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\begin{document}

\title{Current pharmacological treatments for COVID-19: what's next?}



\author[1]{Cristina Scavone}%
\author[1]{Simona Brusco}%
\author[1]{Michele Bertini}%
\author[1]{Liberata Sportiello}%
\author[1]{Concetta Rafaniello}%
\author[2]{Alice Zoccoli}%
\author[1]{Liberato Berrino}%
\author[3]{Giorgio Racagni}%
\author[1]{Francesco Rossi}%
\author[1]{Annalisa Capuano}%
\affil[1]{Università degli Studi della Campania Luigi Vanvitelli}%
\affil[2]{Campus Bio-Medico University}%
\affil[3]{Università degli Studi di Milano}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Starting from December 2019 the novel SARS-Cov-2 has spread all over the
world, being recognized as the causing agent of COVID-19. Since nowadays
no specific drug therapies neither vaccines are available for the
treatment of COVID-19, drug repositioning may offer a strategy to
efficiently control the clinical course of the disease and the spread of
the outbreak. In this paper we aim to describe the main pharmacological
properties, including data on mechanism of action, safety concerns and
drug-drug interactions, of drugs currently administered in patients with
COVID-19, focusing on antivirals and drugs with immune-modulatory and/or
anti-inflammatory properties. Where available, data from clinical trials
involving patients with COVID-19 were reported. A large number of
clinical studies have been registered worldwide and several drugs were
repurposed to face the new health emergency of COVID-19. For many of
these drugs, including lopinavir/ritonavir, remdesivir, favipiravir,
chloroquine and tocilizumab, clinical evidence from literature and real
life settings support their favorable efficacy and safety profile in
improving patients' clinical conditions. Even though drug repurposing is
necessary, it requires caution. Indeed, too many drugs that are
currently tested in patients with COVID-19 have peculiar safety
profiles. While waiting for the results of clinical studies
demonstrating the efficacy of drugs able to reduce symptoms and
complications of COVID-19, the best therapeutic path to pursue is the
development of an effective vaccine able to prevent this infection.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Coronaviruses are a group of single-stranded RNA viruses that are
characterized by a spherical shape, which provides them the typical
''crown'' appearance. These viruses, which were first identified in the
mid-1960s, can be categorized into four subfamilies:
\selectlanguage{greek}α\selectlanguage{english}-/b\selectlanguage{english}-/g\selectlanguage{english}-/d-\selectlanguage{english}Coronavirus. Gamma and delta-coronaviruses are more inclined
to infect birds, while alpha and beta-coronaviruses mainly infect
mammals {[}\textbf{1} {]}. Specifically, \selectlanguage{greek}β\selectlanguage{english}-\selectlanguage{english}coronaviruses include the
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle
East Respiratory Syndrome Coronavirus (MERS-CoV), detected in Guangdong
in 2002 and in Saudi Arabia in 2012, respectively. On December 2019, a
novel \selectlanguage{greek}β\selectlanguage{english}-\selectlanguage{english}Coronavirus, SARS-CoV-2 (\emph{Severe Acute Respiratory Syndrome
Coronavirus 2} ), has emerged in Wuhan (Hubei province, China) where it
was found to be responsible of the new COVID-19 {[}\textbf{2} {]}. After
a rapid spread worldwide of the disease, the World Health Organization
(WHO) announced COVID-19 outbreak a pandemic. According to current
evidence, the epidemic started with animal to human transmission
{[}\textbf{3} {]}. A phylogenetic analysis has demonstrated that the new
coronavirus significantly clustered with the sequence of bat SARS-like
coronavirus {[}\textbf{3} {]}. It has envelopes, and the particles are
round or oval with diameter from 60 to 140 nm {[}\textbf{4} {]}. As for
other coronaviruses, the replication of SARS-CoV-2 starts with the
attachment to the host cell through interactions between the Spike
protein (S protein) and its receptor. In this phase, the virus interacts
with ACE2 receptor and the serine protease TMPRSS2. Once into the cell,
replication and transcription phases start {[}\textbf{5,6} {]}.

The transmission among people occurs through respiratory droplets ad the
incubation time ranges from 3 days to 2 weeks {[}\textbf{7} {]}. In mild
cases SARS-Cov-2 infection can occur with fever, fatigue and dry cough,
while severe cases frequently occur with pneumonia, respiratory and
kidney failure. Apart from respiratory and flu-like symptoms, this
infection may be complicated by lymphopenia and interstitial pneumonia
with high levels of pro-inflammatory cytokines, such as IL-1, IL-2,
IL-6, G-CSF, IP-10, and TNF\selectlanguage{greek}α. \selectlanguage{english}This condition leads to the so-called
''cytokine storm'' which, in turn, can induce acute respiratory distress
syndrome (ARDS), organ failure, sepsis, potentially progressing to
patient's death {[}\textbf{8} {]}. Patients with mild form of COVID-19
shall be eligible for isolation and, sometimes, symptomatic treatments
(mainly paracetamol for fever control). On the other hand, patients
presenting severe pneumonia require hospitalizations and frequently the
access to intensive care units where mechanical ventilation can be
provided. For these patients pharmacological treatments is strongly
needed. Nowadays, no specific drug therapies neither vaccines are
available for the treatment of COVID-19. Since there is no time to
evaluate new drug therapies, drug repositioning may offer a strategy to
efficiently control clinical course of the disease and the spread of
pandemic {[}\textbf{9} {]}.

In this paper we aim to provide an overview of treatments currently
administered in patients with COVID-19, mainly focusing on antivirals
and drugs with immune-modulatory and/or anti-inflammatory properties,
their pharmacological features and achievement in term of patients'
clinical outcomes. A close examination of drugs that are currently under
clinical development is provided as well. The mechanism of action, main
safety concerns and drug-drug interactions of antiviral,
immune-modulatory and anti-inflammatory agents currently used or under
clinical development for the treatment of COVID-19 are reported in table
1.

\textbf{2. Antiviral agents}

A large number of antiviral agents, many of which are used for the
treatment of HIV, hepatitis and flu symptoms, are currently administered
off-label worldwide in patients with COVID-19 or are under clinical
evaluation for the treatment of the disease. Here we discuss the most
used antivirals in terms of pharmacodynamic properties, potential for
the treatment of COVID-19 and data from clinical studies where
available. A brief analysis of antivirals less used is presented as
well.

The combination lopinavir/ritonavir, which is indicated with other
antiretroviral medicinal products for the treatment of human
immunodeficiency virus (HIV-1), have raised increasing interest for the
treatment of COVID-19. Lopinavir is a protease inhibitor with high
specificity for HIV-1 and HIV-2, while ritonavir increases lopinavir
plasma concentration through the inhibition of cytochrome P450
{[}\textbf{10} {]}. This combination was already tested in patients with
SARS infection, demonstrating to be associated with favorable outcomes,
and it is currently evaluated, in combination with interferon \selectlanguage{greek}β, \selectlanguage{english}in
patients with MERS-CoV infection {[}\textbf{11-13} {]}. Cao B et al.
carried out a randomized, controlled, open-label trial in 199
hospitalized patients with severe SARS-CoV-2 infection. Patients were
randomized to receive the combination lopinavir/ritonavir plus standard
care for 14 days or standard care alone. According to study's results,
no differences between the combination treatment and the standard
treatment, in terms of clinical improvement, mortality at 28 days and
percentages of patients with detectable viral RNA, were detected.
Moreover, adverse events, especially gastrointestinal ones, were more
common in the group of patients receiving the combination treatment,
while serious adverse events were more common in the standard-care
group. Authors concluded that in hospitalized patients with severe
Covid-19, no benefit was observed with lopinavir-ritonavir treatment
beyond standard care {[}\textbf{14} {]}. Furthermore, an open-label,
randomized clinical trial, which will compare the efficacy of
lopinavir/ritonavir vs. hydroxychloroquine in 150 patients with mild
COVID-19, is currently ongoing in the Republic of Korea {[}\textbf{15}
{]}. Since clinical evidence on the efficacy and safety of the
combination lopinavir/ritonavir in patients with COVID-19 is still
limited and controversial, further studies are required to confirm a
possible role of these drugs. Nevertheless, this combination is
currently used in Italy in COVID-19 patients with less disease severity
compared with patients evaluated in the study published on NEJM
{[}14,\textbf{16} {]}.

Remdesivir has been recently recognized as a promising antiviral drug
against a broad-spectrum of RNA viruses (including MERS-CoV) infection
in cultured cells {[}\textbf{17} {]}, mice and non-human primate models
{[}\textbf{18} {]}. It is a nucleotide analogue, able to inhibit
RNA-dependent RNA polymerase (RdRp), proteins essential for viral
replication. The drug was initially developed as a treatment for Ebola
and Marburg infections, not demonstrating a clinical efficacy. Antiviral
activities were also demonstrated against single-stranded RNA viruses,
including MERS and SARS-Cov {[}\textbf{19} {]}. Recent results of a
preclinical study indicated that, in vitro, the association
remdesivir/chloroquine could be highly effective in controlling the
SARS-Cov-2 infection {[}\textbf{20} {]}. The efficacy and safety of the
remdesivir are currently evaluated in a phase 3 clinical trial in 453
patients with COVID-19 which will end in May 2020 {[}\textbf{21} {]}. In
addition, a further phase 3 trial is evaluating the efficacy and safety
of remdesivir in 1,000 patients with COVID-19; this study will end in
May 2020 too {[}\textbf{22} {]}. Data from the Italian real clinical
practice showed that the drug has already been used in patients with
COVID-19 at the Spallanzani hospital in Rome, resulting in their full
recovery {[}\textbf{23} {]}. Currently the drug is administered among 12
Italian clinical centers {[}\textbf{24} {]}. Lastly, a case report
highlighted promising results of this treatment in the first US patient
with COVID-19 {[}\textbf{25} {]}.

Favipiravir is a further drug under clinical development. It was
authorized in 2014 in Japan for the treatment of influenza virus
infections. The drug is converted by intracellular phosphoribosylation
into its active form that selectively inhibits RdRp. Since the catalytic
domain of RdRp is expressed in many types of RNA viruses, favipiravir is
effective against a wide range of influenza virus subtypes, but also
against arenavirus, bunyavirus and filovirus {[}\textbf{26} {]}.
Favipiravir has already been used for the treatment of patients with
Ebola and Lassa viruses. However, no clear conclusions about the
efficacy profile of the drug were drawn {[}\textbf{27} {]}. As reported
by Watanabe et al. {[}\textbf{28} {]}, favipiravir was administered
during a clinical trial to 200 patients with COVID-19 at hospitals in
Wuhan and Shenzhen. The results of these studies showed that patients
who received the drug tested negative in a relatively short time (4 days
compared to 11 days in the control group), while the symptoms of
pneumonia significantly reduced. No specific safety concerns have
emerged. Another clinical study carried out in Wuhan showed that
favipiravir-treated patients recovered from fever after an average of
2.5 days, compared to 4.2 days of other patients. Chang Chen et al.
{[}\textbf{29} {]} recently published the results of a randomized
clinical trial (Chictr.org.cn, n. ChiCTR200030254), which compared the
efficacy and safety of favipiravir vs. umifenovir in the treatment of
240 patients with COVID-19, hospitalized in 3 hospitals from 20 February
2020 to 12 March 2020. The results showed that the 7-day clinical
recovery rate was 55.86\% in the umifenovir group and 71.43\% in the
favipiravir group (P = 0.01). In patients with hypertension and/or
diabetes, the time for fever reduction and cough relief was
significantly shorter in favipiravir group than in umifenovir group
(P\textless{}0.001), but no statistically significant difference
regarding to oxygen therapy or non-invasive mechanical ventilation was
found. The most common adverse events were liver enzyme abnormalities,
psychiatric, gastrointestinal symptoms and serum uric acid elevations
(2.5\% of patients in the umifenovir group vs. 13.79\% of patients in
the favipiravir group, P \textless{}0.0001). Lastly, the drug is under
evaluation for the treatment of COVID-19 in a 3-arms, multi-center
randomized controlled trial in combination with tocilizumab
{[}\textbf{30} {]}. At the end of March 2020 the Italian Medicine Agency
(AIFA) started the evaluation of available scientific evidences with the
aim to understand if a clinical program to assess the efficacy and
safety of favipiravir is appropriate {[}\textbf{31} {]}.

Further antiviral agents are considered as potential treatments in
SARS-Cov-2 infection. For these antivirals a brief description is
reported below. Among these, there is the combination
darunavir/cobicistat, which is currently approved for the treatment of
HIV-1 in association with other antivirals. Darunavir is an inhibitor of
the dimerisation and of the catalytic activity of the HIV-1 protease,
while cobicistat is an inhibitor of cytochromes P450 that enhances
darunavir plasma concentrations {[}\textbf{32} {]}. Based on the results
of preclinical studies demonstrating inhibitory effects mediated by this
combination on SARS-CoV-2 {[}\textbf{33,34} {]}, this drug is currently
evaluated in some clinical studies {[}\textbf{35,36} {]}. Lastly, an
analysis carried out by Jeffrey K Aronson of clinical trials on COVID-19
revealed that there are currently more than 20 studies investigating the
efficacy of further antivirals, including triazavirin (non-nucleoside
antiviral drug effective against tick-borne encephalitis virus and
forest-spring encephalitis virus), azidovudine (azidothymidine
nucleoside analogue, inhibitor of HIV reverse transcriptase), umifenovir
(membrane haemagglutinin fusion inhibitor in influenza viruses),
danoprevir (Hepatitis C virus NS3 protease inhibitor) and baloxavir
marboxil (inhibitor of influenza virus cap-dependent endonuclease)
{[}\textbf{37} {]}. Sofosbuvir, galidesivir and tenofovir showed
promising results for use against the newly emerged strain of
coronavirus {[}\textbf{38} {]}. Other antivirals, such as oseltamivir,
peramivir, zanamivir, ganciclovir, acyclovir, and ribavirin, which are
commonly used in clinical practice, are currently not recommended for
COVID-19 {[}\textbf{8} {]}. Even though few evidence have reported the
use of some of these drugs in patients with COVID-19, researchers
highlighted the importance to not give patients drugs of unknown
efficacy, which might be very harmful for patients with severe COVID-19
{[}\textbf{39} {]}.

Recently two other drugs are currently evaluated in patients with
COVID-19, camostat mesilate and nafamostat. These drugs are synthetic
protease inhibitors of trypsin, prostasin, matriptase and plasma
kallikrein. They are approved in Japan for the treatment of chronic
pancreatitis and postoperative reflux esophagitis. Coronaviruses
penetrate the cell through the plasma membrane; this step requires the
activation of superficial proteases, such as TMPRSS2. Specifically,
SARS-CoV-2 enters human cells after that the S protein binds to an ACE2
receptor in the cell membrane. S protein is divided into S1 and S2 by a
protease derived from human cells. S1 binds to its receptor, ACE2. The
S2 is divided by TMPRSS2, with consequent fusion of the membrane. ACE2
and TMPRSS2 are therefore essential for SARS-CoV-2 infection. Both drugs
are able to inhibit the enzymatic activity of TMPRSS2 {[}\textbf{5,40}
{]}. A randomized, placebo-controlled clinical trial (CamoCO-19) is
evaluating the efficacy and safety of camostat mesilate in 180 patients
with COVID-19 {[}\textbf{41} {]}. Furthermore, both drugs will be
evaluated in clinical trials launched by the University of Tokyo
{[}\textbf{42} {]}. Camostat seems well tolerated; common adverse events
include rashes, gastrointestinal disorders and changes in liver enzymes.
Rare adverse events are thrombocytopenia, liver failure and
hyperkalemia. Camostat mesilate was associated to a case of acute
eosinophilic pneumonia {[}\textbf{43} {]}. Another glycoprotein involved
in the passage of the virus inside the cell is CD147, which interacts
with S protein. CD147 also shows pro-inflammatory activity and takes
part in the regulation of cytokine secretion and in leukocytic
chemotaxis during viral infections {[}\textbf{44} {]}. Chinese
researchers have started a clinical trial to test the efficacy and
safety of meplazumab, a monoclonal antibody that binds the CD147
glycoprotein. Even though this drug cannot be defined as an antiviral
agent, its mechanism of action leads to a control in virus replication;
for this reason, it is mentioned among antivirals. The preliminary
results of the Chinese study are promising. Indeed, compared to the
control group, the treatment with meplazumab was earlier associated with
improvement in pneumonia. These results, although preliminary, seem to
confirm the involvement of CD147 in the penetration and replication of
the virus in the body as well as in the development of inflammatory
processes related to the infection {[}\textbf{45} {]}.

Lastly, a recent study carried out by the Monash University's
Biomedicine Discovery Institute and the Peter Doherty Institute of
Infection and Immunity showed that~ivermectin, a medication used for the
treatment of parasite~infestations, in cell culture is able to reduce
the viral RNA of SARS-Cov-2 by 93\% after 24 hours and by 99.8\% after
48 hours. Currently, tests were carried out only \emph{in
vitro}and~clinical trials are strongly need to evaluate if the drug can
be really effective against SARS-Cov-2. The author concluded that the
early administration of an effective anti-viral to patients could limit
their viral load, contrast the disease progressing and prevent its
transmission.~They suggest that ivermectin could be a useful antiviral
in the fight against Covid-19 {[}\textbf{46} {]}.

\textbf{2. Immunomodulatory and anti-inflammatory agents}

As previously reported the SARS-Cov-2 infection can be associated,
especially in severe form, to the exaggerate activation of inflammatory
processes and the development of cytokine storm. Based on this
consideration, several drugs with immunomodulatory properties are
currently evaluated in patients with COVID-19. These drugs include both
synthetic and biological medicines that are able to modulate specific
inflammatory pathways through the inhibition of human interleukin-6
receptor (IL-6R), of the metabolism, motility and chemotaxis of
polymorphonuclear cells, of Janus kinase (JAK) or TNF-\selectlanguage{greek}α \selectlanguage{english}production.

One of the first drugs used in patients with COVID-19 was tocilizumab.
This is a monoclonal antibody that inhibits ligand binding to the IL-6R
and that is authorized for the treatment of rheumatoid arthritis and
systemic juvenile idiopathic arthritis {[}\textbf{47} {]}. Scientific
evidence suggests that the IL-6 pathway plays a key role in guiding the
inflammatory immune response at the level of pulmonary alveoli in
patients affected by COVID-19. Indeed, this immune response produces
damage to the lung parenchyma, which significantly reduces respiratory
function {[}\textbf{48,49} {]}. The drug was first tested in China to
reduce lung complications in 21 patients with severe SARS-CoV-2
infection {[}\textbf{50} {]}. The treatment was associated with a
reduction of oxygen requirement, resolution of computed tomography (CT)
lesions, normalization of lymphocyte count, reduction of C-reactive
protein levels, hospital discharge, with average hospitalization
duration of 13,5 days. Given the achieved clinical outcomes, the drug is
currently used in several Italian hospitals, including the Cotugno
Hospital in Naples. Since tocilizumab seems able to prevent the
hyperactivation of inflammatory pathway, its use can be expected also in
early stages for patients with not severe COVID-19. Currently three
clinical studies, including one that was authorized by the AIFA, are
ongoing {[}\textbf{51-53} {]}. Sarilumab belongs to the same drug class
of tocilizumab and 3 trials are underway to evaluate the efficacy and
safety of this drug, alone or in combination with standard care, in
almost 1,500 patients with COVID-19 {[}\textbf{54-56} {]}.

Two other drugs, chloroquine and hydroxychloroquine, are commonly
off-label used in Chinese and Italian clinical centers for the treatment
of COVID-19 {[}\textbf{57} {]}. These compounds are authorized as
antimalarial drugs and for the treatment of autoimmune diseases,
including lupus and rheumatoid arthritis. Even though both drugs are
considered to be safe with adverse events that are generally mild and
transitory, they can be associated with cardiovascular disorders,
including prolongation of QT that can be life-threatening {[}\textbf{58}
{]}. Some preclinical studies showed that chloroquine has antiviral
activity against SARS coronavirus {[}\textbf{59} {]}, human coronavirus
OC43 {[}\textbf{60} {]} and influenza A H5N1 {[}\textbf{61} {]}
suggesting a possible role in SARS-Cov-2 infection {[}\textbf{62,63}
{]}. Further studies found that chloroquine interferes with terminal
glycosylation of the functional ACE 2 receptor, negatively influencing
the virus-receptor binding. Indeed, results of a clinical study showed
that the combination remdesivir/chloroquine or hydroxychloroquine is
highly effective in control of SARS-Cov-2 infection {[}\textbf{20,64,65}
{]}. Both drugs are currently used in Italy in patients with SARS-Cov-2
infections, including outpatients in early stages of disease, and, given
their particular safety profile, the AIFA recommended to healthcare
professionals to perform a careful evaluation of the patient,
particularly in cases of cardiac conduction disorders,
glucose-6-phosphate dehydrogenase deficiency or the presence of other
concomitant therapies {[}\textbf{66} {]}.

Another drug able to reduce the cytokine storm is colchicine that is
authorized for the treatment of acute attack of gouty arthritis and
pericarditis. The drug reduces the inflammatory response through several
mechanisms: the inhibition of the metabolism, motility and chemotaxis of
polymorphonuclear cells, the inhibition of the adhesion and recruitment
of neutrophils and the modulation of leukocyte-mediated inflammatory
activities {[}\textbf{67-71} {]}. On March 2020 a phase 3 clinical study
(COLCORONA) began. This study will enroll 6,000 outpatients with
COVID-19 with the following characteristics: age [?] 40 years; diagnosis
of COVID-19 in the past 24 hours; at least one risk factor between
age\textgreater{}70 years, diabetes, uncontrolled hypertension, asthma
or COPD, heart failure, fever [?]38.4 \selectlanguage{ngerman}° C in the last 48 hours, dyspnea,
pancytopenia or high neutrophil count and low lymphocyte count; patients
not of childbearing age or using contraception methods {[}\textbf{72}
{]}.

Baricitinib is currently approved for the treatment of rheumatoid
arthritis. It is a selective and reversible inhibitor of JAK1 and JAK2.
These enzymes transduce intracellular signals for cytokines and growth
factors involved in hematopoiesis, inflammation and immune function.
Furthermore, baricitinib blocks the protein kinase 1 associated with AP2
(AAK1), preventing the binding of the virus to the alveolar epithelium
{[}\textbf{70} {]}. A study published in The Lancet suggested that this
drug could represent an additional therapeutic alternative for the
treatment of COVID-19 {[}\textbf{73} {]}. A non-randomized phase II
clinical trial recently started in order to evaluate the efficacy and
safety of baricitinib, lopinavir/ritonavir, hydroxychloroquine and
sarilumab in the treatment of 1,000 hospitalized patients with COVID-19
{[}\textbf{74} {]}. Similarly, sunitinib, fedratinib and ruxolitinib,
which are all selective JAK inhibitors, may be potentially effective
against SARS-CoV-2 in reducing inflammation and cytokine levels,
including interferon-\selectlanguage{greek}γ \selectlanguage{english}and IL-6, and virus endocytosis {[}\textbf{75-78}
{]}.

Aviptadil is an analogue of vasoactive intestinal polypeptide (VIP).
This drug is authorized for the treatment of erectile dysfunction,
sarcoidosis and acute lung damage. The rationale for its use for the
treatment of ARDS is based on the results from preclinical studies
showing that the VIP is highly concentrated in the lung, where it
prevents the activation of caspases NMDA-induced, inhibits IL-6 and
TNF-\selectlanguage{greek}α \selectlanguage{english}production and protects against HCl-induced pulmonary edema
{[}\textbf{79-81} {]}. In a clinical study, 8 patients with severe ARDS
were treated with ascending doses of the VIP. Of these patients, 7 were
successfully extubated and were alive at the five-day time point, 6 left
the hospital and 1 died due to a cardiac event {[}\textbf{82} {]}. A
phase II clinical trial based on patients with COVID-19 infection will
begin shortly.

Eculizumab is a monoclonal antibody approved for the treatment of
atypical hemolytic uremic syndrome, refractory generalized myasthenia
gravis and neuromyelitis spectrum disorders. It is an inhibitor of the
terminal portion of the complement cascade involved in the inflammatory
response. Even though the role of complement cascade in the pathogenesis
of SARS-CoV-2 infections is uncertain, many studies suggested that the
inhibition of complement activation might potentially work as a
therapeutic approach {[}\textbf{83-85} {]}. Based on these
considerations, eculizumab will be tested in the SOLID-C19 clinical
trial in the treatment of patients with severe SARS-CoV-2 and ARDS
{[}\textbf{86} {]}. A phase 2/3 randomized, open-label, study is
investigating the efficacy and safety of emapalumab, a monoclonal
antibody targeting interferon gamma (IFN\selectlanguage{greek}γ\selectlanguage{english}), and anakinra, an antagonist
of IL-1R, in reducing hyper-inflammation and respiratory distress in
patients with SARS-CoV-2 infection {[}\textbf{87} {]}. This study
received the approval by the AIFA {[}\textbf{88} {]}.

Finally, noteworthy is the use of corticosteroids. A recent document
released by the WHO specified that these drugs are adjunctive therapies
for COVID-19. Specifically, it is reported that, according to the
results of a systematic review of observational studies, the use of
corticosteroids in patients with SARS was not associated to survival
benefit {[}\textbf{89} {]}. Similarly, a further systematic review of
observational studies found a higher risk of mortality and secondary
infections with corticosteroids administered in patients with flu
{[}\textbf{90} {]}. However, this effect was not confirmed by a
subsequent study {[}\textbf{91} {]}. Therefore, the WHO recommend for
patients with COVID-19 to use corticosteroids only if they are indicated
for another reason such as exacerbation of asthma or COPD, septic shock
{[}\textbf{92} {]}. Literature data support that corticosteroids do not
add clinical benefits in the treatment of COVID-19 infection
{[}\textbf{93} {]}. On the other hand, some studies reported
improvements in SARS patients treated with methylprednisolone, also in
terms of reduction of IL-8, monocyte chemo-attractant protein-1 and Th1
chemokine IFN-\selectlanguage{greek}γ\selectlanguage{english}-\selectlanguage{english}inducible protein-10 {[}\textbf{94,95} {]}, while one
case reports described positive effects of methylprednisolone on
clinical outcomes of one patient with COVID-19 {[}\textbf{96} {]}. In
conclusion, considering that evidence available is quite conflicting
regarding to the use of corticosteroids in patients with COVID-19, as
recommended by the WHO, their use should underwent a case by case
evaluation.

\textbf{3. Other therapies and future perspectives}

Many other drugs with disparate mechanisms of actions are evaluated in
patients with COVID-19. For instance, a PD-1 immune checkpoint inhibitor
monoclonal antibody, camrelizumab, which recently received a conditional
approval in China for the treatment of relapsed or refractory classical
Hodgkin lymphoma, is evaluated in a phase 2 study involving patients
with SARS-Cov-2 infection. PD-1 and its ligand (PD-L1) are key mediators
in T cell depletion in patients with sepsis. Preclinical studies have
demonstrated that the blockade of PD-1 or PD-L1 can prevent T cell
death, regulate cytokine production and reduce organ dysfunction
{[}\textbf{97,98} {]}. The study was launched on February 2020 to verify
its efficacy in combination with thymosin in 120 patients with severe
pneumonia associated with lymphocytopenia {[}\textbf{99} {]}.

A further experimental monoclonal antibody for the treatment of COVID-19
is bevacizumab, approved for the treatment of metastatic colorectal
cancer, non-small cell lung cancer, metastatic breast cancer and
advanced and/or metastatic renal cell carcinoma. By binding to the
growth factor of vascular endothelial cells (VEGF), a key promoter of
vasculogenesis and angiogenesis, bevacizumab is able to prevent its
biological activity {[}\textbf{100,101} {]}. A key role of VEGF in acute
lung injury and ARDS was confirmed {[}\textbf{102} {]}. Based on these
findings, two clinical trials are currently evaluating the efficacy and
safety of bevacizumab in patients with COVID-19 (BEST-RCT and BEST-CP)
{[}\textbf{103,104} {]}.

Also for thalidomide, a drug widely used in the treatment of
Interstitial Pulmonary Fibrosis, lung damage from paraquat and myeloma,
a possible role for the treatment of COVID-19 was hypothesized. Indeed,
the drug has been reported to be effective against HIV
{[}\textbf{105,106} {]} by modulating TNF-a-induced replication.
Moreover, thalidomide suppresses the production of proinflammatory
cytokines such as TNF-alpha and IL-8 through the inhibition of NF-\selectlanguage{greek}κ\selectlanguage{english}B
{[}\textbf{107} {]}. Two studies are currently testing its efficacy in
patients with COVID19 {[}\textbf{108,109} {]}.

In addition, other drugs are currently evaluated in Chinese clinical
trials involving patients with COVID-19, including fingolimod
{[}\textbf{110} {]}, high-dose Vitamin C, adalimumab, piperaquine, and
leflunomide {[}\textbf{111} {]}. Lastly, considering the key role of
ACE2 for the attachment and cell entry of SARS-Cov-2, researchers
recently suggested that the development of specific neutralizing
monoclonal antibodies that bind to ACE2 might block the virus entry
{[}\textbf{112} {]}.

Lastly, given that the therapy for COVID-19 is dependent on the
patients' immune system, researchers are evaluating two possible
engineering therapies: expanded umbilical cord mesenchymal stem cells in
critically ill patients {[}\textbf{113} {]} and intravenous
immunoglobulin purified from IgG antibodies of patients who recovered
from COVID-19 {[}\textbf{114} {]}. Finally, the development of a vaccine
against SARS-CoV-2 is urgently needed. However, according to Shang W et
al., researchers would bring a new SARS-CoV-2-based vaccine in
approximately 16--20 weeks {[}\textbf{115} {]}. On March 2020, there
were 2 candidate vaccines in phase 1 development (studies
ChiCTR2000030906 and NCT04283461) and 42 candidate vaccines in
preclinical phase of evaluation {[}\textbf{116} {]}. Researchers from
the University of Pittsburgh School of Medicine announced a potential
vaccine against SARS-CoV-2 that was tested in mice and produced
antibodies specific to SARS-CoV-2 able to neutralize the virus
{[}\textbf{117} {]}. Furthermore, an experimental mRNA vaccine against
the pandemic coronavirus was already administered to one person in US
{[}\textbf{118} {]}.

\textbf{4. Conclusion}

Since the beginning of the outbreak, a large number of clinical studies
have been registered worldwide and several drugs were repurposed to face
the new health emergency of COVID-19. We described pharmacological
properties and available clinical data for several drugs, mainly
antiviral, immune-modulatory and anti-inflammatory agents. For many of
these drugs, including lopinavir/ritonavir, remdesivir, favipiravir,
chloroquine and tocilizumab, clinical evidence from literature and real
life settings support their favorable efficacy and safety profile in
improving patients' clinical conditions.

Considering that nowadays no specific treatments are available for
COVID-19, drugs repurposing is necessary but it requires caution.
Indeed, too many drugs that are currently tested in patients with
COVID-19 have an unknown efficacy profile; on the other hand, those with
proven efficacy have a peculiar safety profile, which calls for a strict
monitoring of treated patients. Therefore, patients treated with this
drug should undergo a routine monitoring. Furthermore, as reported by
The Liverpool Drug Interaction Group, particular attention should be
given at adverse events deriving from drug-drug interactions, which
could be very common in patients with COVID-19, given the huge amount of
pharmacological therapies to which they are subjected to {[}\textbf{119}
{]}.

Worldwide regulatory agencies are promoting all interventions to ensure
strategic coordination and guarantee access to effective and safe
medicines, though no proven specific therapies are available to prevent
or treat COVID-19. In addition, on March 18\textsuperscript{th} the EMA
and the US FDA jointly chaired the first global regulatory meeting
experts to support proceeding to first-in-human clinical studies
{[}\textbf{120} {]}. Since SARS-Cov-2 is still an unknown virus, we are
now learning its transmission mechanisms, clinical spectrum of disease,
diagnostics and lethality. While waiting for the results of clinical
studies demonstrating the efficacy of drugs able to reduce symptoms and
complications of COVID-19, the best therapeutic path to pursue is the
development of an effective vaccine able to prevent this infection.

\textbf{Acknowledgements} : We are grateful for the help and support of
the Italian Society of Pharmacology (SIF) and its Section of Clinical
Pharmacology ``Giampaolo Velo''.

\textbf{Competing Interests' Statement:}

None

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\end{enumerate}

\textbf{Hosted file}

\verb`table 1.docx`  available at \url{https://authorea.com/users/309980/articles/440841-current-pharmacological-treatments-for-covid-19-what-s-next}

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