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The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic with a high growth rate of confirmed cases. Therefore, therapeutic options are desperately urgent to fight with this damning virus. As it may take years to develop a specific therapy of COVID-19, it is urgent to emphasize the repurposing of drugs used for other conditions. This study reviewed the most common drugs for COVID-19 based on available online literature representing the latest in vitro clinical trial database, rational of use, adverse effects, potential toxicities, and US National Institute of Health (NIH) recommendation to use for COVID-19. Based on the preliminary data from clinical trials and considering the NIH and FDA recommendation, remdesivir and convalescent blood products are the most promising potential for COVID-19 treatment. The use of chloroquine, hydroxychloroquine, favipiravir, ivermectin, and colchicine might also be effective. However, furthermore, in vivo investigations are needed in detail individually and in combination for possible benefits in humans. Besides, tocilizumab might be deemed as adjunctive therapy for patients with cytokine release syndrome. However, lopinavir-ritonavir, anakinra, and sarilumab had not proven their clinical efficacy. Eventually, sarilumab has been withdrawn from sponsored clinical trials based on the preliminary data. Baricitinib and ruxolitinib have the additive immunosuppressive effect. Consequently, all of these drugs are being evaluated with further studies. In addition, drug-drug interaction and safety concerns must be taken into account before the administration of the recommended drugs.
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COVID-19
A Review on Current Repurposing Drugs for the Treatment
of COVID-19: Reality and Challenges
Md. Shafiul Hossen
1
&Md Abdul Barek
1
&Nusrat Jahan
1
&Mohammad Safiqul Islam
1
Accepted: 24 August 2020
#Springer Nature Switzerland AG 2020
Abstract
The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
has become a global pandemic with a high growth rate of confirmed cases. Therefore, therapeutic options are desperately urgent
to fight with this damning virus. As it may take years to develop a specific therapy of COVID-19, it is urgent to emphasize the
repurposing of drugs used for other conditions. This study reviewed the most common drugs for COVID-19 based on available
online literature representing the latest in vitro clinical trial database, rational of use, adverse effects, potential toxicities, and US
National Institute of Health (NIH) recommendation to use for COVID-19. Based on the preliminary data from clinical trials and
considering the NIH and FDA recommendation, remdesivir and convalescent blood products are the most promising potential for
COVID-19 treatment. The use of chloroquine, hydroxychloroquine, favipiravir, ivermectin, and colchicine might also be effec-
tive. However, furthermore, in vivo investigations are needed in detail individually and in combination for possible benefits in
humans. Besides, tocilizumab might be deemed as adjunctive therapy for patients with cytokine release syndrome. However,
lopinavir-ritonavir, anakinra, and sarilumab had not proven their clinical efficacy. Eventually, sarilumab has been withdrawn
from sponsored clinical trials based on the preliminary data. Baricitinib and ruxolitinib have the additive immunosuppressive
effect. Consequently, all of these drugs are being evaluated with further studies. In addition, drug-drug interaction and safety
concerns must be taken into account before the administration of the recommended drugs.
Keywords COVID-19 .Clinical trial .Convalescent plasma .Remdesivir .Chloroquine .Hydroxychloroquine
Introduction
A dangerous outbreak of atypical pneumonia of unknown
origin was first identified in a group of patients in Wuhan city,
China, at the end of December 2019 [1]. Chinese Centre for
Disease Control identified a novel coronavirus, initially called
2019-nCoV, as a cause of this outbreak. Later, it was officially
renamed to severe acute respiratory syndrome 2 (SARS-CoV-
2) that is the causative factor of a disease known as coronavi-
rus disease-19 (COVID-19) [2]. Due to its high transmission
potential, the SARS-CoV-2 infection has become a global
health threat within weeks [3]. Consequently, the World
Health Organization (WHO) declared the COVID-19 as a
pandemic disease on 11 March 2020. As of 25 July 2020,
about 15,802,717 confirmed cases and 639,228 deaths had
been reported throughout the world in this ongoing pandemic
[4]. The confirmed cases are heterogeneous and divided into
mild (80%), severe (15%), and critical cases (5%) [5].
Notably, several clinical manifestations, such as fever, cough,
dyspnea, and myalgia, with increased serum level of aspartate
aminotransferase, creatinine, creatine kinase, and C-reactive
protein were more frequently observed in the complicated
COVID-19 patients than the uncomplicated group [6,7].
Cytokine storm is only reported in critically ill patients and
responsible for the development of complications leading to
ultimate death associated with COVID-19 [8]. In addition,
approximately 15% of COVID-19 patients will develop se-
vere lung disease due to acute respiratory infection that is
recognized in most cases after 7 to 14 days. The disease se-
verity is characterized by systemic inflammation reactions as-
sociated with cytokine storm [9]. Unfortunately, no antiviral
drug or standard treatment against COVID-19 is currently
This article is part of the Topical Collection on COVID-19
*Mohammad Safiqul Islam
research_safiq@yahoo.com
1
Department of Pharmacy, Faculty of Science, Noakhali Science and
Technology University, Sonapur, Noakhali 3814, Bangladesh
SN Comprehensive Clinical Medicine
https://doi.org/10.1007/s42399-020-00485-9
available which results in the growing rate of morbidity and
mortality. However, it may take years to develop and to eval-
uate the clinical studies of a specific, highly potent antiviral
drug for SARS-CoV-2. Therefore, it is urgent to focus on
previously used antiviral agents and immunomodulating
drugs or other relevant agents to develop the new treatment
or reduce the severity of the disease. The recovery rate of
COVID-19 patients can be increased by repurposing the drugs
that slow down the replication of SARS-CoV-2 and/or de-
crease disease symptoms. In addition, it could also reduce
the pressure on intensive care units by shortening the time
spent in these units that makes a chance for other patients to
get services. Therefore, the quickest way to fight with this
ongoing pandemic is to repurpose the currently available
drugs that have been used clinically with a known safety pro-
file. This article represents the old drugs with preliminary data
of the latest clinical trial that could be potential against
COVID-19 treatment.
Repurposing Drug Therapy Against COVID-19
Remdesivir
Remdesivir, an investigational nucleoside analog, is a broad-
spectrum antiviral medication having in vitro activity against
RNA viruses (belonging to Orthocoronavirinae, Filoviridae,
Paramyxoviridae, and Pneumoviridae families) that is consid-
ered as the most promising drug against SARS-CoV-2. It in-
hibits the RNA-dependent RNA polymerases (RdRps) and
competes with adenosine triphosphate for incorporation into
the nascent viral RNA chains resulting in the premature ter-
mination of viral RNA transcription (Table 1)[1012].
Though remdesivir is not an FDA-approved drug, however,
FDA has issued an Emergency Use Authorization (EUA) to
allow this drug intravenously for hospitalized COVID-19 pa-
tients with severe disease (SpO2 of 94% or less on room air,
requiring supplemental oxygen, mechanical ventilation, or ex-
tracorporeal membrane oxygenation) [13]. The NIH COVID-
19 treatment guidelines also agree to this point; however, they
recommend no clear statement about the patients with mild or
moderate COVID-19 [14]. Notably, the drug is available
through clinical trials for the treatment of children and preg-
nant women with COVID-19 infection [14]. Additionally,
preliminary data from a phase 3 trial (Adaptive COVID-19
Treatment Trial (ACTT-1)) of a study demonstrated that
remdesivir was better than the placebo in shortening the re-
covery time (11 vs. 15 days) of hospitalized adults with
COVID-19 and lung involvement [15]. However, data from
a randomized, open-label phase 3 clinical trial showed no
significant difference between doses for 5 days and 10 days
[16]. Another randomized, double-blind, placebo-controlled,
multicenter trial evaluating efficacy and safety of remdesivir
in SARS-CoV-2-infected hospitalized adults (concurrent
treatment with corticosteroids, interferons, and lopinavir-
ritonavir) found no difference in the time of clinical improve-
ment and similar mortality rate on day 28. A higher percentage
of adverse events was reported in remdesivir patients (66%)
compared with placebo patients (64%) [17]. A recent study
involving 53 hospitalized COVID-19 severe patients from the
USA (n= 22), Europe or Canada (n= 22), and Japan (n=9),
treated with remdesivir, has reported the clinical improvement
of 68% patients and adverse effects including the abnormality
of hepatic function (23%), diarrhea (9%), skin rash (8%),
acute kidney injury (8%), etc. A course (10 days) of
remdesivir (200 mg on day 1, followed by 100 mg daily)
was administered intravenously among these patients.
Nevertheless, the FDA suggested a dose of 200 mg IV once
on day 1, followed by 100 mg IV once daily for 9 in the
Emergency Use Authorization (EUA) statement [13,14].
This dose is also being evaluated in multicenter randomized
trials [14,18,27,53]. Consequently, the authors suggest this
therapy as a well-known potential for COVID-19 treatment as
for now. However, remdesivir should be avoided in patients
with hypersensitivity to remdesivir [13,14] and in patients
with drugs undergo interaction with remdesivir and safety
caution must be taken with renal impairment, infusion-
related reactions, and elevated hepatic enzyme (Table 2)[13,
33].
Favipiravir
Favipiravir is classified as an investigational broad-spectrum
antiviral drug with in vitro activity against RNA viruses [19,
20]. It inhibits the RNA-dependent RNA polymerases
(RdRps), resulting in the premature termination of viral
RNA transcription and thus inhibits the viral RNA synthesis
[19,20](Table1). In March 2020, it was approved in China
for marketing in the treatment of COVID-19 patients despite
having no available pharmacokinetics data. However, a non-
randomized, controlled, open-label trial has recently observed
the efficacy of favipiravir (day 1: 1600 mg twice daily; days
214: 600 mg twice daily) in the treatment of COVID-19
patients compared against lopinavir-ritonavir (days 114:
400 mg/100 mg twice daily). Inhaled interferon-alpha (5 mil-
lion U twice daily) was used with both treatments resulting
from the shorten recovery time for favipiravir (median, 4 days;
range, 2.5 to 9 days) than for lopinavir-ritonavir (median,
11 days; range 8 to 13 days; p< 0.001). Chest imaging im-
provement rate was also higher among favipiravir patients
(91.43%) compared with that of lopinavir-ritonavir patients
(62.22%) on day 14 of the treatment [21]. Therefore, this
preliminary data may help the experts to ahead with further
study and suggest this therapy when treatment is not feasible.
Owing to early embryonic death and teratogenicity observed
in animal studies, this should be avoided during pregnancy
SN Compr. Clin. Med.
Table 1 Summary of the mechanism of action, the latest output of clinical trials, and recommendation to use against COVID-19 of the most common drugs that are being evaluated against COVID-19
Drugs Classification Mechanism of action The main output of clinical trial Recommendation against
COVID-19
References
Remdesivir Investigational nucleoside
analogue
Inhibits the viral RNA synthesis by inhibiting the
RNA-dependent RNA polymerases (RdRps), competes
with adenosine-triphosphate.
Superior effect to placebo, better clinical improvement NIH and FDA recommends
for hospitalized patients
with severe COVID-19
[1018]
Favipiravir Investigational
RNA-dependent RNA
polymerase inhibitor
Inhibits the viral RNA synthesis by inhibiting the
RNA-dependent RNA polymerases (RdRps)
Shortening the recovery time, improved chest image,
better efficacy than lopinavir-ritonavir
Approved in China for
marketing
[1921]
Chloroquine and
hydroxichloroquine
Antimalarial drug Inhibits viral enzymes or processes, ACE2 cellular receptors
acidifies the cell membrane surfaces and involves the
immunomodulation ofcytokinerelease
Active against SARS-CoV-2 inhibits the exacerbation
of pneumonia, hydroxychloroquine is more potent
than chloroquine
Used for whom clinical trial
participation is not
feasible
[10,2226]
Lopinavir-ritonavir HIV protease inhibitor Protease enzyme inhibitors bind to Mpro, a key enzyme for
coronavirus replication
No favorable output was found, alone therapy has no
clinical improvement
NIH recommends against the
use of it outside the
clinical trial.
[2729]
Ivermectin Anti-parasite Inhibits the coupling of the SARS-CoV-2S-protein with the
human ACE2 receptor, boosts the human immunity
Induces approximately 5000-fold reduction in the viral
RNA of SARS-CoV-2 at 48 h
[3032]
Baricitinib and
ruxolitinib
Janus kinases inhibitor Inhibits Janus kinases enzymes and alleviate the signal
transmission due to cytokine storm
Improved clinical symptoms and respiratory parameters
of baricitinib patients compared to control, no
significant improvement between ruxolitinib and
placebo
NIH recommends against the
use of these drugs outside
of clinical trials
[3336]
Anakinra Interleukin-1 inhibitor Inhibits the binding of IL-1 to the interleukin-1 type 1 receptor
(IL-1R1), controls the activation of caspase 1, balance the
inflammatory cytokine
The better output of anakinra plus standard therapy
compared to standard alone therapy
NIH did not give
recommendations for or
against the use of anakinra
[33,3739]
Canakinumab Interleukin-1 inhibitor Suppresses the free IL-1 beta Several doses are being evaluated NIH did not give
recommendations for or
against the use of anakinra
[4043]
Siltuximab,
tocilizumab,
and sarilumab
Interleukin-6 inhibitor Prevent the binding of IL-6 (a pro-inflammatory cytokine) to
IL-6 receptors, stop the cytokine release syndrome
Tocilizumab plus standard therapy suggest the clinical
benefit of tocilizumab as adjunctive therapy,
tocilizumab improves the clinical symptoms,
lymphocyte percentage, CT opacity changes, and
CRP concentration, unexpected preliminary data of
sarilumab
NIH did not give
recommendations for or
against the use, and
sarilumab is being
withdrawn from the
manufacturer-sponsored
trial
[18,33,44,
45]
Nitazoxanide Antiviral Affects the viral genome synthesis, preventing viral entry and
interfering with the N-glycosylation
No clear safety data for patients with renal or hepatic
impairment
No statement found [46]
Colchicine Antigout Inhibits SARS-CoV-2 entry, transport, and replication by
blocking microtubules polymerization
Give activity against flaviviruses but no precise safety
data for COVID-19 patients.
NIH did not give
recommendations for or
against the use of this
therapy
[8,47]
Convalescent blood
products
Blood products Contain the antibodies to SARS-CoV-2 Temperature becomes normal, decrease virus load and
became negative within 12 days, improve CT image,
decreased symptoms
NIH did not give
recommendations for or
against the use of this
therapy
[33,4850]
Fibrinolytic agents Initiate the local fibrinolysis by converting plasminogen to
plasmin on the surface of existing thrombi
Improvement of PaO2/FiO2 (P/F) ratio [51,52]
SN Compr. Clin. Med.
Table 2 List of common interacting agents and their effect; adverse effect and safety concerns of most promising drugs against COVID-19
Drugs (US trade
name)
Dosage forms and strength Common interacting agents Effects of interaction Adverse effects Safety concerns Reference
Remdesivir 100 mg powder for injection;
5 mg/mL solution for injec-
tion
Atropine, scopolamine, belladonna
alkaloid, chloroquine,
hydroxychloroquine, isoniazid,
rifampin, phenytoin, phenobarbital,
dexamethasone, amoxicillin, etc.
Reduce the systemic
exposure of
remdesivir, and thus
reduce its antiviral
activity
Anaphylactoid reactions, angioedema,
nausea, vomiting, fever, headache,
diarrhea, skin rash, hypotension,
tachycardia, bradycardia, elevated
hepatic enzymes. etc.
Infusion-related
reactions, the risk
for elevated hepatic
enzymes, renal
impairment
[13,17]
Favipiravir 200 mg tablet Warfarin, acetyldigoxin, acyclovir,
adefovir dipivoxil, afatinib,
allopurinol, almotriptan, alprostadil,
ambrisentan, etc.
Decrease metabolism of
or excretion of the
respective drug
Decreases red blood cell production
and increases the liver function
parameters such as aspartate
aminotransferase (AST), alkaline
phosphatase (ALP), alanine
aminotransferase (ALT) and total
bilirubin, and increased
vacuolization in hepatocytes
Pregnancy owing to
early embryonic
death and
teratogenicity
effect
[21]
Chloroquine
(Aralen) and
hydroxychloroqu-
ine (Plaquenil)
Chloroquine phosphate 250 mg
tablet; 50 mg/mL solution for
injection and
hydroxychloroquine sulfate
200 mg tablet
Amiodarone, acarbose, acetohexamide,
metformin, sitagliptin, tolbutamide,
insulin, albuterol, ipratropium,
azithromycin, ciprofloxacin,
fluconazole, ketoconazole, tamoxifen,
tetracycline trametinib, vigabatrin,
interferon, antacid, etc.
Severe hypoglycemia,
QT prolongation
retinal damage.
Agranulocytosis, anaphylactic shock,
anaphylactoid reactions, Blurred
vision, confusion, dyskinesia,
elevated hepatic enzymes, QT
prolongation, thrombocytopenia,
retinal damage.
Cardiac arrhythmia,
diabetes, ratinal
demage, G6PD
deficiency,
significant drug
interaction, etc.
[1921,
23]
Lopinavir/ritonavir
(Kaletra)
100 mg/25 mg tablet;
200 mg/50 mg tablet;
(400 mg/100 mg)/5 mL oral
solution
Alfuzosin, triazolam, lovastin,
simvastin, rifampin, ergot alkaloids,
fluconazole, meperidine, cisapride,
naloxegol, apalutamide, sirolimus,
tacrolimus, fentanyl, cyclosporine,
warfarin, phenytoin, phenobarbital,
ketoconazole, itraconazole,
amiodarone, methadone, etc.
Severe hypoglycemia,
QT prolongation, etc.
Allergic reaction, irregular heartbeat,
nausea, vomiting, abdominal pain,
redness erectile dysfunction, libido
decrease, menorrhagia, feeling faint,
headache, heartburn, etc.
Cardiac arrhythmia,
diabetes
[54,55]
Ivermectin
(Stromectol)
3 mg tablet; 6 mg tablet Warfarin, 4-hydroxycoumarin,
abemaciclib, abiraterone,
acalabrutinib, afatinib, aminophylline,
amiodarone, cabazitaxel, zolpidem.
Alteration the
metabolism of or
excretion of the
respective drug
Abdominal pain, asthenia, hypotension,
edema, tachycardia, dizziness,
headache, hyperthermia, insomnia,
depression, ataxia, psychosis,
confusion, seizure, somnolence,
vertigo, pruritus, rash, urticaria,
diarrhea, nausea, vomiting,
eosinophilia, leukopenia, myalgia,
blurred vision, mild conjunctivitis,
punctate opacity, fever,
lymphadenopathy.
Hypersensitivity [3032]
Baricitinib
(Olumiant)
1 mg tablet; 2 mg tablet Azathioprine, abatacept, adalimumab,
anakinra, sarilumab, infliximab,
cyclosporine, probenecid, etc.
Additive immune
suppressive effect
allergic reaction, severe infection, liver
injury, anemia, nausea, runny nose.
Thrombosis, risk GI
perforation, cancer,
neutropenia,
lymphopenia, and
anemia and
[34]
SN Compr. Clin. Med.
Table 2 (continued)
Drugs (US trade
name)
Dosage forms and strength Common interacting agents Effects of interaction Adverse effects Safety concerns Reference
elevated liver
function
Ruxolitinib (Jakafi) 5, 10, 15, 20, and 25 mg tablet Fluconazole, agmatine, alclofenac,
benserazide, bevacizumab,
ketoconazole, erythromycin,
rifampin, etc.
Reduce or interrupt the
effect of the
respective drug
Anemia, balance impairment,
dizziness, headache, labyrinthitis,
Menieres disease, neutropenia,
thrombocytopenia, vertigo, and
orthostatic dizziness
Thrombocytopenia,
anemia and
neutropenia.
[33,36]
Anakinra (kineret) 100 mg per 0.67 ml solution for
injection
Abatacept, adalimumab, baricitinib,
ruxolitinib, sarilumab, tocilizumab,
tofactinib
Additive immune
suppressive effect
Allergic reactions, breathing problems,
severe infection, nausea, vomiting,
diarrhea, headache, joint pain, etc.
Infusion-related
reaction,
thrombocytopenia,
neutropenia
[33,37]
Canakinumab (Ilaris) 150 mg/ml powder for injection
or solution for injection
Abatacept, adalimumab, baricitinib,
ruxolitinib, etc.
Additive immune
suppressive effect
Allergic reaction, severe infection,
diarrhea, nausea, and gastroenteritis.
Hypersensitivity,
severe infection,
renal and hepatic
impairment,
thrombocytopenia,
neutropenia, etc.
[43]
Siltuximab (Sylvant)
and tocilizumab
(Actemra)
Siltuximab 100 mg powder for
injection, 400 mg powder for
injection and tocilizumab
200 mg/10 ml solution for
injection, 400 mg/20 ml solu-
tion for injection
Abatacept, adalimumab, baricitinib,
ruxolitinib, atorvastin, cyclosporine,
lovastin, warfarin, etc.
Additive immune
suppressive effect
Allergic reaction, back pain, breathing
problems, stomach pain, dizziness,
facial flushing, irregular heartbeat,
headache, nausea, vomiting,
angioedema, GI perforation,
hepatotoxicity, visual problems
Risk of GI
perforation, risk of
hepatotoxicity,
thrombocytopenia,
neutropenia,
infusion-related re-
actions
[44,56]
Colchicine (Colcrys) 0.6 mg tablet; 0.6 mg capsule;
0.6 mg/5 ml oral solution
Abacavir, alogliptin, ampicillin,
tianeptine, sulindac, ritonavir,
vilanterol, zaleplon, etc.
Alteration the
metabolism of or
excretion of the
respective drug
Alopecia, diarrhea, vomiting,
leukopenia, granulocytopenia,
thrombocytopenia, pancytopenia,
aplastic anemia, myopathy, elevated
CPK, myotonia, muscle weakness,
rhabdomyolysis
Risk of GI
perforation, renal
impairment,
hepatic
impairment.
[57]
SN Compr. Clin. Med.
[21]. Additional data are being evaluated regarding clinical
efficacy for COVID-19 (Table 2).
Chloroquine, Hydroxychloroquine, and Azithromycin
Chloroquine, the antiprotozoal agent, is indicated for the treat-
ment of malaria, autoimmune diseases, and extraintestinal am-
ebiasis. It influences the hemoglobin digestion by increasing
intravascular pH in malarial parasite cells and interferes with
the nucleoprotein synthesis of the patients [22]. Notably, chlo-
roquine has shown the activity against severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) by inhibiting viral
enzymes or processes such as viral DNA and RNA polymer-
ase, virus assembly, viral protein glycosylation, new virus
particle transport, and virus release. It also inhibits ACE2 cel-
lular receptor, acidifies the surface of the cell membrane that
leads to the inhibition of the fusion of virus, and involves in
the immunomodulation of cytokine release in COVID-19 pa-
tients [10,2224]. However, due to the potential for severe
adverse events and drug interactions, it is not used for treating
COVID-19 patients outside of clinical trials. (Table 2)[58].
However, due to having a clinical benefit in the treatment of
COVID-19 due to SARS-CoV-2, chloroquine is recommend-
ed to treat the hospitalized COVID-19 patients (50 kg or
more) for whom clinical trial participation is not feasible
[25]. Additionally, in vitro preclinical data suggest that chlo-
roquine has activity against SARS-CoV-2 [13,59]. There
have also been reports of potential benefit in inhibiting the
exacerbation of SARS-CoV-2 infection in patients with pneu-
monia; however, specific data are not available [55]. It should
be administrated orally with a meal at the recommended dose
for COVID-19 patients (1000 mg PO on day 1, then 500 mg
PO once daily for 4 to 7 days) [25]. Moreover, chloroquine
should be avoided during pregnancy, and necessary cautions
should be taken during administration to breastfeeding wom-
en as it is excreted into breast milk. Hydroxychloroquine, an
oral disease-modifying antirheumatic drug (DMARD), is an
important drug to treat rheumatoid arthritis, malaria, and sys-
temic lupus erythematosus. Outside of clinical trials, the NIH
COVID-19 treatment guidelines do not recommend the
hydroxychloroquine to use for COVID-19 patients.
However, it is used to treat hospitalized COVID-19 patients
when clinical trial participation is difficult [26]. Notably, an
in vitro analysis observed the hydroxychloroquine as a more
potent drug than chloroquine (EC50 values, 0.72 and
5.47 μM, respectively) for COVID-19 treatment. In addition,
hydroxychloroquine shows fewer drug-drug interactions
(Table 2) than chloroquine with having the ability to control
the cytokine storm and shorten the clinical recovery time
among the SARS-CoV-2-infected patients [23].
Consequently, the US Centers for Diseases Control and
Prevention approved the hydroxychloroquine in treating adult
and adolescent COVID-19 patients for severe cases on 28
March 2020. It was administrated as a loading dose of
400 mg twice daily, followed by a maintenance dose of
200 mg twice daily for 4 days, which showed the superior
effect to chloroquine (500 mg twice daily) in inhibiting
SARS-CoV-2 [23]. This superior effect in shortening the re-
covery time was also confirmed by a randomized controlled
trial in Wuhan, China. This parallel-group, randomized clini-
cal trial of hydroxychloroquine with non-severe COVID-19
patients demonstrated the shortened of cough (3.1 days vs
2 days) and fever (3.2 days vs. 2.2 days) recovery time com-
pared to the standard therapy [60]. Nevertheless, a non-
randomized clinical trial confirmed the significantly greater
proportion of PCR-negative patients treated with
hydroxychloroquine (70%) compared to the control group
(12.5%) on day 6 [61]. Also, a multicenter, parallel, open-
label, randomized trial in 150 adults hospitalized patients
found no significant difference in negative viral conversion
rate, symptoms alleviation rate, and adverse events rate be-
tween hydroxychloroquine and control group [62]. An obser-
vational trial reported that hydroxychloroquine was not asso-
ciated with a significantly higher or lower risk of intubation or
death [63]. Azithromycin, a macrolide antibiotic, is used in
combination with hydroxychloroquine to enhance the efficacy
of hydroxychloroquine. Notably, a study involving 20 severe
COVID-19 patients observed the reinforcement of the effica-
cy of hydroxychloroquine when it was administrated with
azithromycin as a loading dose of 500 mg on the first day
followed by 250 mg once for 25 days. After the administra-
tion of this combination therapy, a positive clinical outcome
was obtained from these COVID-19 patients attributing an
outstanding efficiency in virus elimination [61]. Moreover, a
retrospective analysis found the lower rate of death and ven-
tilation among patients with combination therapy compared to
the individual therapy of hydroxychloroquine [64]. As a re-
sult, hydroxychloroquine plus azithromycin therapy might be
a useful alternative to remdisivir for the treatment of patients
infected with SARS-CoV-2.
However, hydroxychloroquine shows drug-drug interac-
tion (Table 2) with azithromycin resulting in the prolongation
of QTc that must be cautiously considered [33]. In addition, an
observational study of 1438 in-patients found no difference in
mortality among the patients treated with the individual ther-
apy or combination therapy compared with no use of these
agents (adjusted OR 0.84; 95% CI 0.471.51; p=0.56) [65].
Consequently, the authors suggest the individual therapy of
hydroxychloroquine for COVID-19 infection to reduce the
cardiac toxicities.
Lopinavir-Ritonavir and Ribavirin
Protease enzyme, such as papain-like protease and 3 C-like
proteases, is crucial for the survival of virus from
Orthocoronavirinae family. So protease inhibitors (PIs), like
SN Compr. Clin. Med.
lopinavir-ritonavir, are used to target these protease enzymes
(Table 1)[28]. These are indicated for the treatment of HIV-1
infections in adults and pediatric patients in combination with
other antiretroviral medications. However, the antiviral activ-
ity of lopinavir-ritonavir therapy against the treatment of
MERS-CoV is controversial in the tissue culture model [66].
Available data of this therapy regarding the treatment of
COVID-19 due to SARS-CoV-2 are also limited and indeci-
sive. In addition, pharmacodynamics and clinical trial data of
this therapy are not favorable leading to the recommendation
of NIH COVID-19 treatment guidelines against the use of
lopinavir-ritonavir outside of clinical trials [33]. A study, in-
volving hospitalized patients with confirmed SARS-CoV-2
infection (n= 199), did not find any difference in clinical im-
provement with lopinavir-ritonavir therapy compared with the
standard care. Individual therapy of lopinavir-ritonavir (400/
100 mg administered orally twice daily for 14 days) also failed
to show the clinical improvement and reduce the RNA virus
load in patients with severe SARS-CoV-2 [29]. However, it is
administrated orally as a tablet or solution at the conventional
dose for the treatment of SARS-CoV-2 (severe acute respira-
tory syndrome coronavirus 2) and should be taken with food
to minimize the pharmacokinetics variabilities. The oral solu-
tion must be avoided during pregnancy due to containing al-
cohol and propylene glycol [67]. Therapeutic monitoring is
necessary when administrating to patients with hepatic impair-
ment leading to an increase in the concentration of drugs [54].
It is also necessary to monitor the several parameters (such as
blood glucose, CBC with differential, serum bilirubin (total
and direct), serum cholesterol, serum lipid profile, urinalysis)
when lopinavir-ritonavir is concurrently used with other
agents leading to the drug-drug interactions (Table 2)[54,
55]. Notably, authors are not being confirmed to use this drug
for COVID-19, and further study may be introduced to eval-
uate this therapy during pregnancy. In addition, the National
Health Commission and State Administration of Traditional
Chinese Medicine recommended ribavirin (a guanosine ana-
log) for COVID-19 treatment [68]. The effectiveness of this
drug in combination with lopinavir-ritonavir was also proven
against SARS-CoV in patients and tissue culture [69]. The
estimated concentration ribavirin against SARS-CoV was up
to 50 μg/mL [66].
Ivermectin
Ivermectin is a semisynthetic broad-spectrum anti-parasitic
FDA-approved drug that acts on parasite by potentiating
GABA-mediated neurotransmission and by binding to
glutamate-gated chloride channels [70]. Besides, it boosts hu-
man immunity by increasing the IL-1 production and other
cytokines, activating superoxide anion production, and en-
hancing the lymphocyte response to mitogens [30]. It blocks
the HIV replication by inhibiting the interaction between the
HIV-1 integrase protein (IN) and α/β1 heterodimer of the
importin. Additionally, ivermectin has also been shown the
activity to control the disease caused by several RNA viruses
such as dengue, influenza, RSV, and rabies [31]. However, its
broad-spectrum antiviral activity depends on IMPα/β1during
infection. Recently, a molecular modeling study has claimed
the inhibition of the coupling of the SARS-CoV-2S-protein
with the human ACE2 receptor through the binding of iver-
mectin in the RBD region [32]. A recent study with COVID-
19 patients demonstrated the induction of ivermectin in the
reduction of viral RNA of SARS-CoV-2. In a Vero-hSLAM
cell culture model, a single dose of ivermectin induced ap-
proximately 5000-fold reduction in the viral RNA of SARS-
CoV-2 at 48 h [31]. The huge fold of viral reduction within
48 h attracts the experts attention to recommending it against
COVID-19. However, the antiviral concentration of ivermec-
tin was obtained only after a large dose. Notably, the drug
could penetrate the blood-brain barrier and affect GABA-
ergic transmission at large doses [71]. Consequently, human
overdose has been associated with several adverse effects,
including depression, ataxia, psychosis, confusion, and sei-
zure (Table 2)[72]. The safety of ivermectin for human ther-
apy is only obtained at the conventional dose (200 μg/kg)
[73].
Baricitinib and Ruxolitinib
Janus kinases (JAK), intracellular enzymes, are associated
with the signal transmission arising from cytokine interactions
on the cellular membrane and thus influence cellular processes
of immune cell function. Baricitinib and ruxolitinib show their
activity by inhibiting these enzymes to alleviate the signal
transmission due to cytokine storm. They are originally indi-
cated for the treatment of rheumatoid arthritis when tumor
necrosis factor (TNF) inhibitors fail to produce a response
[34]. As JAK inhibitors can alleviate the cytokine storm (may-
be a component of severe COVID-19), they are (including
Baricitinib, ruxolitinib) currently being studied for the treat-
ment of patients with COVID-19-associated cytokine storm
based on the preliminary data of a study involving an immu-
nomodulator (an IL-6 receptor antibody) [74]. A non-random-
ized, open-label trial involving 12 patients with moderate
COVID-19 compared the safety and efficacy of baricitinib
plus lopinavir-ritonavir against a control group treated with
hydroxychloroquine plus lopinavir-ritonavir [35]. All clinical
symptoms and respiratory parameters were improved in
baricitinib patients, while no significant changes were report-
ed in the control group [35]. However, 1 patient from the
investigation group stopped after 10 days due to an increased
liver function test. The oral administration of baricitinib (2 mg
PO once daily for 1014 days and 4 mg PO daily for 7
14 days) is being evaluated in combination with antiviral ther-
apy [75,76]. It can be administrated with or without food.
SN Compr. Clin. Med.
About three-fourth of the administered dose is eliminated in
the urine, and only one-fifth of the dose is eliminated in the
feces. It is largely excreted through urine (69%) as unchanged
drug and feces (15%). Sufficient data are not available on the
placental transfer of the drug to the fetus during pregnancy or
the presence of drugs in breast milk [34]. Concomitant use of
baricitinib with biologic DMARDs, immunosuppressive
agents, Virus Vaccine, OAT3 inhibitors, etc. is not recom-
mended due to having the additive immunosuppressive effect
and increasing the infection risk (Table 2)[34].
Additionally, the efficacy and safety of ruxolitinib were
evaluated in a randomized, multicenter, placebo-controlled,
phase 2 trial in hospitalized patients with severe COVID-19
[36]. Though there was no significant difference in the clinical
improvement between ruxolitinib and the placebo group, the
median time of clinical improvement was higher for
ruxolitinib. Adverse events were observed among 80% of
ruxolitinib compared to 71.4% of placebo patients [36].
Notably, due to having a broad immunosuppressive effect,
they are recommended against the use of JAK inhibitors out-
side of clinical trials by the NIH COVID-19 treatment guide-
lines [33]. Therapeutic monitoring is needed in patients with
anemia, lymphopenia, neutropenia, serious infection, and lip-
id elevations.
Anakinra
Anakinra is an interleukin-1 receptor antagonist (IL-1Ra).
Recombinant DNA technology using an Escherichia coli bac-
terium is applied to produce the drug [37]. It competitively
inhibits the binding to the interleukin-1 type 1 receptor (IL-
1R1) and thus blocks the effects of IL-1, specifically IL-
1alpha and IL-1beta in the inflammatory system. It maintains
the balance effects of inflammatory cytokines by reducing the
IL-1, known as primary pro-inflammatory cytokines, associ-
ated with rheumatoid arthritis [37]. It is indicated for the treat-
ment of familial cold autoinflammatory syndrome associated
with the inhibition of IL-1beta, IL-6, and IL-8 in affected skin.
It also inhibits the increased IL-6 serum concentrations after
cold exposure [77]. It controls the activation of caspase 1,
leading to the deduction of active interleukin derivatives in-
volving IL-1 beta and IL-18. However, the NIH COVID-19
treatment panels did not give any recommendations for or
against the use of anakinra due to the lack of available clinical
data [33]. Depending on preliminary data from other anti-
interleukin medications, researchers have introduced several
studies to evaluate the use of anakinra for COVID-19 treat-
ment [38,39]. A study is evaluating the dose 200 mg IV every
8 h for 7 days (that is to be reduced to 100 mg for 15 days in
patients with renal impairment), in patients with macrophage
activation syndrome (MAS) infected with SARS-CoV-2, or
immune dysregulation. For patients with COVID-19, 100 mg
IVinfusionevery6hfor15daysiscurrentlybeing
investigated. Use of 5 mg/kg infused over 60 min twice daily
was investigated in 29 COVID-19 patients with moderate-to-
severe acute respiratory distress and hyper inflammation
resulting higher survival rate for patients receiving anakinra
plus standard therapy (90%) compared with that of patients
receiving standard therapy alone (50%) on day 21 [38,39]. A
dose of 100 mg SC injection once daily for 28 days or until
hospital discharge is also being evaluated [78]. After checking
the patients neutrophil count, Anakinra should be adminis-
trated monthly for the first 3 months of therapy, and then
quarterly for up to 1 year [79]. It is associated with the in-
creased risk of various infections, hematologic side effects,
headache and arthralgia, increased risk of cancer, hypersensi-
tivity reactions including anaphylactoid reactions, angioede-
ma, urticaria, rash (unspecified), and pruritus, etc. (Table 2)
[37]. However, the reaction at the injection site is the most
common adverse reaction of anakinra subcutaneous adminis-
tration [37]. Concomitant use of anakinra with biologic
DMARDs, immunosuppressive agents, Virus Vaccine,
OAT3 inhibitors, etc. is not recommended due to having the
additive immunosuppressive effect and increasing the infec-
tion risk [37]. Due to a lack of sufficient available data on
anakinra use during pregnancy and on breastfeeding, it should
be avoided if possible [37].
Canakinumab
Canakinumab, a human monoclonal antibody, binds with the
interleukin (IL)-1 beta and blocks its interaction with the IL-
1b receptor leading to the reduction of biologically active IL-
1b. Unbound IL-1 beta in tissue increases the probability of a
disease flare by stimulating serum amyloid A protein (SAA)
and C-reactive protein (CRP) production. Canakinumab sup-
presses the free IL-1 beta by binding with it that reduces the
IL-1 beta production to the rate found in normal subjects [40,
41]. It is indicated for the treatment of IL-1 beta-induced in-
flammatory diseases, such as cryopyrin-associated periodic
syndromes (CAPS), Muckle-Wells syndrome (MWS), and
familial cold autoinflammatory syndrome (FCAS) [80]. The
NIH COVID-19 treatment guidelines did not give any recom-
mendations for or against the use of canakinumab for the
treatment of IL-1 beta-induced COVID-19 due to having a
lack of clinical data [33]. As preliminary data are available
from other anti-interleukin medications, experts have started
several studies based on these data to evaluate the use of
canakinumab for COVID-19 [42,81]. The dosing regimens
having under investigation for COVID-19 therapy are includ-
ed 4 mg/kg and 8 mg/kg IV once for patients with 40 kg or
less; 300 mg and 600 mg IV once for more than 40 kg pa-
tients; 450 mg IV once for patients with 40 to 59 kg body
weight; 600 mg IV once for patients with 60 to 80 kg and
750 mg IV once for patients with more than 80 kg. All doses
are to be infused over 2 h after diluting in 250 mL of 5%
SN Compr. Clin. Med.
dextrose [42,81]. Diarrhea (20%), nausea (14%), and gastro-
enteritis (11%) are the most commonly reported adverse reac-
tions associated with canakinumab. This therapy should be
avoided for the patients with a confirmed hypersensitivity to
canakinumab, need to take caution in patients with hepatic
disease or renal impairment. If canakinumab is needed to
use in patients with infection, therapeutic monitoring must
be required to maintain the immunosuppressive effect [43].
Concomitant use of canakinumab with biologic DMARDs,
immunosuppressive agents, Virus Vaccine, OAT3 inhibitors,
etc. results in an additive immunosuppressive effect and in-
creasedinfectionrisk(Table2). So, co-administration of
canakinumab with this agent must be avoided if feasible.
Canakinumab crossed the placenta following a linear fashion
as pregnancy progresses, increasing the potential fetal risk
during the second and third trimesters. But data are not suffi-
cient regarding the presence of canakinumab in breast milk or
its effects on milk production and breast-fed infant [43].
Siltuximab, Tocilizumab, and Sarilumab
Interleukin-6 (IL-6) antagonists prevent the binding of IL-6 (a
pro-inflammatory cytokine) to IL-6 receptors. They are clas-
sified as antineoplastic and immunomodulating monoclonal
antibody (interleukin-6 inhibitors) that block the binding of
IL-6 with both soluble and membrane-bound IL-6 receptors
resulting in the prevention of T cell activation, induction of
immunoglobulin secretion, initiation of hepatic acute-phase
protein synthesis, and proliferation, differentiation, and stim-
ulation of hematopoietic precursor cell [44]. They may be
used in COVID-19 patients to stop the cytokine release syn-
drome [44,45,82]. Notably, due to a lack of clinical data, the
National Institutes of Health (NIH) COVID-19 treatment
guidelines do not give any recommendations for or against
the use of IL-6 receptor inhibitors, such as siltuximab, toci-
lizumab, and sarilumab[33].
Several studies have begun to evaluate the efficacy of
siltuximab in COVID-19 treatment based on the preliminary
data from a study with another IL-6 receptor antibody [72,73,
78]. A siltuximab single dose of 11 mg/kg via intravenous
infusion over 1 h is being evaluated for COVID-19 treatment
[72,73,78]. A retrospective study involving 21 patients with
COVID-19 induced pneumonia/ARDS, who received
siltuximab therapy, found an outcome of 33% patients for con-
dition improved with reduced need for ventilation; 43% for
condition stabilized; 24% for condition worsened and required
intubation [73]. Moreover, preliminary data of a retrospective
review involving 21 patients treated with tocilizumab plus stan-
dard COVID-19 therapy suggest the clinical benefit of toci-
lizumab as adjunctive therapy [45]. This therapy improves the
clinical symptoms, CT opacity changes, lymphocyte percent-
age, and CRP concentrations in patients leading to the addition
of tocilizumab in some protocols for use. Consequently, the
dosage regiment, 4 to 8 mg/kg/dose (usual dose: 400 mg; max-
imum dose: 800 mg) IV once, is evaluated in combination with
antiviral therapy followed by the second dose administration in
patients with no clinical response 8 to 12 h after the first infu-
sion. If required, the third dosewouldadministrate16to24h
after the first dose [45]. On the other hand, the 200 mg dose of
sarilumab, used intravenously in severe hospitalized patients, is
being withdrawn from manufacturer-sponsored trials based on
preliminary data; however, the 400 mg IV dose used to treat
critical hospitalized patients is still being evaluated [83]. Both
doses are being studied outside of manufacturer-sponsored tri-
als [84,85]. Besides, the subcutaneous administration of either
200 or 400 mg once is being studied in combination with an-
tiviral therapy [18,85]. Additional clinical efficacy data for
COVID-19 are being evaluated. All of these drugs show sev-
eral adverse events such as dermatologic, hematologic, gastro-
intestinal (GI), metabolic adverse events, infections, edema. In
addition, this therapy should be monitored carefully with cau-
tion in patients who are receiving a CYP3A4 substrate (e.g.,
oral contraceptives, lovastatin, atorvastatin), due to having
drug-drug interactions (Table 2)[44,56]. Cautions should be
concerned with the risk of GI perforation, hepatotoxicity, and
patients with thrombocytopenia and neutropenia [56]. Due to
its teratogenic effect and potential for serious adverse reactions
in the breast-fed infant, siltuximab is not recommended during
pregnancy and breastfeeding [44]. In addition, tocilizumab and
sarilumab may affect labor and obstetric delivery [44,56].
Nitazoxanide
Nitazoxanide, an antiprotozoal drug, has previously been
shown the broad spectrum of antiviral activity against human
and animal coronaviruses [86]. It shows its antiviral activity
by affecting viral genome synthesis, preventing viral entry,
and interfering with the N-glycosylation [46]. Notably,
nitazoxanide acts on the SARS-CoV-2 by interfering with its
spike protein that is highly N-glycosylated [87]. This drug also
potentiates the production of type 1 interferons [46]. After the
administration of nitazoxanide, it rapidly produces the metab-
olite named tizoxanide in humans that is being evaluated
against SARS-CoV-2 infection. Tizoxanide has also demon-
strated similar activities to nitazoxanide for viruses and other
pathogens [88]. Though the safety of nitazoxanide is well
understood, it has no precise safety data for patients with renal
or hepatic impairment. Additionally, based on the existing
data, the antiviral activity of nitazoxanide for SARS-CoV-2
requires further study.
Colchicine
Colchicine derived from autumn crocus has both anti-
inflammatory and antiviral properties [8,47]. Now, this drug
is already used for Mediterranean fever, gout, Behcets
SN Compr. Clin. Med.
disease, and pericarditis [89]. Colchicine might be preventing
cytokine storm and decrease COVID-19 severity. Colchicine
inhibits microtubules polymerization that is essential for
SARS-CoV-2 entry, transport, and replication [90]. Besides,
this drug modulates several pro- and anti-inflammatory path-
ways. It has been reported that colchicine significantly de-
creases virus replication in flaviviruses, such as dengue and
Zika viruses, hepatitis virus and HIV viral load [47]. A study
on 4745 patients was reported that colchicine significantly
decreased cardiovascular risk and pneumonia [79].
Treatment with 1 mg of colchicine on day 8 and then
0.5 mg/day was reported to be beneficial found in a case report
of a COVID-19-infected patient [91]. The absorption of col-
chicine occurs in the jejunum and ileum and accumulates in
tissues that is metabolized in the liver and the intestine by
cytochrome P (CYP) 450 3A4 and P-glycoprotein (P-gp)
[47]. Overdose of colchicine has been associated with several
adverse effects, including diarrhea, GIT adverse event, head-
ache, fever, and myopathy [57].
Convalescent Blood Products
Convalescent blood products are obtained from the serum or
whole blood of patients who have recovered from the
COVID-19 infections that may contain the antibodies to
SARS-CoV-2. This product may be of various forms, includ-
ing convalescent serum or whole blood, pooled human immu-
noglobulin, high titer immunoglobulin, and polyclonal or
monoclonal antibodies [48]. Centrifugation or membrane fil-
tration are the two different ways for plasma therapies [92].
However, owing to a lack of clinical data, the NIH COVID-19
treatment panels do not give any suggestions for or against the
use of a convalescent plasma [33]. Clinical trials are being
investigated to justify the use of convalescent blood products
against the COVID-19 infection. A randomized, open-label,
multicenter trial for evaluating the safety and efficacy of this
therapy against severe and life-threatening COVID-19 found
no significant difference of clinical improvement and mortal-
ity on 28 days between patients with convalescent blood prod-
ucts plus and slandered therapy (51.9% and 15.7%) and pa-
tients with standard therapy alone (43.1% and 24%).
However, both groups experienced with transfusion-related
adverse events [21]. In a case series of 5 patients confirmed
with COVID-19 and ARDS having several criteria, such as
high viral load after antiviral treatment, PAO2/FIO2 less than
300 and mechanical ventilation, two consecutive transfusions
of 200 mL250 mL convalescent plasma (total dose: 400 mL)
are given to the selected patients. Notably, after plasma infu-
sion, body temperature became normal within 3 days in 4 to 5
patients; virus load decreased and became negative within
12 days; ARDS resolved in 4 patients by day 12 and 3 patients
were weaned from mechanical ventilation within 2 weeks of
treatment [49]. Three infected health workers in Taiwan
received plasma therapy and resulted in a significantly re-
duced viral load with increased anti-SARS-CoV IgM and
IgG [92]. Another case series study was conducted among 6
patients of confirmed COVID-19 with abnormalities on chest
CT where patients received at least 1 cycle (range, 1 to 3
cycles, 200 ml per cycle) of convalescent plasma over
30 min [23]. All patients had recovered from abnormal chest
CT, decreased symptoms, and released from the hospital.
Nevertheless, safety data were also collected from 5000 hos-
pitalized patients with severe and life-threatening COVID-19
infection, who received 200 mL to 500 mL convalescent plas-
ma, which demonstrated only 35 serious adverse events
(SAEs) within 4 h of transfusion, 15 deaths and 21 non-
lethal SAEs. The 7-day mortality rate was only 14.9% [93].
Therefore, the convalescent plasma may become a promising
and potential therapy in the treatment of severe COVID-19
infection.
Fibrinolytic Agents
Central line thrombosis, pulmonary congestion with micro-
vascular thrombosis, coagulopathy, and occlusion are ob-
served in severe COVID-19 infection. ARDS is developed
by fibrin deposition in the pulmonary microvasculature [94].
Notably, fibrinolytic agents initiate the local fibrinolysis by
converting plasminogen to plasmin on the surface of existing
thrombi. A case series study was conducted with 3 critically ill
patients with ARDS and respiratory failure where patients
received alteplase intravenously, leading to the improvement
of the PaO2/FiO2 (P/F) ratio by 11% to 100% in all the 3
patients. Bleeding problems make this agent limited to use
[94].
However, the improvements were transient. Efficacy data
of other fibrinolytic agents, including defibrotide, are being
investigated for the treatment of COVID-19 [92,93].
Conclusion
COVID-19 has become a pandemic with a high growth rate of
confirmed and death cases. Unfortunately, no specific therapy
has been approved against this deadly virus as for now. So it is
important to focus on the repurposing drugs that may show
their activity against COVID-19. In addition, there may have
numerous drugs with potentially good in vitro efficacy against
COVID-19. Hence, clinicians should have rapid access to
information from the clinical trial. Also, the clinical trial and
the reports of these trials should be of high quality and out of
bias as these reports will guide the clinician to make decision
on which drug to use, their dosage regimens, and the
inclusion-exclusion criteria. Thus, clinical trials should be de-
signed with care to get robust results. Clear scientific in vitro
and preclinical in vivo evidence is needed to select the
SN Compr. Clin. Med.
therapies for specific treatment. Based on the preliminary clin-
ical data of safety and efficacy, we have identified some drugs
for COVID-19 that has been validated to have acceptable
safety and pharmacokinetics profile. Apart from them,
remdesivir and convalescent blood products are the most
promising potential for COVID-19 treatment as a well men-
tionable clinical improvement was found in their clinical out-
put. Eventually, the evidence of a negative load of the virus
was observed in convalescent blood plasma therapy. In addi-
tion, the US NIH recommends the use of remdesivir against
severe COVID-19 patients. The use of chloroquine,
hydroxychloroquine, favipiravir, tocilizumab, ivermectin,
and colchicine might also be effective as a treatment option
for COVID-19 but need more investigation for recommenda-
tion. Notably, favipiravir was approved for marketing on 28
March 2020 for the treatment of COVID-19. In addition, toci-
lizumab might be deemed as adjunctive therapy for patients
with cytokine release syndrome. However, some drugs, such
as lopinavir-ritonavir, have not proven their clinical efficacy
against COVID-19. Sarilumab has been withdrawn from the
sponsored clinical trials based on the preliminary data.
Anakinra, Janus Kinase inhibitors (baricitinib and ruxolitinib)
are not recommended due to having an additive immunosup-
pressive effect. Therefore, it is necessary to choose the treat-
ment option by evaluating their clinical efficacy, adverse ef-
fects, drug-drug interaction, and safety concern before admin-
istration of the treatment.
AuthorsContributions Authors MSH and MAB equally participated in
the conduction of the review. MSH, MAB, and NJ did the initial literature
search and participated in preparing the manuscript. MSI designed the
concept and edited and revised the manuscript. The final manuscript was
read and accepted by all contributors.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
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... The viral structure of SARS-CoV-2 comprises structural proteins, such as spike, membrane, nucleocapsid, and envelope proteins ( Figure 1). There is a paucity of knowledge pertaining to the treatment therapies for COVID- 19 and to antiviral drugs [9]. The rapid spread of COVID-19 has resulted in unprecedented diseases such as lupus erythematosus [21,[26][27][28]. ...
... Hydroxychloroquine contains a hydroxyl group and is less toxic, with a better safety profile [30,31]. It was previously used to treat diseases such as lupus, rheumatoid arthritis, and malaria, since it exhibits immunomodulatory activities [9,[31][32][33][34]. A study conducted by Yao et al. (2020) tested hydroxychloroquine and chloroquine in vitro on the Vero cell line. ...
... Ivermectin-also referred to as Stromectol [9]-is derived from avermectin, which is produced by Streptomyces avermitilis [41]. Ivermectin is classified as a broad-spectrum antiparasitic drug [42,43], and it was previously utilised in the treatment of diseases such as river blindness and lymphatic filariasis, as well as in the treatment of parasitic worm infections [41,43]. ...
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The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.
... As COVID-19-associated MIS is in many ways similar to systemic inflammatory rheumatic diseases, numerous drugs used for the treatment of rheumatic conditions have been repurposed in COVID-19 [7,9,10]. These agents include corticosteroids, anti-cytokine biologics, as well as JAK inhibitors [7,9,10]. ...
... As COVID-19-associated MIS is in many ways similar to systemic inflammatory rheumatic diseases, numerous drugs used for the treatment of rheumatic conditions have been repurposed in COVID-19 [7,9,10]. These agents include corticosteroids, anti-cytokine biologics, as well as JAK inhibitors [7,9,10]. Among these compounds, the IL-6 receptor (IL-6R) inhibitor tocilizumab (TCZ) has been effective in several randomized clinical trials (RCT) in Stage 2b-3 COVID-19 [11][12][13][14]. ...
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Introduction: Interleukin 6 receptor inhibition by tocilizumab (TCZ) has been effectively used worldwide for the treatment of multisystem inflammatory syndrome (MIS) associated with COVID-19. In this single centre study, we compared the outcome of COVID-19 pneumonia in TCZ-treated vs. untreated (control) patients. We wished to compare TCZ administration in the general ward vs. in the intensive care unit (ICU). We also studied the role of a consulting rheumatologist in the management of severe COVID-19 pneumonia. Patients and methods: In our patients, COVID-19 pneumonia was confirmed by SARS-CoV-2 PCR, chest X-ray, and CT. We compared patients selected for TCZ treatment with TCZ-untreated age- and sex-matched controls. All patients received corticosteroids. In the TCZ-treated group, patients received one or two doses of TCZ 8 mg/kg IV in combination with corticosteroids. We recorded age, sex, symptom duration, oxygen saturation (SaO2), partial arterial oxygen pressure (PaO2), total white blood cell (WBC), absolute neutrophil, absolute lymphocyte and platelet counts, CRP, ferritin, IL-6, LDH, procalcitonin (PCT), and D-dimer. The primary outcome parameters were the need for ICU, ventilation, death, and time of hospitalisation. Results: Altogether, 104 patients, 52 TCZ-treated and 52 TCZ-untreated, were included in this study. At baseline, the TCZ-treated patient group indeed had more pronounced COVID-19-related MIS compared to controls. Consultation with a rheumatologist was performed in 60% vs. 40% of cases. Nineteen patients (37%) received one, while 33 (63%) received two TCZ doses. TCZ was administered to 28 patients (54%) in the general ward and to 24 (46%) in the ICU. TCZ treatment was found to be safe in our COVID-19 pneumonia patients. TCZ treatment favourably influenced MIS biomarkers, and was associated with better clinical outcomes compared to controls. Patients receiving TCZ treatment in combination with corticosteroids already in the general ward exerted much better outcomes than those treated in the ICU. Consultation with a rheumatologist also improved outcome. Conclusions: We successfully used TCZ in combination with corticosteroids in Hungarian COVID-19 pneumonia patients. We pointed out the importance of early treatment already in the general ward, and the involvement of a rheumatologist in making treatment decisions.
... A lot of investment in them has especially focused on their potential to combat emerging infectious diseases and COVID-19 is putting that potential to test [15,71]. Scientists developed a successful influenza vaccine was in 1953 where they injected viruses into fertilized eggs, which were then incubated to allow viral replication within the eggs [72]. These replicated viruses are then explored for developing two classical vaccine formulations, where the virus is either weakened (Live attenuated [34,70,72]. ...
... Scientists developed a successful influenza vaccine was in 1953 where they injected viruses into fertilized eggs, which were then incubated to allow viral replication within the eggs [72]. These replicated viruses are then explored for developing two classical vaccine formulations, where the virus is either weakened (Live attenuated [34,70,72]. These approaches are still in use today, although different cell cultures have replaced the use of eggs. ...
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A virus when replicates itself from one generation to another, tends to change a little bit of its structure. These variations are called mutations. History says that SARS CoV-2 originated from the virus reservoirs of animals, specifically non-human mammals like bats and minks. Since then, there are evolutionary changes in its genome due to recombination in divergent strains of different species. Thus, making the virus more robust and smarter to sustain and evade immune responses in humans. Probably, this has led to the 2019 SARS CoV-2 pandemic. This chapter tracks the evolutionary trails of the virus origin, its pathogenesis in humans, and varying variants with the coming times. Eventually, the chapter overviews the available vaccines and therapies to be followed for SARS CoV-2.
... Increased risk of infections and cancer, hematologic effects, headache, joint pains, anaphylaxis, skin conditions, abdominal pains, and diarrhea are mentioned as adverse effects of anakinra [348,349]. As for canakinumab, the most common effects are GI complications, including diarrhea, nausea, and gastroenteritis [350]. For some of the JAK inhibitors, studies have reported an increased risk of serious infections, headaches, and possibly increased risk of cancer. ...
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... Other antivirals include lopinavir and remdesivir. The replication and survival of the SARS-CoV-2 can depend on the cleavage of polyproteins by 3-chymotrypsin-like protease and papainlike protease, similar to other viruses of the Orthocoronavirinae family(Hossen et al., 2020). Lopinavir targets these protease enzymes, and ritonavir inhibits the enzyme cytochrome P450, increasing the plasma concentration of lopinavir(Scavone et al., 2020). ...
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Introduction This review highlights the potential mechanisms of neuromuscular manifestation of COVID‐19, especially myasthenia gravis (MG). Methods An extensive literature search was conducted by two independent investigators using PubMed/MEDLINE and Google Scholar from its inception to December 2020. Results Exacerbations of clinical symptoms in patients of MG who were treated with some commonly used COVID‐19 drugs has been reported, with updated recommendations of management of symptoms of neuromuscular disorders. Severe acute respiratory syndrome coronavirus 2 can induce the immune response to trigger autoimmune neurological disorders. Conclusions Further clinical studies are warranted to indicate and rather confirm if MG in the setting of COVID‐19 can pre‐existent subclinically or develop as a new‐onset disease.
... However, the clinical presentation of confirmed cases could be heterogeneous: almost 80% of confirmed cases with mild pneumonia, 15% comprised with critical pneumonia with shortness of breathing, and 5% evolved critical ill reported with respiratory failure, with multiple vital organ failure resulting in death [1]. Notably, several clinical manifestations reported with an increase in the level of C-reactive protein, aspartate aminotransferase enzyme, creatine kinase were more often in severely infected patients with COVID-19 as a comparison to mildly infected patients [2]. Causing the large pro-inflammatory event of cytokine storm in severely ill patients, resulting in the high number of mortalities recorded in COVID-19. ...
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The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, created a rapidly unfolding health crisis, especially in the initial phases of the pandemic. In the early stages of the pandemic, various strategies were proposed for COVID-19 prophylaxis and treatment with very little scientific evidence available. Among these proposed treatments were ivermectin and chlorine dioxide, which were both used widely in Peru for both disease prevention and treatment without considering their problematic side effects. For instance, ivermectin was part of an approved therapeutic scheme based on in vitro data, although its efficacy in humans was not demonstrated. In addition, chlorine dioxide was never shown to be effective but causes threatening side effects. In this article, we discuss current information regarding chlorine dioxide and ivermectin in the context of the COVID-19 pandemic, with a focus on experiences in Peru.
Chapter
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The new coronavirus first appeared in December 2019 in Wuhan, China, being officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV), as well as the name of the disease has been described as COVID-19 (coronavirus disease 2019). In March 2020, the disease was considered a global pandemic, with currently more than 514 million cases worldwide, with 6.4 million deaths. Severe cases of COVID-19 progress to acute respiratory distress syndrome (ARDS), on average about 8–9 days after the onset of symptoms. It is also worth mentioning that the severity of the disease in patients is not only due to the viral infection but also due to the host response. This phase, called a cytokine storm, reflects a state of systemic immune activation, with high levels of cytokines, such as IL-6, IL-1b, IL-2, IL-12, IL-18, TNF, and interferon gamma (IFN-γ). In this sense, the management of the disease largely depends on symptomatic and supportive treatments. For severely or critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis, in addition to supplemental oxygen, mechanical ventilation, and ARDS-specific therapies, antiviral and antibiotic treatments should also be considered. Thus, the purpose of this chapter is to describe the pathophysiology and treatment of SARS-CoV-2 infection.
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A novel species of coronavirus has engulfed the entire world. Its severity and rate at which it transmits have left no country untouched. Massive replication has brought mutation in the genomic sequence of the virus. Due to this, many newer variants of SARS-COV-2 have come into play. Many therapies are available for covid 19, such as Remdesivir, Baricitinib, Molnupiravir, etc., but none are effective at preventing SARS-CoV-2 infection. Even most of the efficacious vaccines against the earlier variants are now inefficacious against, the newer variants. So, the people already vaccinated with the primary course of vaccination are at risk of reinfection and symptomatic COVID 19 illness.Furthermore, the initial immune response produced by these vaccines may have diminished with time, paving the pathway for discussion on the absolute need for time off and booster doses for vaccinated people. Some developed countries like the U.K and Israel favor the booster dose strategy, while some defy it, claiming it is necessary to vaccinate unvaccinated people first rather than giving vaccines multiple times. In this article, we have explained the necessity of booster doses in tackling newer variants. However, for the time being, devising a variant-specific vaccine seems promising to hiatus this transmission.©2022iGlobal Research and PublishingFoundation. All rights reserved.
Article
Background Due to the high incidence and mortality of the worldwide COVID-19 pandemic, beneficial effects of effective antiviral and anti-inflammatory drugs used in other diseases, especially rheumatic diseases, were observed in the treatment of COVID-19. Methods Clinical and laboratory parameters of eight included cohort studies and five Randomized Control Trials between the baricitinib group and the control group were analyzed on the first day of admission and days 7, 14, and 28 during hospitalization. Results According to the meta-analysis result of eight included cohort studies with 2088 patients, the Pooled Risk Ratios were 0.46 (P<0.001) for mortality, 6.14 (P< 0.001) for hospital discharge, and the mean differences of 76.78 (P< 0.001) for PaO2/FiO2 ratio was -47.32 (P= 0.02) for CRP, in the baricitinib group vs. control group on the seventh or fourteenth day of the treatment compared to the first day. Based on the meta-analysis of five RCT studies with 11825 patients, the pooled RR was 0.84 (P= 0.001) for mortality and 1.07 (P= 0.014) for patients’ recovery. The mean differences were -0.80 (P<0.001) for hospitalization days, -0.51(P= 0.33) for time to recovery in the baricitinib group vs. control group. Conclusions Baricitinib prescription is strongly recommended in moderate to severe COVID-19. Systematic review registration PROSPERO registration number: CRD42021254541
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Background Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19). Methods We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale. Results In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P=0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P=0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%). Conclusions In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.)
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Background Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy. Methods We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in United States Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 hours of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation. Findings A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio (aHR), 1.83; 95% CI, 1.16 to 2.89; P=0.009) but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80 to 2.15; P=0.28). Both the propensity score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78 to 1.82; P=0.42 and aHR, 2.11; 95% CI, 0.96 to 4.62; P=0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72 to 1.66; P=0.69 and aHR, 1.25; 95% CI, 0.59 to 2.68; P=0.56, respectively), compared to the no HC group. Conclusions Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin. Funding University of Virginia Strategic Investment Fund.
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Background Accumulating evidence proposed JAK inhibitors as therapeutic targets warranting rapid investigation. Objective This study evaluated the efficacy and safety of ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor, for COVID-19. Methods We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe COVID-19. Results Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus SoC treatment (22 patients) or placebo based on SoC treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in intervention group and 21 patients in control group were included in the study. Treatment with ruxolitinib plus SoC was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed CT improvement at D14 compared with 13 (61.9%) patients from the control group (P = 0.0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at D28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. Conclusions Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population. This trial is registered at www.chictr.org.cn as ChiCTR-OPN-2000029580.