combination therapies that included IVM. Further, it was
evident that IVM played an effective role when utilized for prophylaxis. It was noticed
that studies investigating the prophylactic potential of IVM included a higher number of
subjects and were mostly conducted retrospectively.
Researchers have developed and studied targeted delivery formulations of IVM
through the nasal route for COVID-19 in both animals and humans and reported im-
proved pharmacokinetics, higher concentrations in the nasopharynx/lungs, and better
resolution of clinical manifestations. With these promising outcomes, it would be rea-
Pharmaceuticals 2022, 15, 1068 15 of 18

sonable to assume that another door could be opened for the role of IVM in COVID-19.
Some safety concerns regarding prolonged IVM use revolved around its impact on the gut
microbiome and the toxicity resulting from high and frequent dosing. Therefore, IVM use
for COVID-19 has the merit to be explored further on a larger scale with more emphasis on
its safety.

Author Contributions: Conceptualization, I.S.A. and H.A.; Methodology, H.A., I.S.A.; B.H., S.D.
and Y.A.; Software, Not applicable; Validation, I.S.A., H.A. and M.R.-Q.; Formal Analysis, I.S.A.,
H.A., B.H., S.D. and Y.A.; Investigation, H.A., B.H., S.D. and Y.A.; Resources, I.S.A. and H.A.; Data
Curation, I.S.A., H.A. and M.R.-Q.; Writing—Original Draft Preparation, H.A., I.S.A., B.H., S.D.
and Y.A. Writing—Review and Editing, I.S.A., H.A. and M.R.-Q.; Visualization, I.S.A. and H.A.;
Supervision, I.S.A.; Project Administration, I.S.A.; Funding Acquisition, Not applicable. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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