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Expert Review of Anti-infective Therapy
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierz20
Possible therapeutic agents for COVID-19: a
comprehensive review
Khaled Mosaad Elhusseiny , Fatma Abd-Elshahed Abd-Elhay & Mohamed
Gomaa Kamel
To cite this article: Khaled Mosaad Elhusseiny , Fatma Abd-Elshahed Abd-Elhay & Mohamed
Gomaa Kamel (2020): Possible therapeutic agents for COVID-19: a comprehensive review, Expert
Review of Anti-infective Therapy, DOI: 10.1080/14787210.2020.1782742
To link to this article: https://doi.org/10.1080/14787210.2020.1782742
Accepted author version posted online: 13
Jun 2020.
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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group
Journal: Expert Review of Anti-infective Therapy
DOI: 10.1080/14787210.2020.1782742
Article type: Review
Possible therapeutic agents for COVID-19: a comprehensive review
Khaled Mosaad Elhusseiny1,2 #, Fatma Abd-Elshahed Abd-Elhay3#, Mohamed Gomaa
Kamel3#*
1Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
2Sayed Galal University Hospital, Cairo, Egypt.
3Faculty of Medicine, Minia University, Minia 61519, Egypt.
#Authors equally contributed the work.
*Corresponding author:
Mohamed Gomaa Kamel,
Faculty of Medicine, Minia University,
Minia 61519, Egypt
E-mail: mohamedgomaa@s-mu.edu.eg
Phone number: 201090717950
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Abstract
Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged in
China. There are no available vaccines or antiviral drugs for COVID-19 patients. Herein, we
represented possible therapeutic agents that may stand as a potential therapy against COVID-19.
Areas covered: We searched PubMed, Google Scholar, and clinicaltrials.gov for relevant
papers. We showed some agents with potentially favorable efficacy, acceptable safety as well as
good pharmacokinetic profiles. Several therapies are under assessment to evaluate their efficacy
and safety for COVID-19. However, some drugs were withdrawn due to their side effects after
demonstrating some clinical efficacy. Indeed, the most effective therapies could be organ
function support, convalescent plasma, anticoagulants, and immune as well as antiviral
therapies, especially anti-influenza drugs due to the similarities between respiratory viruses
regarding viral entry, uncoating, and replication. We encourage giving more attention to
favipiravir, remdesivir, and measles vaccine.
Expert opinion: A combination, at least dual or even triple therapy, of the aforementioned
efficacious and safe therapies is greatly recommended for COVID-19. Further, patients should
have a routine assessment for their coagulation and bleeding profiles as well as their
inflammatory and cytokine concentrations.
Keywords: Coronavirus, Infection, COVID-19, Outbreak, Bat, Pandemic, Therapy, Drug,
Vaccine, Immunization
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Article highlights
• SARS-CoV-2 is now much more hazardous than expected compared to previous outbreaks.
• There are no available vaccines or specific antiviral drugs for COVID-19 patients.
Consequently, the current treatment protocols are depending mainly on supportive treatment
and trying previously used drugs due to our experience on the posology, safety profile, side
effects, as well as drug interactions of these drugs.
• Herein, we investigated the potential therapeutics for COVID-19 patients based on the
previously documented antiviral activity either against SARS- and MERS-CoVs or other
viral infections and based on the ongoing or published SARS-CoV-2 studies.
• Several therapies are under assessment to evaluate their efficacy and safety for COVID-19.
On the other hand, some drugs have been withdrawn due to their side effects after
demonstrating some clinical efficacy while COVID-19, as of today, is essentially
untreatable, except for supportive management.
• Indeed, the most effective therapies could be organ function support, convalescent plasma,
anticoagulants, and antiviral therapy.
• We encourage giving more attention to favipiravir, remdesivir, and measles vaccine.
• Convalescent plasma was associated with reduced mortality during the 1918 influenza,
SARS, 2009 influenza H1N1, and Ebola outbreaks.
• ALPS and ECMO should be considered under strict indications and contraindications or
that leads to waste of resources and additional complications.
• Tocilizumab, as an anti-IL-6 receptor, has a promising therapeutic potential.
• Antibiotics for pneumonia are essential in case of bacterial infection only otherwise it may
fuel bacterial resistance.
• Undoubtedly, a combination, at least dual or even triple therapy, of the aforementioned
efficacious and safe therapies is greatly recommended for COVID-19 due to the disease
nature but giving great attention that mild, moderate, and severe patients may have different
regimens and combinations based on the disease severity is important as well.
• Further, patients should have a routine assessment for their coagulation and bleeding
profiles as well as their inflammatory and cytokine concentrations.
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1. Introduction
In December 2019, an outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-
CoV-2) has emerged in Wuhan, China[1]. Since then, >7 million infected cases and >400,000
deaths from 2019 CoV disease (COVID-19) have been identified exceeding the total numbers of
infected and died patients from SARS and the Middle East respiratory syndrome (MERS). The
virus transmits mainly through respiratory droplets and can be asymptomatic for 2-14 days[2].
Approximately 80% of the patients present with mild symptoms and the overall mortality rate is
nearly 5.6%, but it reaches >14% in some countries such as Italy and the UK, mainly due to the
old-age population[3]. Undoubtedly, SARS-CoV-2 is now much more hazardous than expected
compared to previous outbreaks such as the H1N1 pandemic, which caused 12,429 deaths over a
year while SARS-CoV-2 caused more than 13,000 over 5 weeks in the USA[4]. Notably,
commonly reported complications are pneumonia, acute respiratory distress syndrome (ARDS),
RNAaemia, neurological complications, and multi-organ failure that may primarily begin with
fever, cough, myalgia, and fatigue[5,6]. Developing severe COVID-19 is linked to many
possible risk factors and populations, including old-aged, hypertensive, diabetic, and/or
immunocompromised patients[7].
Unfortunately, there are no available vaccines or specific antiviral drugs for COVID-19 patients.
Consequently, the current treatment protocols are depending mainly on supportive treatment and
trying previously used drugs. Undoubtedly, underscoring the use of an old drug as an antiviral
treatment is an interesting strategy due to our experience on the posology, safety profile, side
effects, as well as drug interactions of these drugs. Phylogenetic analysis reveals that SARS-
CoV-2 has 79% identity to SARS-CoV and 50% identity to MERS-CoV[8,9], thus they share
some similar genetic and clinical characteristics. Subsequently, researchers started to try
clinically accessible drugs previously suggested for SARS- and MERS-CoVs. Thence, we here
represented possible therapeutic agents that may stand as a potential therapy against COVID-19
and shed light on their adverse effects and potential toxicities (Figure 1 and Table 1). We have
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searched PubMed, Google Scholar, and Clinicaltrials.gov for relevant papers discussing possible
therapeutic agents for COVID-19 from inception to date.
2. Antimicrobial Agents
2.1. Nucleoside Analogues (Polymerase Inhibitors)
Ribavirin is a guanosine analogue that has antiviral activity against hepatitis C virus, respiratory
syncytial virus, and viral hemorrhagic fevers[10]. It acts mainly through incorporation into viral
RNA, instead of guanosine, and this is subsequently toxic to the viral genome. Ribavirin has
been given with interferon-α to MERS-CoV patients[11], however, it failed to show response
among critically-ill patients[12]. Meanwhile, it showed uncertain clinical improvement when
used at an earlier stage[13]. Interferon-α is usually given with ribavirin to enhance and modulate
host immunity and because ribavirin was found to be not able to reduce viral RNA when given
alone[14,15]. Regarding COVID-19, a high dose of ribavirin found to limit viral infection in
vitro[16]. Thus, ribavirin might have the potential to act against COVID-19, yet this requires
large-sized clinical trials, however, caution should be taken as ribavirin has an associated risk of
hemolytic anemia and significant hemoglobin reduction. Moreover, it may result in fatigue, rash,
leukopenia, and teratogenicity[13].
Favipiravir is another guanine analogue that may act through distinctive mechanisms, including
inhibiting RNA polymerase and inducing toxic mutations in the viral genome[17]. Favipiravir
showed antiviral activity against influenza A H1N1, yellow fever, and Ebola[17–19].
Interestingly, Wang and colleagues reported that a high dose of favipiravir was able to reduce
COVID-19 loads in vitro[16]. Further, in a randomized controlled trial (RCT) of COVID-19
patients, favipiravir was compared to arbidol. The outcome of recovery was determined at day
seven post-treatment administration as return of oxygen saturation, respiratory rate, and body
temperature to their normal ranges. On the seventh day, 61.2% of patients who received
favipiravir showed clinical recovery, while only 51.7% of patients of the arbidol group
recovered. However, this difference in recovery rate was not significant. Additionally,
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favipiravir significantly relieved cough among the favipiravir group. Favipiravir is generally
tolerable; however, it is noteworthy that patients who took favipiravir experienced some adverse
events, including gastrointestinal track disturbance (13.79%), elevation of liver function
enzymes (8.62%), and psychiatric symptoms (4.31%)[20].
The therapeutic antiviral potential of remdesivir was evaluated against Ebola and Nipah viruses,
filoviruses, pneumoviruses, paramyxoviruses, as well as MERS- and SARS-CoVs[21–23]. Its
active form is analogous to adenosine, acting through inhibition of RNA polymerase and
therefore inhibiting viral replication[24–26]. It was reported to be highly potent in vivo against
SARS-CoV-2[16]. A recent study demonstrates in simian Vero E6 cells infected with SARS-
CoV-2 that remdesivir is inhibitive against SARS-CoV-2 at EC90 of 1.76 µM, a concentration
achieved in vivo in nonhuman primate models[26,27]. It has been demonstrated that remdesivir
effectively inhibited SARS-CoV-2 of human liver cancer Huh-7 cells also, which are sensitive
to SARS-CoV-2[16]. The prophylactic and therapeutic efficacious effect of remdesivir has been
shown recently against MERS-CoV in rhesus monkeys[28]. Prophylactic therapy of rhesus
monkeys with remdesivir initiated 12 hours or 24 hours before MERS-CoV inoculation
prevented virus-induced disease entirely, or provided a significant clinical benefit, with a
reduction in clinical signs, reduced virus replication, and prevented the lung lesions or decreased
its severity[28]. Moreover, Holshue and coworkers reported that they used remdesivir in treating
a 35-old man infected with SARS-CoV-2. The patient’s health was promoted with remdesivir
and supportive therapy[29]. In addition to that, a cohort of 53 critically-ill COVID-19 patients,
they received remdesivir with supportive measures. Of these 53 patients, 30 patients were
intubated on mechanical ventilation. On follow-up, 68% of the patients improved clinically,
including 17 of the intubated patients were extubated. After then, 47% were successfully
discharged[30]. There is very limited evidence on remdesivir safety, however, in an RCT of
patients with Ebola virus, one patient who took remdesivir had hypotension and cardiac arrest
following remdesivir cessation[31]. Yet, it was not clear if this effect was related to the
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discontinuation of remdesivir or the Ebola virus. A recent trial with remdesivir on a
compassionate use to 53 COVID-19 patients receiving oxygen support or mechanical ventilation
showed that 200 mg intravenous remdesivir at day 1, followed by 100 mg daily for 9 days,
resulted in clinical improvement in 68% of the patients[30]. Yet, the mortality rate was 18%
among patients receiving invasive ventilation and 5% among patients not receiving invasive
ventilation[30], suggesting that remdesivir is a good agent for COVID-19 patients not receiving
invasive ventilation. On the contrary, a recent study in China evaluated the role of remdesivir
and found that it was not associated with a difference in time to clinical improvement. Yet,
patients receiving remdesivir had an insignificant faster time to clinical improvement than those
receiving placebo among patients with symptom duration of ≤10 days. Besides, side effects were
revealed in 66% of remdesivir versus 64% of the placebo group while the 28-day mortality was
similar between the two groups (14 versus 13%, respectively). Consequently, remdesivir was
stopped early because of adverse events in 12% of patients versus 5% of patients who stopped
placebo early[32]. In a recent randomized open-label study, 200 severe patients received
remdesivir for 5 days, meanwhile, 197 patients took a 10-day course of remdesivir. There was
no significant difference in clinical improvement between both remdesivir treatment
courses[33]. Reported side effects in COVID-19 studies include nausea, constipation,
respiratory failure, and blood biomarkers of organ impairment, including low albumin, low
potassium, low red blood cells, and platelets that help with clotting, and jaundice. Moreover,
gastrointestinal problems, elevated liver enzymes, and infusion site reactions were reported as
well[33,34].
Of note, penciclovir was one of the first agents that were evaluated against SARS-CoV-2. It is
usually used against herpes viruses as it is a guanosine analogue that inhibits herpes DNA
polymerase enzyme, consequently, it inhibits virus replication. The in vitro study done by Wang
et al. assessed the efficacy of penciclovir against isolates of SARS-CoV-2. Penciclovir was
found to have a half-maximal effective concentration (EC50)=95.96 μM; indicating a relatively
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low efficacy against SARS-CoV-2[16,26]. Another group of researchers found that penciclovir
could effectively inhibit the RNA-polymerase of SARS-CoV-2, suggesting that it may have the
potential to be further investigated in clinical trials[35]. However, penciclovir is not absorbed
well when taken orally. Moreover, there is limited evidence regarding its safety in pregnancy
and breastfeeding with headache and nausea as the most common side effects[36].
2.2. Protease Inhibitors
Camostat mesilate, or camostat mesylate, is a synthetic serine protease inhibitor developed for
oral squamous cell carcinoma, and dystrophic epidermolysis. In a trial, 95 patients received
200 mg camostat mesilate three times daily for 2 weeks and showed only mild, but no severe
side effects in patients with dyspepsia associated with non-alcoholic mild pancreatic disease[37],
demonstrating that camostat mesilate is a well-tolerated intervention. In Japan, nafamostat
mesilate, as a clinically confirmed and synthetic serine protease inhibitor, was approved for the
treatment of acute pancreatitis, disseminated intravascular coagulation, and for anticoagulation
in the extracorporeal circulation[38–40].
In a screening of 1,100 drugs approved by the FDA, nafamostat mesilate was shown to inhibit
spike protein-mediated viral membrane fusion with transmembrane protease-serine 2
(TMPRSS2)-expressing lung Calu-3 host cells by inhibiting TMPRSS2 protease activity in
MERS-CoV[41]. Since the spike proteins of MERS-CoV and SARS-CoV-2 have similar
characteristics, nafamostat mesilate showed inhibiting action against SARS-CoV-2 in simian
Vero E6 cells[16], proposing that nafamostat mesilate can protect against the SARS-CoV-2
infection. Moreover, nafamostat mesilate was administered intravenously at 240 mg per day for
5 days without severe side effects in a phase 2 RCT in severe acute pancreatitis patients[38].
Darunavir, an FDA approved antiviral agent for HIV, is an inhibitor of HIV protease
enzyme[42]. Darunavir is usually combined with other drugs such as cobicistat or ritonavir[43].
This addition leads to increased half-life and serum level of darunavir because cobicistat
suppresses CYP3A4; an enzyme that normally metabolizes darunavir. A computational-based
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study identified darunavir as a potential inhibitor of SARS-CoV-2 replication. It also suggested
that darunavir might, somehow, target the spike protein of SARS-CoV-2[44]. Of note, darunavir
is mostly tolerable with rash, nausea, and diarrhea as the commonest adverse events.
Notwithstanding, darunavir should be carefully monitored in patients with hepatitis since its
hepatotoxic effect was documented[45–47]. To date, there is limited evidence about the efficacy
of darunavir/cobicistat combination for COVID-19 patients. Therefore, we encourage
conducting further preclinical and clinical studies.
Furthermore, lopinavir/ritonavir combination has been thought to have promising antiviral
activity against SARS-CoV-2. The combination was initially developed for HIV[48]. Besides,
its efficacy was tested for SARS-, MERS-CoVs, and SARS-CoV-2[27,49,50]. Lopinavir acts
through inhibiting the HIV-protease enzyme; a vital enzyme for the virus life cycle[51] while,
ritonavir; a CYP3A4 inhibitor, was added to increase efficacy and serum levels of lopinavir[52].
Chu et al. showed in vitro antiviral activity of lopinavir/ritonavir combination against SARS-
CoV[49]. Besides, Chan et al. concluded that animals infected with MERS-CoV had lower viral
loads when treated with lopinavir/ritonavir than control animals[53]. However, another group of
researchers demonstrated that the combination has no in vitro activity against SARS-CoV[54].
Furthermore, another researchers’ group showed that lopinavir/ritonavir combination, alone, has
no role in reducing viral loads of MERS-CoV. They also showed that INF-β may be superior to
this combination in terms of reducing viral loads. Moreover, they concluded that a combination
of remdesivir and INF-β is superior, as well, to lopinavir/ritonavir combination[55]. As regard to
COVID-19, lopinavir/ritonavir revealed significant antiviral activity in three Chinese
patients[56]. Another case report showed that lopinavir/ritonavir significantly reduced viral
loads in a 54-year old Korean patient[57]. On the other side, a group of researchers conducted an
RCT to investigate lopinavir/ritonavir efficacy against COVID-19. They administered
lopinavir/ritonavir to 99 patients while standard treatment was given to 100 patients. They
reported that they found no significant difference between the two groups in terms of clinical
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improvement, mortality rate, and viral load reduction[58]. The safety profile of
lopinavir/ritonavir should not be ignored since many side effects were frequently reported
including nausea, diarrhea, and asthenia[58,59].
2.3. Other Antimicrobial Agents
Glycyrrhizin is used clinically for a long time due to having anti-inflammatory,
immunosuppressive[60], anti-tumor, and antiviral properties against several viruses such as
flaviviruses[61], and hepatitis C[62], herpes[63], as well as human immunodeficiency
viruses[64]. Of note, it is relatively nontoxic and was found to exhibit activity against SARS-
CoV in vitro[65] as well as clinically with a selectivity index (ratio of antiviral activity to
toxicity) of 67[60]. Cinatl et al. evaluated the antiviral potential of glycyrrhizin, ribavirin,
pyrazofurin, 6-azauridine, and mycophenolic acid against clinical isolates from SARS patients
and it was the most potent in the suppression of the SARS-CoV replication[60]. It suppressed
viral adsorption and penetration and was most effective when administered both during and after
the viral adsorption period[60]. It was proposed that its mode of action is mediated by inducing
the nitrous oxide pathway and also has an effect on cellular signaling pathways such as protein
kinase C, casein kinase II, as well as transcription factors[60,66]. Glycyrrhizin may be a
potential therapeutic agent for SARS-CoV-2 infection with proper monitoring since its known
adverse events (hypokalemia, hypertension, and irregular heart rhythm)[67] can be controlled
despite its administration in high dosage in clinical trials, unlike the ribavirin which had many
adverse events such as hemolysis after being administrated to SARS patients[60].
At the beginning of the SARS-CoV-2 outbreak, light has been shed over chloroquine, an
antimalarial drug, especially after an article demonstrated an in vivo high selectivity index of
chloroquine against SARS-CoV-2[16,26]. In a small RCT of 30 COVID-19 patients,
hydroxychloroquine was compared to standard supportive care. The authors did not find any
significant difference between both groups in terms of viral clearance and clinical response[68].
Meanwhile, a letter by Gao et al. reported, without patients’ data, that chloroquine phosphate
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was found to be superior to the control group, in terms of improving pneumonia and assisting
patients’ recovery[69]. Moreover, an expert consensus recommended a ten-day course of 500
mg of chloroquine phosphate twice daily[70]. Another in vitro study compared
hydroxychloroquine with chloroquine and suggested the superiority of hydroxychloroquine over
chloroquine[71], especially because it is safer, cheaper, and suitable for pregnant women.
Additionally, in a small non-randomized study, researchers reported that 14 of 20 patients,
treated with hydroxychloroquine, had negative PCR on the sixth day following the drug
administration. Meanwhile, only 2 of 16 patients had negative results in the control group on the
sixth day. They also reported that azithromycin augmented the therapeutic effect of
hydroxychloroquine on six patients compared to hydroxychloroquine alone[72]. Indeed, the use
of chloroquine had been initially supported by in vitro and weak human studies and some
countries have put it in their guidelines although both could lead to QT prolongation separately
and, thus if combined with azithromycin, they may lead to serious adverse events[73,74].
Previous reports suggested that inhibiting T-helper cell proliferation and interleukin-2 (IL-2)
production or responsiveness may boost the inflammatory response accidentally, subsequently,
it could affect patients’ outcomes unfavorably[75,76] as it was in Chikungunya viral infection.
Moreover, such combination in overdoses is extremely toxic, especially in patients with
preexisting cardiovascular problems, and could lead to hypoglycemia, neuropsychiatric effects,
drug-drug interactions, and idiosyncratic hypersensitivity events. Later on, the findings of
another uncontrolled observational study of mildly affected 80 COVID-19 patients receiving
hydroxychloroquine with azithromycin were reported[72]. Of these patients, 81.3% discharged
from the hospital, three patients were admitted to the intensive care unit (ICU), one patient died
while 14 patients were still hospitalized at the study endpoint[77]. Another observational
retrospective one-armed study of 1,061 patients, who were given hydroxychloroquine plus
azithromycin, reported that 91.7% of the patients had a good clinical and virological outcome in
10 days with the observation of mild adverse effects, including gastrointestinal, transient blurred
vision, headache, and insomnia in 2.3% of patients[78]. On the other hand, 92 COVID-19
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patients requiring oxygen therapy was administered hydroxychloroquine and compared to 89
controlled patients who did not receive hydroxychloroquine. There was no difference between
the overall survival at day 21 between both treatment and control groups (89 and 91%,
respectively)[79]. Similarly, in patients with persistent mild to moderate COVID-19,
hydroxychloroquine plus standard of care did not lead to a significantly higher probability of
negative conversion than the standard of care alone. Moreover, the hydroxychloroquine group
had higher adverse events than the control group[80]. In addition, an analysis of 96,032 COVID-
19 patients’ data revealed an increased risk of in-hospital mortality with either
hydroxychloroquine or chloroquine with or without a macrolide; compared to control patients
who were not given any of these therapeutics[81]. In a double-blinded RCT of hospitalized
COVID-19 patients, two different dosages of chloroquine, (600 mg twice daily for 10 days
compared to 450 mg twice on day 0 then 450 mg once for four days), were given as adjuvant
therapy to the standard care for both treatment arms, the researchers had to discontinue the trial
because of the observed high fatality rate among higher dosage arm (10-day chloroquine course)
and recommended against giving a high dose of chloroquine to COVID-19 patients[82].
Nitazoxanide is another potential therapeutic for COVID-19. It has shown a broad spectrum of
anti-parasitic and antiviral activity acting against rotavirus, norovirus, chronic hepatitis B,
influenza, respiratory syncytial virus, canine CoVs through distinctive mechanisms[83–87]. It
was found to overexpress interferon regulatory factor-1 that inhibited the replication of human
norovirus[87]. Moreover, it was found to be active against MERS-CoV, murine, and bovine
CoVs through inhibition of the viral N protein expression[86]. Additionally, it suppresses the
production of inflammatory cytokines, including IL-2, IL6, and IL-10[88]. Besides, the in vitro
efficacy of nitazoxanide against SARS-CoV-2 was reported[16,26]. The most commonly
reported side effects of nitazoxanide are mild, including headache, skin rash, fever, vomiting,
and abdominal pain[89,90]. To date, 11 registered trials are trying to investigate its safety and
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efficacy in COVID-19 patients either alone or in combination with ivermectin or
hydroxychloroquine with their findings yet to be revealed[91].
Umifenovir (known as arbidol) has a wide range of antiviral activity against influenza A and
B[92]. It acts mainly through inhibition of membrane fusion between the viral envelope and host
cell membrane, therefore, preventing viral entry and infectivity[93]. Arbidol, also, may enhance
the host immune response by activation of macrophages and induction of interferons[92]. In
vitro studies showed that arbidol has antiviral activity against hepatitis B, C, and Ebola viruses,
poliovirus, as well as human herpes virus-8[94,95]. This broad-spectrum antiviral activity has
made arbidol standing as a potential therapeutic against SARS-CoV-2. It is worth mentioning
that arbidol may have a synergistic effect when combined with an immunomodulatory drug
(IMOD); a drug used in HIV patients to induce the production of CD4 lymphocytes and
interferon gamma[96]. Moreover, Deng et al. conducted a retrospective cohort study, in which
16 patients received a combination of lopinavir/ritonavir plus oral arbidol compared to a group
of 17 patients who received only lopinavir/ritonavir. They found that viral loads disappeared
after 14 days in 15 of 16 and 7 of 17 patients in lopinavir/ritonavir and arbidol versus in
lopinavir/ritonavir only group, respectively[97]. Notably, arbidol is generally safe; with
gastrointestinal disturbance symptoms as the most common adverse events[98]. Currently,
registered clinical trials are investigating its safety and efficacy and comparing it to standard
care or lopinavir/ritonavir combination. We also encourage conducting more trials, however, we
also suggest evaluating its efficacy when combined with IMOD in COVID-19 patients.
Furthermore, ivermectin, an approved antiparasitic medication[99], has been proposed as a
potent inhibitor against COVID-19. Ivermectin had an in vitro antiviral activity against HIV-1
and dengue virus[100,101]. It mitigates West Nile and influenza viruses as well[102,103]. It acts
mainly by inhibiting the viral nuclear import and therefore inhibit its replication. Interestingly,
Caly et al. reported that ivermectin was able to eliminate all RNA from infected cells with
SARS-CoV-2 in 48 hours. They hypothesized that ivermectin has a high probability of being a
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strong inhibitor of COVID-19 replication in human patients, especially when given early. They,
also, found no adverse effects on tested cells[104]. However, it should be tried with caution
because it may need very high doses to work and its safety in pregnancy has not been yet
concluded[105]. Moreover, severe side effects about potentiation of the GABAergic synaptic
transmission, and causing ataxia, psychosis, depression, confusion, and convulsions were found
in a few patients[106].
Baloxavir marboxil, a potent anti-influenza drug, inhibits viral replication by inhibiting the
protein synthesis, which is a different mode of action from neuraminidase inhibitors like
oseltamivir. Thus, it was demonstrated that the baloxavir marboxil/oseltamivir combination has
a synergistic antiviral effect in experimental and clinical studies[107,108]. They also
demonstrated no side effects nor effect on their shared pharmacokinetics with no need for dose
adjustment when combined[108].
3. Targets for Angiotensin-Converting Enzyme (ACE)
ACE-II receptor has been established as a primary receptor for SARS-CoV-2. Kuba et al.
noticed a reduction in ACE-II expression, in the lung tissue, indicating that this reduction may
play a role in lung injury mediated by SARS-CoV[109]. This finding was consistent in an in
vivo study conducted on a mouse infected with influenza A as well. Notably, the administration
of recombinant ACE-II enhanced the survival of the mice, lessened lung edema, and improved
lung histopathology and function, and lessened lung edema[110]. Indeed, it does not only
compensate for the low lung ACE-II expression, but also might act, theoretically, as a decoy to
SARS-CoV-2, and subsequently naturalizing the virus through binding to the virus instead of
host receptors. Therefore, we encourage conducting RCTs investigating its safety and efficacy in
patients with COVID-19. Nevertheless, attention should be directed, primarily, to address its
safety. In hemodynamically-stable patients with ARDS, recombinant ACE-II was administered
in a pilot clinical trial. Although there were no negative hemodynamic effects, dysphagia, rash,
and acute renal failure were documented[111].
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ACE-II inhibitors were suggested as possible medications for COVID-19[112], especially in
patients with hypertension, it was noted that they reduced the pulmonary inflammatory response
and mortality. Notwithstanding, they could result in a compensatory increase in ACE-I by
negative feedback due to downregulating ACE-II, consequently that will lead to more ACE-II
resulting in excessive binding to ACE-II receptor in the lungs which increases pulmonary
vascular permeability, ultimately that results in pulmonary edema.
4. Immunotherapy and Immunomodulators
Convalescent plasma is another potential therapy against COVID-19 as well. Indeed,
convalescent plasma was suggested that it may have a good impact on SARS-CoV
patients[113,114]. It is noteworthy that the WHO recommended the use of convalescent plasma
during Ebola outbreaks[115]. It is worth mentioning as well that improvement in clinical status
in five critically ill patients with COVID-19 and ARDS was noted following the administration
of convalescent plasma containing neutralizing antibodies[116]. In contrast, in an RCT by Li et
al. who added convalescent plasma to standard treatment, compared with standard treatment
alone, did not see a statistically significant improvement in time to clinical improvement within
28 days. Of note, it was associated with some clinical improvement in severely ill patients, but
not in critically ill patients which could be because antibody therapies generally work best when
administered earlier in the disease course[117,118]. Further, its application still has many
setbacks including the accessibility to sufficient donors, risk of disease transmission, as well as,
its adverse events early after transfusion such as nausea, fever, and skin rash[119].
Monoclonal antibodies (MABs) have been suggested as a potential therapeutic for COVID-19
based on the previous evidence of their promising effect on SARS- and MERS-CoV in vivo and
in vitro[120–124]. MABs, indeed, are preferred over convalescent plasma in terms of being
specific with no risk of transmitting blood-borne infections. The mechanism of MABs is mainly
targeting a specific protein, especially the receptor-binding domain (RBD) of the S1 subunit,
thereby, blocking its binding to the host receptor, subsequently preventing viral entry[125,126].
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Another possible target is the S2 subunit which is responsible for fusion between the virus and
host cell membrane. Indeed, several MABs were previously produced to target the RBD of S1
and S2 subunits of SARS-CoV. Their preclinical studies showed promising potential treating
and preventive effects[120–124]. Therefore, owing to the similarity between the spike protein of
SARS- and SARS-CoV-2, it is worth investigating their effect on COVID-19 patients. However,
their main challenge is their production for being not cost-effective and laborious.
The so-called cytokine storm in severely affected patients has highlighted the rationale to
investigate the efficacy of therapeutic agents directed against cytokines. IL-6 antibody was
detected to be one of the highest cytokines among ICU COVID-19 patients with cytokine storm.
Tocilizumab, a monoclonal antibody, antagonizes IL-6 by binding to both serum and
transmembrane IL-6 receptors; preventing IL-6 from binding to its receptors and thereby
preventing its inflammatory-mediated response[127]. Tocilizumab is the first approved anti-IL-6
monoclonal antibody. It is used mainly in rheumatoid disease[128], systemic juvenile idiopathic
arthritis[129], steroid-refractory chronic graft-versus-host disease[130], and cytokine release
syndrome[127]. Xu et al. reported the use of tocilizumab in 21 Chinese patients with severe
COVID-19. Nineteen patients had lung opacities observed in their CT chest. The fever was
resolved in all patients in the first day post-tocilizumab administration. All patients had rapid
clinical improvement and discharged from the hospital with no observed tocilizumab-related
adverse events[131]. Another prospective study of 100 critical COVID-19 patients found
consistent results of rapid clinical response[132]. It has been recommended that tocilizumab
dose better to be repeated, even in COVID-19 patients who failed to show a response after the
first dose, to get a higher response[133]. Although tocilizumab has a tolerable profile in previous
indications, caution should be taken as septic shock developed in two COVID-19 patients
besides gastrointestinal perforation that occurred in one COVID-19 patient[132]. Moreover,
tocilizumab could be associated with an increased risk of opportunistic infections, leukopenia,
and/or lymphopenia. Furthermore, like other MABs, the high cost of tocilizumab might be
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challenging as well. Many registered trials are still trying to further investigate the safety and
efficacy of tocilizumab either alone or in combination with other agents such as favipiravir[134].
Other anti-IL-6 agents, including olokizumab and siltuximab, are being investigated with their
final results yet to be revealed.
In addition to that, there is rising limited evidence about the use of mesenchymal stem cells
(MSCs) in treating COVID-19-associated pneumonia. This suggestion is based on the
immunomodulatory function of MSCs. It is believed that MSCs, when injected intravenously,
may secrete anti-inflammatory paracrine factors, and therefore, they may counteract the
damaging cytokine storm of COVID-19. Additionally, they may reach the pulmonary circulation
and protect and/or regenerate the damaged pulmonary epithelial cells[135]. The effectiveness of
MSCs was previously documented in patients with acute graft-versus-host disease unresponsive
to steroid therapy, as well as, patients with systemic lupus erythematosus (SLE)[136,137].
Meanwhile, in patients with moderate-to-severe ARDS, MSCs infusion showed general
tolerability, yet, they had low efficacy that still to be investigated further[138,139]. Liang et al.
reported the use of MSCs in a critically-ill female patient affected with COVID-19. They found
that MSCs improved the clinical outcome of the patient with no adverse events[140]. Another
study enrolled seven patients, with COVID-19, and administered MSCs to them. They noticed a
modulatory effect on them, in terms of the disappearance of cytokine-producing cells. Also, they
noticed the correction of COVID-19 associated lymphocytopenia. Subsequently, the health of
the seven patients was improved[141].
Baricitinib is proposed as an immunomodulatory via inhibiting the cytokine storm caused by
COVID-19 and consequently the extensive inflammation of the lung tissue. It mostly inhibits
JAK 1 and 2 enzymes and subsequently inhibiting cytokines’ gene expression. It also might
inhibit AP2-associated protein kinase 1, an enzyme that promotes virus entry in the host cells
and the intracellular assembly of virus particles[142–144]. A caution, however, is needed when
using immunomodulators with immunocompromised patients whereas the commonest side
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effects are upper respiratory tract infections, nausea, cold sores from herpes simplex, and
shingles from herpes zoster[145].
Another proposed treatment is interferons. Interferon-α has been usually used in the treatment of
viral hepatitis[146] and some various types of cancers, including leukemia and
melanoma[147,148]. Interestingly, interferon-α was found to be effective in vitro against SARS-
CoV but with a low selectivity index than interferon-β[149]. In addition to that, a retrospective
cohort study reported that a combination of interferon-α and ribavirin improved the clinical
status of patients infected with MERS-CoV[150]. Fatigue, anorexia, and weight loss are among
the most common side effects of interferon-α but, thankfully, dose-limited[146]. Currently, its
safety and efficacy are being evaluated in clinical trials for both treating COVID-19[151,152]
and, possibly, a way of enhancing immunity and preventing COVID-19 among medical
staff[153].
It is worth mentioning that it is advised against the use of corticosteroids in COVID-19 affected
patients[154]. Corticosteroids may suppress lung inflammation in theory; however, clinical
outcomes were found to be worse in patients affected with either SARS-, or MERS-
CoVs[155,156].
5. Organ Function Support
5.1. Artificial Liver Blood Purification System (ALPS)
ALPS showed the ability to clear the serum cytokine storm which has the main role of
developing respiratory failure through the severe inflammatory response. Previously, ALPS
revealed its efficacy when used in severe H7N9 influenza critically-ill patients with cytokine
storm[157]. For COVID-19, ALPS blocked the cytokine storm successfully in severely affected
Chinese patients and supported, in part, their clinical status[158]. ALPS is indicated if serum
cytokines level is five times the upper-normal level given the daily deterioration of the lung on
imaging[159]. Yet, the high cost and less availability of ALPS make it to be used in strict
situations and upon indications.
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5.2. Extracorporeal Membrane Oxygenation (ECMO)
ECMO was previously used in the influenza A pandemic[160] and MERS-CoV[161] with
promising results. ECMO simply removes CO2 from the patient’s blood and adds oxygen,
therefore allowing a better chance for the lungs to improve under treatment. In a retrospective
cohort study on severely affected MERS patients, ECMO was placed to 17 patients in contrast to
18 control patients indicated for ECMO but it was not available for them. The ECMO group had
a significantly better PaO2/FiO2 ratio than the control group on day 14 (138 and 36,
respectively). Moreover, the ECMO group had lower mortality than the control group[161].
ECMO is reserved for COVID-19 patients with severely refractory hypoxemia. This effective
cardiopulmonary support method is, however, very limited, needs high expertise level, and
unfortunately can be a source of SARS-CoV-2 transmission between patients and treating
physicians. Hence, physicians are advised to take strict infection-control measures when dealing
with ECMO-treated patients.
6. Other Therapeutic Agents
We also highlight the importance of adding prophylactic anticoagulants in critically-ill patients
admitted to the ICU. There are two reasons behind this suggestion; firstly, owing to the
previously documented increased risk of deep venous thrombosis and pulmonary embolism in
long-time hospitalized patients[162]. Secondly, antiphospholipid antibodies can temporarily
appear in the serum of critically-ill patients with viral infections[163]. The observed adversely-
affected outcome in patients with COVID-19-related hypercoagulable state, emphasizes the
importance of prophylactic anticoagulants. Moreover, in COVID-19 mechanically-ventilated
patients, the administration of systemic anticoagulants was associated with lower in-hospital
mortality rate compared to patients who did not take systemic anticoagulants (29.1 and 62.7%,
respectively). However, for all hospitalized patients including patients who did not require
mechanical ventilation, there was no difference in in-hospital mortality[164]. Another
retrospective study of 499 severe COVID-19 patients reported a significant difference in
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mortality rate between patients (with >6 fold of upper normal D-dimer) who received low-
molecular-weight heparin (LMWH) compared to patients who did not take anticoagulant
therapy (32.8 and 52.4%, respectively)[165]. Indeed, LMWH, such as enoxaparin, acts by
inhibiting factor Xa, is preferred to use over unfractionated heparin (UFH) that acts through
binding to antithrombin III that consequently inhibits thrombin and factor Xa leading to
immediate anticoagulant action[166]. The preference of LMWH to UFH is mainly because there
is no laboratory monitoring needed. Further, resistance to UFH was observed in 80% of ICU-
admitted COVID-19 patients[167]. LMWH prophylaxis dose is indicated for all hospitalized
COVID-19 patients. It is worth mentioning if the creatinine clearance is 15-30 ml/minute; the
dose should be lowered to 30 mg once per day[168]. Yet, for patients with creatinine clearance
<15/minutes, UFH should be used instead of LMWH. Two COVID-19 patients were taking
prophylactic LMWH dose, however, they developed acute limb ischemia[169]. This may
indicate that prophylactic dose might not be effective in patients with a high D-dimer level,
thereby therapeutic doses should be given instead in those patients. Both UFH and LMWH are
associated with the risk of bleeding and heparin-induced thrombocytopenia (HIT), especially
UFH[170,171]. Thence, fondaparinux, an inhibitor of activated factor Xa, can be used instead of
heparin in patients who developed and/or have a history of HIT[172].
Dayrit and colleagues have interestingly proposed using coconut oil and its derivatives in
treating patients infected with COVID-19[173]. Indeed, coconut oil was observed to has
antiviral activity against HIV with, notably increased counts of CD4 and CD8 six weeks after its
administration[174,175]. Its antiviral activity is thought to be due to inhibition of viral
replication, disrupting viral binding to host cells, as well as, damaging the viral envelope. Based
on its reported viral activity, availability, and being safe, clinical trials of coconut oils against
COVID-19 are recommended.
Hesperidin is a natural derivative of citrus fruits. It has shown a protective effect against
influenza A virus at the early stage of infection through inhibition of viral neuraminidase
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(sialidase) enzyme, important for the virions release from infected cells[176]. A group of
researchers investigated its efficacy against SARS-CoV-2. Interestingly, hesperidin bound to
RBD of SARS-CoV-2 spike protein, and therefore inhibited the interaction between ACE-II
receptor and spike protein. This step, subsequently, inhibited viral entry inside host cells. This
finding encourages conducting more trials on hesperidin, because it is cheap, available, with no
adverse effects, except for the low incidence of nausea and vomiting[177].
It is noteworthy that we encourage conducting trials on the efficacy of live recombinant measles
vaccine (rMV) for SARS-CoV-2. Notably, a rMV, that expresses the RBD of S1 subunit of the
spike protein of SARS, was reported to be able to induce a highly robust humoral response
enabling cross-reactivity and protection against SARS, with good safety profile[178–181].
Nevertheless, this vaccine is contraindicated in pregnancy[182]. It also may result in
thrombocytopenia and febrile seizures, yet with, thankfully, low incidence[183]. The
aforementioned in vitro findings of rMV encourage giving more attention to target the spike
protein of SARS-CoV-2.
We also suggest giving COVID-19 patients influenza and pneumococcal vaccinations. In
particular, high-risk patients, including patients with severe comorbidities and elderly patients.
This will reduce the risk of developing concurrent respiratory infections. The same suggestion
was reported before among patients with SLE[184,185]. Chang et al. analyzed the risk of
mortality and morbidity in SLE patients who took and who did not take influenza vaccinations.
Vaccinated patients had fewer times of hospitalization, and ICU admission, as well as a lower
mortality rate[186]. Owing to the safety profile of influenza and pneumococcal vaccinations,
except for the reported adverse events of headache, injection site reactions, and systemic
reaction[187], it is advised that all COVID-19 patients may benefit from their vaccination
immune response even patients who are taking immunomodulatory agents since the
immunogenicity of these vaccinations were previously found to be still safe and immunogenic
with immunosuppressive therapeutics except for rituximab[184,188–192].
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7. Expert opinion
In this review, we assessed the potential therapeutics for COVID-19 patients based on the
previously documented antiviral activity either against SARS- and MERS-CoVs or other viral
infections and based on the ongoing or published SARS-CoV-2 studies. We showed some
agents with potentially favorable efficacy, acceptable safety as well as good pharmacokinetic
profiles in vitro, in vivo and/or in humans. Several therapies are under assessment to evaluate
their efficacy and safety for COVID-19. On the other hand, some drugs have been withdrawn
due to their side effects after demonstrating some clinical promise[193] while COVID-19, as of
today, is essentially untreatable, except for supportive management[194,195]. Indeed, the most
effective therapies could be organ function support, convalescent plasma, anticoagulants, and
antiviral therapy, especially anti-influenza drugs due to the similarities between respiratory
viruses regarding viral entry, uncoating, and replication[26]. We encourage giving more
attention to favipiravir, remdesivir, and measles vaccine. Of note, convalescent plasma was
associated with reduced mortality during the 1918 influenza, SARS, 2009 influenza H1N1, and
Ebola outbreaks[114,196,197]. Ribavirin is a broad-spectrum antiviral drug; yet, the clinical
effects are unclear, and side effects should be considered. Besides, ALPS and ECMO should be
considered under strict indications and contraindications or that lead to a waste of resources and
additional complications. Moreover, tocilizumab likely possesses a better effect than other anti-
IL-6 receptors MABs. Antibiotics for pneumonia are essential in case of bacterial infection only
otherwise it may fuel bacterial resistance.
Undoubtedly, a combination, at least dual or even triple therapy, of the aforementioned
efficacious and safe therapies is greatly recommended for COVID-19 due to the disease nature
but giving great attention that mild, moderate, and severe patients may have different regimens
and combinations based on the disease severity is important as well. Further, patients should
have a routine assessment for their coagulation and bleeding profiles as well as their
inflammatory and cytokine concentrations.
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Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Figure Legends
Figure 1. SARS-CoV-2 replication cycle with target therapeutic agents. Abbreviations;
CM=camostat mesilate, NM=nafamostat mesilate, IL-6=interleukin-6, ACE=angiotensin-
converting enzyme.
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Table 1. Summary of possible therapeutic agents for SARS-CoV-2. 1
Dru
g
Mechanism Common Uses Common Side Effects/Limitations
Nucleoside Analo
g
ues (Pol
y
merase Inhibitors)
Ribavirin A guanosine analogue incorporates into viral RNA, instead of
guanosine, and is toxic to the viral genome
HCV, RCV, and viral
hemorrhagic fevers
Hemolytic anemia, fatigue, rash,
leukopenia, and teratogenicity
Favipiravir A guanine analogue, inhibiting RNA polymerase and inducing
toxic mutations
influenza A H1N1, yellow
fever, and Ebola
Gastrointestinal tract disturbance, the
elevation of liver function enzymes,
and psychiatric symptoms
Remdesivir Analogous to adenosine inhibits RNA polymerase and viral
replication
Ebola Blood biomarkers of organ
impairment, gastrointestinal problems,
elevated liver enzymes, and infusion
site reactions
Penciclovir Inhibition of RNA polymerase Herpesvirus Headache and nausea
Protease Inhibitors
Camostat mesilate Serine protease enzyme inhibitor Oral squamous cell
carcinoma and dystrophic
epidermolysis
Dyspepsia
Nafamostat mesilate Serine protease enzyme inhibitor Acute pancreatitis, DIC Acute systemic reaction
Darunavir A protease enzyme inhibitor, and target for spike protein of
SARS-COV-2
HIV Rash, nausea, and diarrhea,
hepatotoxic
Cobicistat CYP3A4 inhibitor HIV Jaundice, skin rash, depression, and
headache
Lopinavir Protease enzyme inhibitor SARS-, and MERS-CoV,
and HIV
Nausea, diarrhea, and asthenia
Ritonavir CYP3A4 inhibitor SARS-, and MERS-CoV,
and HIV
Nausea, diarrhea, and asthenia
Other Antimicrobial A
g
ents
Glycyrrhizin Inhibits viral adsorption and penetration, induces the nitrous oxide
pathway and affects cellular signaling pathways such as protein
kinase C, transcription factors, as well as casein kinase II
HCV, upper respiratory
tract infections, and as
anti-inflammatory,
immunosuppressive, anti-
tumor, and antiviral
Hypokalemia, hypertension, and
irregular heart rhythm
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properties against
flaviviruses, herpes
viruses, and human
immunodeficiency virus
Chloroquine, and
Hydroxychloroquine
Increasing pH in host-cell lysosomes which in turn inhibits the
hydrolytic activity of protease enzymes that are required for
processing of viral glycoproteins. They also may interfere with the
terminal glycosylation of the ACE-II receptor. They could
negatively influence the virus-receptor binding and abrogate the
infection.
Malaria QT prolongation
Nitazoxanide Downregulation of expression of N protein Rotavirus and giardiasis Vomiting, fever, skin rash, and
abdominal pain
Arbidol (Umifenovir) Inhibits fusion between viral and cellular membrane, activation of
macrophages and induction of interferons
HBV, HCV, Ebola virus,
poliovirus, as well as
human herpes virus-8
Gastrointestinal disturbance
Ivermectin Inhibition of viral nuclear import and therefore inhibit its
replication
Various parasitic
infections
Neurotoxicity
Baloxavir marboxil/Oseltamivir Viral endonuclease inhibitor and neuraminidase inhibitor,
respectively
Influenza A and B viruses -
Tar
g
ets for ACE
ACE-II inhibitors Downregulating ACE-II Hypertension Increases pulmonary vascular
permeability and pulmonary edema.
Recombinant Agents Dilatation of SARS-CoV-2 levels via reduction of ACE-II
expression
SARS-CoV Dysphagia, rash, and acute renal
failure
Immunotherap
y
and Immunomodulators
Convalescent plasma Binds to SARS-CoV-2, blocks infection, binds to infected cells
and changes the immune system
Ebola, SARS-CoV Nausea, fever, and skin rash, risk of
diseases transmission
Monoclonal antibodies Targeting a specific protein, especially the RBD of S1 subunit,
thereby, blocking its binding to host receptor (viral entry) and
targeting S2 subunit (fusion between the virus and host cell
membrane)
SARS- and MERS-CoVs Not cost-effective and laborious
Tocilizumab Anti-IL-6 antibody Rheumatoid arthritis and
systemic juvenile
Increase the risk of opportunistic
infections, lymphopenia and
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idiopathic arthritis leukopenia
MSCs Immunomodulatory (secrete anti-inflammatory paracrine factors),
counteract the cytokine storm, protect and/or regenerate the
damaged pulmonary epithelial cells
Acute graft-versus-host
disease, and SLE
-
Baricitinib Inhibition of JAK 1 and 2 enzymes (cytokines’ gene expression),
AP2-associated protein kinase 1 (viral entry) and the intracellular
assembly of virus particles
SLE Immunosuppression, upper respiratory
tract infections, nausea, cold sores
from herpes simplex, and shingles
from herpes zoster
INF-α and β Stimulate innate antiviral immunity SARS-, and MERS-CoVs,
hepatitis, leukemia, and
melanoma
Fatigue, anorexia, and weight loss
Corticosteroids Cytokine storm-targeted therapy and immunosuppression SLE Immunosuppression
Or
g
an Function Support
ALPS Cytokine storm-targeted therapy and organ function support --
ECMO Cytokine storm-targeted therapy and organ function support -Very limited, high expertise level,
and a source of SARS-CoV-2
transmission
Other Therapeutic A
g
ents
Anticoagulants - DVT, PE, stroke and heart
attacks
Bleeding
Coconuts Disrupting viral binding to host cells and damaging the viral
envelope
HIV -
Hesperidin Inhibition of viral neuraminidase (sialidase) enzyme and the
interaction between the ACE-II receptor and the spike protein
(inhibition of viral entry)
Influenza A virus Nausea and vomiting
Measles vaccine
Expresses the RBD of S1 subunit of the spike protein of SARS
and induces a highly robust humoral response enabling cross-
reactivity and protection against SARS
Measles Contraindicated in pregnancy,
thrombocytopenia and febrile seizures
Abbreviations; ALPS=artificial liver blood purification system, ECMO=extracorporeal membrane oxygenation, HCV= Hepatitis C virus, 2
ACE=angiotensin-converting enzyme, MSCs= mesenchymal stem cells, INF=interferon, HIV=human immunodeficiency virus, SARS=severe acute 3
respiratory syndrome, MERS= middle east respiratory syndrome, RCV=respiratory syncytial virus, SLE=systemic lupus erythematosus, 4
RBD=receptor binding domain. 5
6
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