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\begin{document}

\title{Mechanisms of action and adverse effects of the major therapeutic agents
in trial for COVID-19 therapeutics: a review of literature.}



\author[1]{Emeka Ogiji}%
\author[2]{Obumneme  Ezeanosike}%
\author[1]{Casimir Ofor}%
\author[2]{Edak Ezeanosike}%
\author[2]{Charles Maduba}%
\author[3]{Samuel Ghasi}%
\affil[1]{Ebonyi State University}%
\affil[2]{Alex Ekwueme Federal University Teaching Hospital Abakaliki}%
\affil[3]{University of Nigeria}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Coronavirus disease 2019, an infectious viral disease caused by severe
acute respiratory syndrome coronavirus 2 has been declared a global
pandemic by World Health Organisation. The race to find an effective
cure for it is on. Most of the candidate drugs in various clinical
trials are being re-purposed but none has been approved as at date. It
is pertinent for the bedside physicians to understand the mechanisms of
action of these agents and their peculiar adverse effects so they are
properly guided on the risk/benefit of the drugs they choose in managing
COVID-19 patients. In this review, we aimed to review the mechanisms of
action and adverse effects of the major drugs in clinical trials for
COVID-19 therapeutics. Clinicaltrials.gov, the international clinical
trials platform of the WHO, the EU clinical trials register and the
Cochrane Central Register of Controlled Trials were searched for
registered clinical trials. Studies in therapeutic trials were
considered eligible for the work. Frequency table was made for the most
common trialled drugs and the mechanisms of actions and adverse effects
of the selected drugs were reviewed. 10 studies were selected for review
in a descending order of their frequency in different therapeutic trials
and these are ritonavir, lopinavir, chloroquine/hydroxychloroquine,
interferon, remdesvir, favipravir, umifenovir, darunavir, tocilizumab
and methylprednisolone. The bedside physicians need to understand the
mechanisms of action of these agents and their peculiar adverse effects
so they are properly guided on the risk/benefit of the drugs they choose
in managing COVID-19 patients.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Coronavirus disease 2019 (COVID-19), an infectious viral disease caused
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was
first reported in Wuhan in the Hubei province of China in December 2019
(Lu et al., 2020). It was declared a public health emergency of
international concern and subsequently a global pandemic by World Health
Organisation on 20th January 2020 and 11\textsuperscript{th} March 2020
respectively (WHOa, 2020). As at 17\textsuperscript{th} May 2020, there
were about 4.5 million confirmed cases of COVID-19 and well over 300 000
deaths resulting from the pandemic globally (WHOb, 2020).

Most of the cases of COVID-19 (about 80\%) are asymptomatic (Crosby et
al., 2020). In the initial symptomatic phase of the disease, there could
be flu-like clinical features like sore throat, dry cough, rhinorrhea,
fever and fatigue. Myalgia, shortness of breath, haemoptysis, chest
pain, diarrhea, nausea and vomiting, headache and confusion may set in
subsequently. In the later phase, complications like acute respiratory
distress syndrome (ARDS), pneumonia, arrhythmia and septic shock may set
in (Chen et al., 2020; Yan et al., 2020; Huang et al., 2020; Wang, D. et
al, 2020)\textbf{.} It has also been observed that the symptoms are
usually more severe in elderly patients with co-morbidities, in patients
with allergic conditions like asthma, and patients with chronic
obstructive pulmonary disease (Yang et al., 2020).

As at date, neither drug nor vaccine has been approved for the treatment
or prevention of this dreaded pandemic that has plunged the entire world
into confusion and fear as well as socio-economic
straits\textbf{.}However, a combination of oxygen therapy, mechanical
ventilation, drugs like antivirals, antibiotics and other supportive
therapies appear to give promising clinical outcomes in the management
of COVID-19 patients (Yan et al., 2020). These therapeutic agents are
being used on ``off-label'' basis as they have not been approved for use
in COVID-19 patients. This ``off-label'' use is a way of drug
repurposing (drug repositioning) in the bid to find fast-tracked remedy
for the disease. Drug repurposing can be said to be the process of
identifying and developing new uses for existing drugs (Ashburn \& Thor,
2004).

A recent study shows that as at 20\textsuperscript{th} March 2020, about
344 interventional studies had been registered on clinical trials
registries including ClinicalTrials.gov, WHO ICTRP, EU Clinical Trials
Register, and Cochrane Central Register of Controlled Trials (Lythgoe \&
Middleton, 2020). Also, WHO had on 18\textsuperscript{th} March 2020
launched a clinical trial called \textbf{SOLIDARITY} to trial the four
most promising drug candidates for COVID-19 treatment, namely:
chloroquine/hydroxychloroquine, remdesvir, lopinavir/ritonavir and
lopinavir/ritonavir/interferon beta-1a. This mega clinical trial is
involving participants across over 90 countries (WHOc, 2020). Also, as
at 14\textsuperscript{th} April 2020, over 600 clinical trials on this
subject matter had been registered with the WHO with about 133 of them
being for therapeutic purposes.\textsuperscript{\textbf{12}} Putting the
therapeutic drug candidates together, they fall into about four major
therapeutic groups: antivirals, antimalarials,
immunosuppressants/immunomodulators and antibiotics. The antiviral
candidates include remdesvir, favipiravir, lopinavir/ritonavir,
ostelmavir, ganciclovir, peniclovir, umifenovir, triazavirin, baloxavir
marboxil, danoprevir/ritonavir, azvudine, sofosbuvir/ledipasvir,
sofosbuvir/daclatasvir, darunavir/cobicistat, emtricitabine/tenofovir
and ribavarin. The antibiotics include azithromycin, pirfenidone,
carimycin and teicoplanin. The antimalarials are the chloroquine/
hydroxychloroquine whereas the immunosuppressants/immunomodulators
include glucocorticoids (corticosteroids, methylprednisolone,
dexamethasone), anti-cytokines (tocilizumab, adalimumab, eculizumab,
sarilumab, ixekizumab) pegylated interferon with ribavarin,
lopinavir/ritonavir/interferon beta-1a (Lythgoe \& Middleton, 2020;
WHOc, 2020). This list is not exhaustive but enough to show that the
race to find effective therapeutics for COVID-19 is certainly on and
hopefully, some of these drug candidates will make it through the
clinical trials and get formal approval.

\textbf{Objectives}

\begin{enumerate}
\tightlist
\item
  To review the mechanisms of action of the major drugs in clinical
  trials for COVID-19 therapeutics and
\item
  To highlight some of major adverse effects of these drugs to properly
  guide the moment-by-moment decision making of the front-line
  physicians.
\end{enumerate}

\textbf{Methods}

We identified records of trials from online registries including
Clinical trials.gov, the International clinical trials platform of the
WHO, the EU clinical trials register and the Cochrane Central Register
of Controlled Trials. We collated all registered trials and identified
interventional studies focusing on therapeutic strategies. This
identified 1835studies. After removing duplicates, we had 915 studies
from where we selected 490 which focused on therapeutic interventions
having further removed studies on preventative interventions and vaccine
trials. Another 150 studies were removed which was based on Chinese
traditional and complementary interventions, leaving a total of 228
studies from where we selected the 10 most drugs studies which was
tested in 170 trials as shown in the PRISMA flow diagram\textbf{(Figure
1} ).

\textbf{Data extraction.}

Data extraction was done using an excel spreadsheet developed for the
purpose. We collected data on the trial registration, year/month of
commencement, registration body, the status of the trial, type of study
(vaccine trial/therapeutic trial), and the candidate drugs. We collated
only the agents in the different trials and analysed them in the
frequency table shown in \textbf{Appendix 1} to show the most common
drugs under investigation across different trials.

\textbf{RESULTS}

Figure 2 shows a graph frequency of the drugs that are in the
therapeutic trials while Table 1 shows the selected drugs which featured
in at least 5 trials. The ten drugs are being investigated in 170 trials
either independently or in combination.

\textbf{Discussion}

\textbf{Major therapeutics in clinical trials for COVID-19 treatment.}

The summary of the mechanisms of action and adverse effects of the major
drugs in the trials for COVID-19 is as shown in \textbf{Table 2.}

Antivirals

\textbf{Lopinavir/ Ritonavir}

Lopinavir and ritonavir are protease inhibitors approved for use in
human immunodeficiency virus (HIV) 1. They are among the drugs being
trialled for possible repurposing in COVID-19 treatment.
Lopinavir/ritonavir is usually given as a combination therapy as
ritonavir is said to increase the half-life of lopinavir by inhibiting
the cytochrome P450 that metabolises it. Protease inhibitors generally
prevent maturation of the viral particles by binding to the HIV-1
protease enzyme and preventing the cleavage of Gag-pol polyproteins
(group-specific antigen-polymerase). This leads to the production of
nascent immature, defective viral particles that are non-infectious (Yan
et al, 2020; Dionne, 2019; Sheahan et al., 2020; Painstil \& Cheng,
2019; Tobaiqy et al., 2020).

The adverse effects that have been reported with lopinavir/ritonavir
include nausea and vomiting, diarrhea, anemia, hyperlipidaemia, alanine
transaminase elevation, impaired cognition or memory, insomnia and skin
toxicity (Su et al, 2019; Jespersen et al., 2018; Dionne, 2019; Silva et
al., 2020). It is therefore instructive to be cautious in administering
lopinavir/ritonavir to patients that have impaired liver functions,
dyslipidaemia and psychiatric disposition.

\textbf{Remdesvir}

Remdesivir is an investigational drug in trial for Ebola and COVID-19.
It is a phosphoraramidate nucleotide prodrug with the chemical formula:
Pyrrolo{[}2,1-f{]}{[}triazin-4-amino{]} Adenine C-Nucleoside. It is said
has broad-spectrum \emph{in vitro} activity against RNA viruses like
Ebola, Marburg, MERS-CoV, SARS-CoV. It becomes active after
phosphorylation to a triphosphate in the host's cell. Remdesivir targets
the viral RNA-dependent RNA polymerase (RdRp) which is the complex
protein the coronaviruses use for the replication of their RNA genomes.
Its mechanism of action in human is not fully understood but \emph{in
vitro} and non-human evidence suggests that it might be that it inhibits
RdRp thereby causing premature termination of viral RNA transcription
process leading to termination of the overall RNA synthesis (Tchesnokov
et al., 2019; Jordan et al., 2018; Brown et al., 2019; Amirian \& Levy,
2020; Sheahan et al., 2020).

A recent preliminary report from one the clinical trial groups for
remdesvir suggests the drug caused 31\% improvement in the days taken
for the recovery of COVID-19 patients (Nature, 2020).

The adverse effects of the drug will likely be emerging as the clinical
trials progress.

\textbf{Favipravir}

This viral polymerase inhibitor is approved, in Japan, for the treatment
of novel strains of the influenza virus unresponsive to current
antivirals. Its activity spectrum spreads across A, B and C strains of
the virus. Favipravir becomes active after ribosylation and
phosphorylation. This triphosphorylated favipravir competitively inhibit
the viral RNA-dependent RNA polymerase (RdRp) of influenza virus known
as polymerase basic 1 transcriptase thereby interfering with the viral
replication (Hayden \& Shindo, 2019; Beigel et al., 2019; Principi et
al., 2019; Furuta et al., 2013; Madelain et al., 2016).

Favipravir is well tolerated clinically but the adverse effects that can
be associated with its use include diarrhoea, teratogenicity, increased
serum uric acid levels, elevated levels of transaminases, reduced
neutrophil counts (Hayden \& Shindo, 2019; Principi et al., 2019;
Madelain et al., 2016).

\textbf{Darunavir}

Darunavir is a protease enzyme inhibitor with activity against HIV-1. It
prevents HIV replication through binding to the enzyme, stopping the
dimerization and the catalytic activity of HIV-1 protease. SARS-CoV-2
being an RNA virus also uses protease enzyme which the drug inhibits,
hence the drug is one of the antiviral candidates in clinical trial for
the treatment of COVID-19.

Darunavir has bimodal activity against HIV-1 protease, enzymatic
inhibition and protease dimerization inhibition. It has a high genetic
barrier to the development of HIV-1 drug resistance (Aoki et al., 2018).

Adverse effects include blurred vision, sweating, increased urination,
difficulty in breathing, jaundice, myalgia, facial puffiness,
tachycardia, sore throat and vomiting (Antinori et al., 2019; Delicio et
al., 2018).

\textbf{Umifenovir}

Umifenovir is an indole-based hydrophobic dual-acting direct
antiviral/host-targeting agent used for the treatment and prophylaxis of
influenza and other respiratory infections. It has been in use in the
treatment of influenza in China and Russia for so many years (Fink et
al., 2020; Pshenichnaya et al., 2019).

It has been reported to have inhibitory effects on a diverse array of
viruses, including DNA and RNA viruses (SARS-CoV-2 is an RNA virus) as
well as capsid and membrane-enclosed viruses (Fink et al., 2020;
Pshenichnaya et al., 2019). Umifenovir inhibits the entry of the
influenza virus at the late stage by binding directly to influenza
haemagglutinin (HA) and inhibiting its ability to transit to an
activated conformation. It also impairs fusion by intercalation into the
viral or target membrane, thereby rendering the membrane less yielding
for fusion.

Major adverse effect is hypersensitivity in children. It is administered
orally with an elimination half life of 17-21 hours (Fink et al., 2018;
Hulseberg et al., 2019).

Antimalarials

\textbf{Chloroquine/hydroxychloroquine (CQ/HCQ)}

Chloroquine, a 9-aminoquinolne, has been in clinical use since the
20\textsuperscript{th} century. Hydroxychloroquine is the hydroxylated
(and safer) form of chloroquine. CQ/HCQ was approved for the treatment
of malaria and autoimmune disorders like rheumatoid arthritis, systemic
lupus erythematosus, Sj\selectlanguage{ngerman}ögren syndrome, etc. Its antimalarial use has
been largely suspended due to resistance (Devaux et al., 2020; Shama,
2020; D'Alessandro et al., 2020; Haladyj et al., 2018; Al-Bari, 2015;
Savarino et al., 2003).

CQ/HCQ also has interesting antiviral activities and strong
immunomodulatory effects that have led to robust scientific discussions
that have culminated to several trials for possible approval for
treatment of emerging viral diseases.

Its immunomodulatory effect occurs by the suppression of T-cells
production/release of the cytokines - tumour necrosis alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}), the
interleukins (IL 1, 2, 6 or 18) and interferon alpha and gamma (IFN-\selectlanguage{greek}α,γ\selectlanguage{english})
which mediate the inflammatory complications of several viral diseases
especially in COVID-19.

CQ/HCQ inhibits viral replication in many ways:

Inhibition of the pre-entry step of the viral cycle by interfering with
viral particles binding to their cellular cell surface.

(b) Impairment of the early stage of virus replication by interfering
with the pH-dependent endosome-mediated viral entry of susceptible
viruses (like flaviviruses, retroviruses, and coronaviruses) by
increasing both the endosomal and lysosomal pH leading to non-fusion
with the host cell.

(c) Interference with the post-translational modification of the viral
proteins thereby making the nascent viral particles non-infectious
(Devaux et al., 2020; Shama, 2020; D'Alessandro et al., 2020; Haladyj et
al., 2018; Al-Bari, 2015; Savarino et al., 2003).

Adverse effects are rarely seen with CQ/HCQ use. However, there could be
gastrointestinal upset and hypersensitivity skin reactions (generalized
pustular rash, urticaria, erythroderma). There are also chances of
macular retinopathy, cardiomyopathy, arrhythmias, QT interval
prolongation. There could also be dizziness, tinnitus, headaches and
nightmares (D'Alessandro et al., 2020; Haladyj et al., 2018)\textbf{.}

Immunosuppressants/immunomodulators

\textbf{Interferons}

Interferons are proteins that can induce a non-specific resistance to
viral infections by several mechanisms, including the inhibition of
protein synthesis, inactivation of viral RNA, and enhancement of
phagocytic and cytotoxic mechanisms (Ozato et al., 2007). The interferon
(IFN) system represents the first line of defence against a wide range
of viruses (in this instance, SARS-CoV-2). Viral infection rapidly
triggers the transcriptional induction of IFN-\selectlanguage{greek}β \selectlanguage{english}and IFN-stimulated genes
(ISGs), whose protein products act as viral restriction factors by
interfering with specific stages of the virus life cycle, such as entry,
transcription, translation, genome replication, assembly and egress
(Subramanian et al., 2018; O'Brien et al., 2020).

Interferons activate macrophages that engulf antigens and natural killer
cells (NK cells), a type of immune T-cells that are integral in the
innate immune system. Adverse effects include, fever, myalgia,
confusion, leucopenia, elevated liver enzymes (O'Brien et al., 2020;
Prokunina-Olsson et al., 2020).

\textbf{Methylprednisolone}

Methylprednisolone is a synthetic corticosteroid with inflammatory and
immunomodulating properties which could be beneficial in reducing the
massive inflammatory response that SARS-CoV-2 induces. It binds to and
activates specific nuclear receptors which have \selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β \selectlanguage{english}isoforms. The
complex formed binds to specific glucocorticoid response elements (GREs)
resulting in altered gene expression and inhibition of pro-inflammatory
and cytokine production. This agent also decreases the number of
circulating lymphocytes, induces cell differentiation and stimulates
apoptosis in sensitive tumour cell populations thereby increasing
survival and accumulation of neutrophils at inflammatory sites as well
as induction of basophil apoptosis (Ferrara et al., 2009; Williams,
2018; Ponticelli \& Locatelli, 2018).

The clinical indications include scleroderma, ulcerative colitis,
asthma, vitiligo, autoimmune cytopenia and nephritic syndrome.

The adverse effects are cataract, glaucoma, hypertension, pancreatitis,
myopathy, osteoporosis, psychosis, hyperglycaemia, hypocalcaemia,
metabolic acidosis and secondary adrenal insufficiency (Wang, Y et al.,
2020; Zhou et al., 2020).

\textbf{Tocilizumab}

Tocilizumab is a genetically-engineered monoclonal antibody humanized
from a mouse antihuman interleukin 6 (IL-6) receptor antibody. It has a
broad-spectrum immunomodulatory activity. It inhibits IL-6 from binding
to both membrane-bound and soluble receptors. IL-6 is a cytokine
produced by the various immune cells in response to molecular patterns
and affects multi-inflammatory cells. IL-6 is involved in
differentiation of CD-4 cells into Th-17 cells that play a significant
role in various immune-mediated diseases. SARS-COV-2 is thought to
induce massive cytokine storm, especially IL-6, therefore, the
inhibition of this IL-6 by tocilizumab significantly blocks this pathway
and consequent inflammatory sequelae associated with COVID-19 disease
(Karkkhur \& Hasanreisoghi, 2019; Luo et al., 2020).

The clinical indications include rheumatoid arthritis, juvenile
idiopathic arthritis and non-infectious uveitis.

The adverse effects associated with tocilizumab include upper
respiratory tract infections, elevated liver enzymes,
hypercholesterolaemia, gastritis, mouth ulcers, gastrointestinal
perforation (Luo et al., 2020).

\textbf{Limitations}

COVID -19 is new. Trials are being registered and updated almost weekly,
so it is impossible to give the most current status of therapeutic
trials world-wide. We selected the most trialled drugs as at the time of
initiation of review.

Some trials were conducted in languages other than English and were not
reviewed.

The number of drugs under trials are too many and practically not
feasible to review all in this context.

\textbf{Conclusions}

The race to find an effective cure for COVID-19 is on. Most of the
candidate drugs in various clinical trials are being re-purposed but
none has been approved as at date. It is pertinent for the bedside
physicians to understand the mechanisms of action of these agents and
their peculiar adverse effects so they are properly guided on the
risk/benefit of the drugs they choose in managing COVID-19 patients.

\textbf{Abbreviations}

COVID-19: Coronavirus disease 2019

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2

SARS-CoV: Severe acute respiratory syndrome coronavirus

MERS-CoV: Middle East respiratory syndrome coronavirus

ARDS: Acute respiratory distress syndrome.

HIV: Human immunodeficiency virus

WHO ICTRP: World Health Organisation International Clinical Trials
Registry Platform.

EU: European Union

CQ/HHQ: Chloroquine/hydroxychloroquine

IL-6: interleukin-6

TNF: Tumour necrosis factor

HA: Hemagglutinin

CD-4: Cluster of differention 4

Th-17 cells:T Helper 17 cells

NK cells: natural killer cells

IFN: Interferon

ISGs: interferon-stimulated genes

RNA: Ribonucleic acid

DNA: Deoxyribonucleic acid

RdRp: RNA-dependent RNA polymerase

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\textbf{Table 1. The most common drugs under investigation across
different trials and selected drugs which featured in at least 5
trials.}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
S/N & Drug candidate & Number of trials\tabularnewline
\midrule
\endhead
1 & Ritonavir & 38\tabularnewline
2. & Lopinavir & 34\tabularnewline
3 & Chloroquine/hydroxychloroquine & 31\tabularnewline
4 & Interferon alpha & 22\tabularnewline
5 & Remdesvir & 10\tabularnewline
6 & Favipravir & 9\tabularnewline
7 & Umifenovir & 9\tabularnewline
8 & Darunavir & 6\tabularnewline
9 & Tocilizumab & 6\tabularnewline
10 & Methylprednisolone & 5\tabularnewline
& Total & 170\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Summary of the mechanisms of action and adverse effects
of the major drugs in trial for COVID-19.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Candidate drug}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Drug class}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Current indication}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Mechanism of action}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Adverse effects}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Status of clinical trials}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Lopinavir/ritonavir\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Protease inhibitors (antiviral)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
HIV-1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of protease by preventing the cleavage of Gag-pol
polyproteins.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Nausea and vomiting Diarrheoa Anemia Hyperlipidaemia, ALT elevation
Impaired cognition/memory Insomnia\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
On-going for SARS and COVID-19 (ChiCTR2000029539)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Chloroquine/hydroxychloroquine\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Antimalarials\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Malaria Autoimmune diseases\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Suppression of cytokine (TNF, IL, IFN) production/release. Inhibition of
viral replication.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gastrointestinal upset Generalized pustular rash Urticaria, Erythroderma
Macular retinopathy Cardiomyopathy Arrhythmias QT interval prolongation.
Dizziness Tinnitus, Headaches Nightmares\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
On-going for COVID-19. ChiCTR2000029609 (ICTPR);
EUCTR2020-001406-27-FR\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Remdesvir\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Phosphoraramidate nucleotide (antiviral).\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Under trial for Ebola.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of RdRp causing premature termination of viral RNA
transcription.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Will likely emerge as clinical trials unfold.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
In phase II clinical trial for Ebola (NCT03719586); In phase III
clinical trials for COVID-19 (NCT04252664)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Favipiravir\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Viral polymerase inhibitior\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Influenza strains unresponsive to current antivirals.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition the RdRp of influenza virus (polymerase basic 1
transcriptase) thereby interfering with the viral replication.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diarhhoea Teratogenicity Increased serum uric acid levels Increased
levels of transaminases Reduced neutrophil counts\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
In clinical trial for COVID-19. (ChiCTR2000029548)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Darunavir\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Viral Protease inhibitor\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
HIV -1 Infection\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of protease by preventing the cleavage of Gag-pol
polyproteins.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Blurred vision Sweating, Myalgia Constipation Diarrhoea Jaundice Facial
puffiness Difficulty in breathing Vomiting Tachycardia\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
On-going (NCT04304053)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Umifenovir\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Antiviral\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Influenza\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
It binds directly to influenza haemagglutinin (HA) and inhibit its
ability to transit to an activated conformation. It also impairs fusion
by intercalation into the viral or target membrane, thereby rendering
the membrane less yielding for fusion.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hypersensitivity in children\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Recruiting stage of clinical trial. NCT04273763\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Interferon\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Immunomodulatory (Antiviral)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Multiple sclerosis. Hepatitis B and C virus infections. HPV Kaposi
sarcoma.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of the activation of autophagy-inducing kinase, AMPK in
viruses. It also activates macrophages that engulf antigens and natural
killer cells (an immune T-cells).\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Fever Myalgia Hepatopathy Difficulty in breathing Anaphylactic reactions
Depression Suicidal ideation\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
In clinical trial for COVID-19 PER-010-20\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Methylprednisolone\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Anti-inflammatory. Immunomodulatory.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Asthma. Vitiligo. Scleroderma Adrenal insufficiency. Nephrotic syndrome.
Autoimmune cytopenia.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Binds to and activates specific receptors, resulting in altered gene
expression and inhibition of pro-inflammatory cytokine production.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cataract Glaucoma Hypertension Peptic ulcer disease Pancreatitis
Hyperglycaemia Hypocalcaemia Metabolic acidosis Growth suppression
Secondary adrenal insufficiency\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
On-going NCT04263402\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Tocilizumab\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Immunomodulator. Anti-inflammatory.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Rheumatoid arthritis. Juvenile idiopathic arthritis. Non-infectious
uveitis.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of interleukin-6 (IL-6) binding to both membrane-bound and
soluble receptors (IL-6R) in the system resulting in immunomodulation
and anti-inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Upper respiratory tract infections. Elevated liver enzymes.
Hypercholestrolaemia Gastritis Mouth ulcers Gastro-intestinal
perforation.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
On-going. EUCTR2020-001442-19-ES\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1. PRISMA flow diagram showing how the drug candidates
were selected.}

\textbf{Figure 2. Frequency of drugs currently in COVID-19 therapeutic
trial}

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/338549/articles/465053-mechanisms-of-action-and-adverse-effects-of-the-major-therapeutic-agents-in-trial-for-covid-19-therapeutics-a-review-of-literature}

\textbf{Appendix 1: The frequency of drugs under investigation across
different trials in COVID-19 therapeutics}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Drug candidate\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Frequency\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Percent of responses\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Percent of cases\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Chloroquine/hydroxychloroquine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
13.6\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
25\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Lopinavir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
34\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14.91\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ritonavir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16.67\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30.65\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Interferon alpha\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9.65\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Favipravir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3.95\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7.26\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ASCO9\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Oseltamivir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Remdesvir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.39\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8.06\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Umifenovir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3.95\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7.26\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Triazavirin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Baloxavir marboxil\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Danoprevir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Azvudine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.75\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3.23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sofosbuvir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ledispasvir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Daclatasvir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Darunavir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.63\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.84\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Cobicistat\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Emtricitabine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Tenofovir\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pirfenidone\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Carimycin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Methylprednisolone\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.19\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Tocilizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.63\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.84\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Adalimumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Eculizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sarilumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ixekizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ribavirin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Bromhexine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Tranilast\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Thymosin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ebastine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Dexamethasone\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fingolimod\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Appendix 1 continued from previous page}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Drug candidate\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Frequency\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Percent of responses\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Percent of cases\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Meplazumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Leflumide\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Camrelizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ulinastatin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Bevacizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Thalidomide\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Suramin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Enoxaparin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Vitamin C\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Tetrandine\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sildenafil\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Heparin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Losartan\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.44\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

