European Journal of Pharmacology 889 (2020) 173644

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Full length article

Treatment for COVID-19: An overview

Cristina Stasi a, b, *, Silvia Fallani a, Fabio Voller a, Caterina Silvestri a
a
Epidemiology Unit, Tuscany Regional Health Agency, Florence, Italy
b
Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus-2 (SARS-CoV-2) that causes
COVID-19 a severe acute respiratory syndrome, a characteristic hyperinflammatory response, vascular damage, micro­
SARS-CoV-2 angiopathy, angiogenesis and widespread thrombosis. Four stages of COVID-19 have been identified: the first
Antiviral agents
stage is characterised by upper respiratory tract infection; the second by the onset of dyspnoea and pneumonia;
Inflammation inhibitors
the third by a worsening clinical scenario dominated by a cytokine storm and the consequent hyperinflammatory
Antirheumatic drugs
Low molecular weight heparins state; and the fourth by death or recovery. Currently, no treatment can act specifically against the SARS-CoV-2
infection. Based on the pathological features and different clinical phases of COVID-19, particularly in patients
with moderate to severe COVID-19, the classes of drugs used are antiviral agents, inflammation inhibitors/
antirheumatic drugs, low molecular weight heparins, plasma, and hyperimmune immunoglobulins. During this
emergency period of the COVID-19 outbreak, clinical researchers are using and testing a variety of possible
treatments. Based on these premises, this review aims to discuss the most updated pharmacological treatments to
effectively act against the SARS-CoV-2 infection and support researchers and clinicians in relation to any current
and future developments in curing COVID-19 patients.

1. Introduction cumulative dose of viral exposure and the efficacy of the local innate
immune response (IgA, IgM, MBL antibodies) is crucial in the evolution
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of COVID-19. In particular, this model identifies the first stage of
is an RNA virus genetically located within the genus Betacoronavirus COVID-19, which is characterised by upper respiratory tract infection,
that uses a glycoprotein (spike protein) to bind to the angiotensin- accompanied by fever, muscle fatigue and pain. Nausea or vomiting and
converting enzyme 2 (ACE2) receptor. After binding, the serine prote­ diarrhoea are infrequent in this initial stage of the disease. The second
ase TGRBSS2 facilitates virus entry into the cell (Matricardi et al., 2020). stage is characterised by the onset of dyspnoea and pneumonia.
The results of a recent study (Long et al., 2020) on COVID-19 patients The third stage is characterised by a worsening clinical scenario
showed that 100% of patients tested positive for IgG about 17–19 days dominated by a cytokine storm and the consequent hyperinflammatory
following the onset of symptomatology, with a peak of 94.1% after state that determines local and systemic consequences causing arterial
20–22 days. In addition, the study found that there was an increase in and venous vasculopathy in the lung with thrombosis of the small ves­
SARS-CoV-2 specific IgG and IgM antibody titres after the first 3 weeks sels and evolution towards serious lung lesions up to ARDS and in some
following the onset of symptomatology, but no correlation was found cases to disseminated intravascular coagulation (DIC) (Matricardi et al.,
between IgG levels and patients’ clinical characteristics (Long et al., 2020; Agenzia Italiana del Farmaco, 2020 a). Acute cardiac and renal
2020). Following infection with SARS-CoV-2 some infected individuals damage, sepsis and secondary infections were the other complications
may remain asymptomatic or only present with mild upper respiratory most frequently reported in this phase (Huang et al., 2020). The fourth
symptoms, others develop pneumonia and severe acute respiratory stage is characterised by death or recovery (Matricardi et al., 2020).
distress syndrome (ARDS) that requires intubation in intensive care and Mortality is associated with advanced age, the presence of comorbid­
presents complications with an inauspicious outcome. A model (Matri­ ities, greater disease severity, worsening of respiratory failure, high
cardi et al., 2020) has recently been published based on literature levels of D-Dimer and C-reactive protein, low lymphocyte counts and
studies in which it is emphasised that the balance between the infections (Agenzia Italiana del Farmaco, 2020 a).

* Corresponding author. Observatory of Epidemiology, Tuscany Regional Health Agency, Florence, Italy.
E-mail address: cristina.stasi@gmail.com (C. Stasi).

https://doi.org/10.1016/j.ejphar.2020.173644
Received 16 July 2020; Received in revised form 3 October 2020; Accepted 8 October 2020
Available online 11 October 2020
0014-2999/© 2020 Elsevier B.V. All rights reserved.
C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

Currently, no treatment is very effective in treating the SARS-CoV-2 results of data analysis of the compassionate use of remdesivir in a small
infection, but the classes of drugs that are mainly used include antiviral cohort of severe COVID-19 patients. Clinical improvement was found in
agents, inflammation inhibitors, low-molecular-weight heparins, 36 out of 53 patients in whom it was possible to analyse the data (68%).
plasma, and hyperimmune immunoglobulins. Based on the pathological Of the sixty-one subjects that underwent remdesivir treatment, statistics
features and different clinical stages of COVID-19, clinical researchers from eight of these were not analysed (7 subjects had no post-treatment
are using and testing a variety of possible treatments. In the early stages data and 1 had a dosage error). Of the fifty-three subjects for whom it
of SARS-CoV-2 infections, antiviral agents could prevent the progression was viable to analyse the data, thirty subjects (57%) underwent me­
of the disease, whilst immunomodulatory plus antiviral agents appear to chanical ventilation and four (8%) received extracorporeal membrane
improve clinical outcomes in patients with critical COVID-19. oxygenation. Patients receiving invasive ventilation were older than
Based on these premises, this review aims to discuss the above those receiving non-invasive oxygen help at baseline, they were mainly
mentioned pharmacological treatments to combat the infection and men, had greater ranges of alanine aminotransferase (ALT) and creati­
support researchers and clinicians in current and future developments nine and a greater occurrence of comorbidities, such as hypertension,
for curing COVID-19 patients. More specifically, this review summarises diabetes, hyperlipidaemia and bronchial asthma. Although limited, the
the main therapeutic strategies that have been proposed so far for study results show that remdesivir may also have therapeutic advan­
COVID-19 in randomised controlled trials, clinical and experimental tages in patients with severe Covid-19.
research studies, case series, and observational retrospective and lon­ Goldman et al. (2020) published the first results of the phase 3 trial
gitudinal studies, providing a summary (Table 1) of the different classes (randomised, open-label) on the use of remdesivir in hospitalised pa­
of drugs used and also highlighting the different stages in which these tients. Remdesivir was administrated for 5 or 10 days in patients with
drugs improve symptomatology or decrease the mortality rate. severe Covid-19. Patients who received concomitant treatment (within
24 h before starting remdesivir treatment) with other potentially active
2. Treatment for COVID-19 drugs against Covid-19 were excluded. Patients were randomly divided
in a 1:1 ratio for intravenous administration of remdesivir for 5 or 10
2.1. Antiviral agents days at a dosage of 200 mg on day 1 and 100 mg once a day on the
following days. The primary endpoint of the trial was to evaluate the
Several protease inhibitors (e.g. darunavir, atazanavir) currently clinical status on day 14. Three hundred and ninety-seven patients were
used for treating HIV could inhibit the viral replication of SARS-CoV-2 randomised (200 patients in the group on therapy for 5 days and 197 on
by inactivating the proteases, which are fundamental for replication. therapy for 10 days).
The Italian Medicines Agency (Agenzia Italiana del Farmaco - AIFA) Among those who did not participate in the entire therapy for 10
approved the ARCO-Home study that aims to test the efficacy of days, motives included clinic discharge, unfavourable events and dying
darunavir-cobicistat, lopinavir-ritonavir, favipiravir and hydroxy­ (6%). On day 14, clinical improvement was found in 64% of patients in
chloroquine as therapies at home in an early COVID-19 population to the 5-day treatment group and 54% in the 10-day group. The authors
prevent the progression of the infection towards serious or critical conclude that the effects discovered exhibit no great distinction in
clinical forms with the need to resort to hospitalisation and invasive effectiveness between a 5-day and a 10-day cycle of intravenous
procedures such as intubation (Documents - AIFA, 2020). administration of remdesivir in patients with severe Covid-19 who
We will review herein some of the evidence on treatment with pro­ required mechanical ventilation at baseline, and although further
tease inhibitors, nucleotide analogues, and new antiviral agents in the studies on high-risk groups are needed to establish the shortest period of
treatment of different stages of COVID-19. therapy, they suggest that patients undergoing mechanical ventilation
could benefit from 10-day treatment with remdesivir.
2.1.1. Lopinavir/ritonavir A new randomised controlled trial (NCT04280705) was conducted
The main drugs used in the context of the national emergency on 1063 patients, with the same dosing cycle and administered dose of
management plan for COVID-19 include lopinavir/ritonavir, which is remdesivir used in the compassionate use of this antiviral agent in a
mainly used in COVID-19 patients with less severe symptoms and in the small cohort of patients (Beigel et al., 2020). Beigel et al. (2020) pre­
early stages of the disease, managed both at home and in the hospital. sented data on 1059 patients, including 538 assigned remdesivir and
Previous experiences with SARS-CoV-1 and MERS infections suggest 521 on placebos. Sixty main and 13 secondary centres were involved in
that this drug may improve some patients’ clinical parameters (Gul this trial. The average age of the patients was 58.9 years and 64.3% were
et al., 2020). A randomised, controlled, open-label study on oral male. Available data showed that patients assigned remdesivir treat­
lopinavir-ritonavir for severe COVID-19 involved 199 hospitalised adult ment had an average hospitalisation time of 11 days, compared to 15
patients infected by SARS-CoV-2 (Cao et al., 2020). In addition to the days on placebos, with a mortality estimate of 7.1% in
infection criterion, the enrolled patients had an oxygen saturation remdesivir-treated patients compared to 11.9% of those on placebos.
(SaO2) of 94% or less during respiration in ambient air or a ratio be­ The results of the study suggest starting remdesivir treatment early
tween partial oxygen pressure (PaO2) and inspired oxygen fraction before lung disease progression requiring mechanical ventilation.
(FiO2) of less than 300 mm Hg. Patients were randomly assigned to Based on these studies, our opinion is that some antivirals are
receive lopinavir-ritonavir in addition to standard therapy. The control promising in paucisymptomatic patients to prevent the progression of
group was treated with standard care only (N = 100 patients). The the SARS-CoV-2 infection (U. S. National Library of Medicine. Clin­
primary endpoint was the time to clinical improvement. Despite the icalTrial.gov, 2020a; U. S. National Library of Medicine. ClinicalTrial.
important effort of the researchers who carried out a randomised clinical gov, 2020b.) and remdesivir appears to shorten recovery times for
trial during a pandemic emergency, the results did not have the expected hospitalised patients (Fig. 1).
effects. Lopinavir-ritonavir therapy was not associated with significant
clinical improvements compared to standard therapy, nor was it asso­ 2.1.3. New molecules
ciated with improvements in 28-day mortality and the nasopharyngeal Dai et al. (2020) developed 2 molecules capable of blocking the
persistence of viral RNA detected at different time points. protease enzyme that allows replication of SARS-CoV-2: molecules 11a
and 11b. To verify the enzyme’s inhibitory activity, the research team
2.1.2. Remdesivir assessed the capacity of these molecules to interfere with SARS-CoV-2
Remdesivir, belonging to the class of nucleotide analogues, was activity in cell cultures in vitro. Both molecules showed satisfactory
previously used in the Ebola virus epidemic in Africa and is currently anti-SARS-CoV-2 activity in cell culture. Furthermore, neither of the two
used in moderate and severe COVID-19. Grein et al. (2020) described the compounds caused significant cytotoxicity. Both the

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C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

Table 1
Main characteristics of the overviewed studies and their findings.
Studies, Year Study Design Main inclusion criteria No of patients/ Interventions/treatments Findings
Enrollment

Cao, B. et al., 2020. Randomised, Hospitalised adult SARS- 199 patients Patients randomly assigned Similar mortality rate observed
Chinese Clinical Trial Register controlled, open- CoV-2 infected patients, January 18, (1:1) to receive either in lopinavir – ritonavir group
number, ChiCTR2000029308. label trial and 94% SaO2 (ambient 2020–February 3, lopinavir-ritonavir (400 mg and and SOC group (19.2% vs.
air) or a PaO2/Fio2 ratio 2020. 100 mg, respectively) b.id. for 25.0%; difference, − 5.8
< 300 mm Hg 14 days plus SOC or SOC alone. percentage points; [95% CI,
− 17.3 to 5.7]).
No benefit observed in
Lopinavir–Ritonavir group vs
SOC group.
Grein, J. et al., 2020. Compassionate- Hospitalised adult SARS- 53 patients Patients received a 10-day Clinical improvement
use cohort. CoV-2 infected patients January 25, 2020,- course of Remdesivir (200 mg i. observed in 36 of 53 patients
and 94% SaO2 (ambient March 7, 2020 v. on day 1, and 100 mg daily (68%).
air) or receiving oxygen for the remaining 9 days)
support
Beigel, J.H. et al., 2020. Double-blind, Hospitalised adult SARS- 1063 patients Patients randomly assigned to A 10-day course of Remdesivir
ClinicalTrials.gov Register randomised, CoV-2 infected patients February 21, receive either Remdesivir (200 was superior to placebo in
number, NCT04280705. placebo-controlled and ≤94% SaO2 2020–April 19, 2020 mg on day 1, and 100 mg daily number of days to recovery
trial for up to 9 additional days) or (median, 11 vs 15 days;
placebo for up to 10 days recovery rate ratio, 1.32 [95%
CI, 1.12 to 1.55]) and in
recovery according to ordinal
scale score at day 15 (OR, 1.50;
95% CI, 1.18 to 1.91).
Guaraldi, Gul et al., 2020. Retrospective, Adults (≥18 years) with 1351 patients All patients treated with SOC Reduced risk of invasive
observational severe COVID-19 February 21, (ie, supplemental oxygen, mechanical ventilation or
cohort study pneumonia, admitted to 2020–April 30, hydroxychloroquine, death (AHR: 0⋅61, 95% [CI
tertiary care centres 2020. azithromycin, antiretrovirals, 0⋅40–0⋅92]; p = 0⋅020)
and low molecular weight observed in Tocilizumab group
heparin), and a non-randomly
patients’ selected subset also
received tocilizumab.
Cantini, F. et al., 2020. Observational, Hospitalised adults with 191 patients 113 patients treated for 2 weeks 2-week case fatality rate was
retrospective, COVID-19 moderate February 20, with Baricitinib 4 mg/day p.o. significantly lower in the
longitudinal study pneumonia 2020–May 5, 2020. plus lopinavir/ritonavir tablets Baricitinib-arm vs controls;
250 mg/bid; ICU admission was requested
Control-arm: 78 patients in 0.88% (1/113) vs 17.9%
treated with (14/78) patients in baricitinib-
hydroxychloroquine plus arm vs control-arm; discharge
lopinavir/ritonavir. rate was significantly higher in
the Baricitinib-arm.
RECOVERY Collaborative Group, - Randomised 1. Aged at least 18 years 11,303 patients Drug: Lopinavir-Ritonavir Among patients in ordinary
2020. controlled, open- 2. Hospitalised March 19, Drug: Corticosteroid care program, 28-day
Clinicaltrial.gov Register label trial 3. SARS-CoV-2 infection 2020–June 8, 2020 Drug: Hydroxychloroquine mortality was higher or
number (suspected or confirmed) Drug: Azithromycin Biological: intermediate in those needed
NCT04381936 4. No medical history that Convalescent plasma ventilation or only oxygen,
might, in the opinion of Drug: Tocilizumab respectively.
the attending clinician, In dexamethasone group,
put the patient at mortality was 1/3 lower in
significant risk if he/she ventilated patients and 1/5
were to participate in the lower in oxygen-treated
trial subjects.
Follow-up was completed for
over 94% of the enrolled
patients.
Tang, N. et al., 2020. Retrospective, Hospitalised adult 449 patients All patients received antivirals No difference in 28-day
cohort study patients with severe January 1, and appropriate supportive mortality in heparin users and
COVID-19 2020–February 13, therapies after admission. nonusers (30.3% vs 29.7%, P
2020 Ninety-nine (22.0%) patients = 0.910).
received heparin treatment for The 28-day mortality of
up to 7 days. heparin users was lower than
nonusers in patients with SIC
score ≥4 (40.0% vs 64.2%, P
= 0.029), or D-dimer >6-fold
of upper limit of normal
(32.8% vs 52.4%, P = 0.017).
Shen, Cao et al., 2020. Case series Adult COVID-19 patients 5 patients Patients received convalescent Improvement in clinical status
and ARDS and the January 20, plasma (between 10 and 22
following criteria: severe 2020–March 25, days after admission) with a
pneumonia with rapid 2020 SARS-CoV-2-specific antibody
progression and (IgG) binding titer > 1:1000
continuously high viral and a neutralization titer > 40
load despite antiviral obtained from 5 recovered
treatment; PaO2/FiO2 COVID-19 patients
(continued on next page)

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C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

Table 1 (continued )
Studies, Year Study Design Main inclusion criteria No of patients/ Interventions/treatments Findings
Enrollment

<300; and mechanical

ventilation.
Goldman, J.D. et al., 2020 Randomised, Hospitalised patients 397 patients Patients randomly assigned By day 14, a clinical
Clinicaltrial.gov Register open-label trial (age>12 years) SARS- (1:1) to receive Remdesivir i.v. improvement >2 points on the
number CoV-2 infection for either 5 days or 10 days ordinal scale occurred in 64%
NCT04292899 confirmed by PCR within (200 mg on day 1 and 100 mg of patients in 5-day group and
4 days before daily on subsequent days). in 54% in 10-day group.
randomization After adjustment for baseline
No mechanically clinical status, similar clinical
ventilated status at day 14 was found in
10-day group and 5-day group
(P = 0.14).
Adaptive Randomised trial for Multi-arm parallel Adult (age ≥18 years) Expected sample Control arm. No specific Ongoing
therapy of COrona virus randomised with confirmed SARS- size: 175–435 within antiviral treatment. No results available
disease 2019 at home with oral controlled clinical CoV-2 infection, two months of the Arm-1. One tablet of Darunavir
antivirals (ARCO-Home trial - (five-arms). symptomatic for < 5 days start of the project (800 mg) + Cobicistat (150 mg)
study), 2020 before starting therapy (April 20, 2020). for 14 days.
Eu CT number: and without criteria for Arm-2. Two tablets of
2020-001528-32 immediate Hydroxychloroquine (each
hospitalisation. tablet = 200 mg) b.i.d. on day 1
and one tablet b.i.d. on day 2 to
day 10.
Arm-3. Two tablets of
Lopinavir/Ritonavir b.i.d. for
14 days. Each tablet contains
200 mg of Lopinavir and 50 mg
of Ritonavir.
Arm-4. Nine tablets of
favipiravir (each tablet = 200
mg) b.i.d. on day 1 and 4 tablets
b.i.d. on day 2 to day 10.
A randomised, double-blind, Randomised, Adult hospitalised 330 patients (Date of Patients randomly assigned Ongoing
placebo-controlled, double-blind, patients with severe Approval: March 30, (2:1) to receive blinded No results available
multicenter study to evaluate placebo-controlled COVID-19 pneumonia 2020) treatment of either Tocilizumab
the safety and efficacy of (one or two doses of
tocilizumab in patients with tocilizumab i.v., at a dose of 8
severe covid-19 pneumonia, mg/kg to a maximum of 800 mg
2020 per dose) or a matching placebo
Eu CT number: 2020-001154- (one or two doses),
22 respectively.
Efficacy and Safety of Open label, Hospitalised SARS-CoV-2 54 patients Active arm: Emapalumab No results available
Emapalumab and Anakinra in controlled, parallel infected patients (age > (Date of Approval: (infusion every 3rd day for a
Reducing Hyperinflammation group, 3-arm 30 to < 80 years), April 20, 2020) total 5 infusions, at day 1: 6
and Respiratory Distress in diagnosis as per hospital mg/kg and at the other days: 3
Patients With COVID-19 routine mg/kg)
Infection, 2020 Active arm: Anakinra (400 mg/
Clinicaltrial.gov Register day in total, divided into 4
number doses given every 6 h for 15
NCT04324021 days)No Intervention: SOC
according to local practice
BARICIVID-19 STUDY: Multicenter Adult hospitalised 126 patients All patients were treated with No results available
MultiCentre, randomised, randomised patients COVID-19 (Date of Approval: SOC.
Phase IIa clinical trial controlled PoC pneumonia April 22, 2020) 63 patients received baricitinib
evaluating efficacy and (phase IIa) clinical 4 mg p.o., 1 tablet daily for 14
tolerability of Baricitinib as trial days.
add-on treatment of patients Patients with eGFR >30 and <
with COVID-19 compared to 60 mL/min and those with age
standard therapy, 2020 >75 years was treated with ½
Eu CT number: 2020-001955- tablet daily (2 mg) for 14 days.
42 The control group (63 patients)
was treated with SOC
U. S. National Library of Randomised, Adults hospitalised with 500 patients Active arm: Convalescent No results available
Medicine. ClinicalTrial.gov, Parallel COVID-19 infection (Date of Approval: Plasma
2020 b. Convalescent Plasma Assignment August 4, 2020) 450–550 mL of plasma
vs. Standard Plasma for containing anti-SARS-CoV-2
COVID-19, 2020 antibody titer ideally > 1:320
Clinicaltrial.gov Register (minimum titer per FDA
number Guidelines for convalescent
NCT04344535 plasma).Control arm: Standard
Donor Plasma
450–550 mL of plasma with low
titer to anti-SARS-CoV-2
antibodies

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C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

Abbreviations: SaO2: oxygen saturation; PaO2/Fio2 ratio: partial oxygen pressure (PaO2)/inspired oxygen fraction (FiO2); b.i.d.: bis in die; SOC: standard of care; i.v.:
intravenous; CI: confidence interval; OR: Odds ratio; ARDS: acute respiratory distress syndrome; PCR: polymerase-chain-reaction; AHR: adjusted hazard ratio; p.o.: per
os.

intraperitoneally). Further pharmacokinetic trials (area under the curve

- AUC, half-life and clearance rate) of the intravenous compounds sug­
gested further studies on compound 11a. An in vivo toxicity study,
conducted on animals, did not demonstrate obvious toxicity by sug­
gesting that molecule 11a may represent a good candidate for human
clinical trials.

2.2. Immunomodulatory drugs

Numerous experimental and clinical pieces of evidence have shown

that an important part of the damage caused by the virus is linked to an
altered inflammatory response and, in some patients, to an abnormal
release of pro-inflammatory cytokines such as interleukin-6 (IL-6),
interferon-gamma, and tumour necrosis factor alpha. For this reason, in
addition to being based on previous experience demonstrated in patients
with SARS, anti-inflammatory drugs (particularly monoclonal anti­
bodies) are used in the COVID-19 emergency, which have been used in
rheumatology for some years to inhibit the immune response. In this
section, we will discuss the possible role played by anti-IL6, anti-IL-1,
JAK inhibitors, corticosteroids, antimalarials, heparins, and immuno­
globulins, particularly in the treatment of moderate/severe COVID-19.

2.3. Tocilizumab

The most used drug in the therapy of COVID-19 was Tocilizumab

(antibody directed against the Il-6 receptor). This drug was authorised
by AIFA on 3 April in a phase III, multicentre, randomised, double-blind
Fig. 1. A proposed potential therapeutic algorithm based on current studies
study to investigate its safety and efficacy (Agenzia Italiana del Farmaco,
and clinical trials
§ In the early stages of COVID-19, one or a combination of antiviral agents
2020b). Subsequently, AIFA made a summary of the Italian
could be used as a prophylactic or early treatment option to decrease viral load, non-comparative study on tocilizumab “TOCIVID-19′′ available, pro­
transmission and prevent progression to the later stage of the disease. The early moted by the National Cancer Institute of Naples. Although it has some
treatment is under evaluation in some clinical trials (U. S. National Library of limitations, the results suggest that the drug can significantly reduce
Medicine. ClinicalTrial.gov, 2020a; U. S. National Library of Medicine. Clin­ mortality at one month, while its impact is less relevant on early mor­
icalTrial.gov, 2020b) tality (14 days) (Executive summary – AIFA, 2020). The results of the
*In the early stage, specific adjustment of glucocorticoid therapy could be retrospective observational cohort study by Guaraldi et al. (2020)
needed based on specific reasons (i.e. in adrenal insufficient patients (Isidori included adults (≥18 years) with severe COVID-19 pneumonia, hospi­
et al., 2000)). WHO suggests not to use corticosteroids in the treatment of pa­ talised at the tertiary care centres of Bologna and Reggio Emilia between
tients with non-severe COVID-19 as the treatment brought no benefits (World
21 February and March 24, 2020, and at a tertiary assistance centre in
Health Organization, 2020 b).** Based on the clinical status, anticoagulants
Modena between 21 February and April 30, 2020. The purpose of this
could be administered to prevent thrombotic phenomena starting from the
pulmonary circulation as a consequence of hyperinflammation. multicentre study was to evaluate the efficacy of Tocilizumab treatment
Several studies showed that inflammatory cytokines (Il-1, IL-6), c-reactive in addition to usual care in reducing mortality and the likelihood of
proteins (CPR), fibrinogen, D-Dimer, ferritin and other biomarkers are signifi­ invasive mechanical ventilation in a cohort of patients with severe
cantly elevated in patients with more advanced disease. Therefore, specific COVID-19 pneumonia compared to the cohort of patients who received
immunomodulators and corticosteroids are useful to counteract and prevent the standard treatment.
cytokine storm and anticoagulants to prevent thrombotic events. The antiviral Patients were regarded as eligible for tocilizumab therapy if they had
remdesivir appears to shorten recovery times for hospitalised patients. a SaO2 of less than 93% and a partial oxygen pressure (PaO2)/inspired
oxygen fraction (FiO2) ratio of less than 300 mm Hg in ambient air or a
immunofluorescence method and the quantitative PCR (Polymerase reduction of over 30% in the PaO2/FiO2 ratio in the 24 h preceding
Chain Reaction) were used to detect the antiviral activity of 11a and 11b hospitalisation. Of the 1351 patients admitted, 544 (40%) with severe
in real-time. Study results showed that 11a and 11b had an acceptable COVID-19 pneumonia were included in the study. The usual care group
antiviral effect on SARS-CoV-2. To discover the further pharmacological included older patients with less severe cases of the disease and the
potential of 11a and 11b molecules, both have been investigated for group treated with intravenous tocilizumab included the most
their pharmacokinetic properties in animal experiments. The intraperi­ compromised patients. Of the 365 patients treated with the usual care,
toneal and intravenous administration of compound 11a had a half-life 57 (16%) needed mechanical ventilation, whilst of the 179 patients
(T1/2) of 4.27 h and 4.41 h, respectively, a high maximum concentra­ treated with tocilizumab, 33 (18%) needed mechanical ventilation. New
tion (Cmax = 2394 ng/mL), and a bioavailability of 87.8% when com­ episodes of infection were carefully monitored in the group treated with
pound 11a was administered intraperitoneally. The metabolic stability tocilizumab compared to the group with standard therapy, of the 179
of 11a in mice was also good. Compound 11b, when administered total patients who underwent tocilizumab treatment, new infections
intraperitoneally (20 mg/kg), subcutaneously (5 mg/kg) and intrave­ were diagnosed in 24 patients (13%), compared to 14 (4%) of the 365
nously (5 mg/kg), showed good pharmacokinetic properties (intraperi­ patients treated with usual care. 20% of the patients treated with usual
toneal and subcutaneous bioavailability was 80% greater, and a half-life care died, compared with 7% of patients treated with tocilizumab. The
longer than 5.21 h was recorded when 11b was administered authors concluded that both the intravenous and subcutaneous

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C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

administration of tocilizumab may be able to reduce the risk of invasive inflammation, such as worsening lymphocytopenia (a marker of pro­
mechanical ventilation or death in patients with severe COVID-19 gression and severity of COVID-19) and assessment of classification of
pneumonia. Even if the results of the study are promising, they should C-reactive as an indication of worsening inflammation. The dose and
be confirmed through ongoing randomised trials. administration of anakinra are particularly relevant. Due to its short
On 17 June, the preliminary results of the “RCT-TCZ-COVID-19 - plasma half-life, both intravenous and subcutaneous administration
Early Administration of Tocilizumab” study, which was carried out in 24 should be taken into consideration. A short half-life is useful to limit the
Italian centres, were published on the AIFA website (Agenzia Italiana del duration of the drug’s action in case of adverse effects, but variation in
Farmaco, 2020c). This multi-centre, open-label study mainly aimed to the dosage must be avoided for a constant and guaranteed bioavail­
evaluate the effectiveness of the early administration of tocilizumab in ability and to avoid a harmful rebound of inflammation. Pharmacoki­
patients with COVID-19 pneumonia. netic studies have shown that the subcutaneous route could guarantee
The study estimated the enrolment of 398 patients, but the analysis an adequate plasma concentration with a bioavailability ranging from
of data carried out on 123 enrolled patients showed a similar rate of 80 to 95%. The studies conducted so far report different endpoints in
aggravation in the first two weeks in patients randomised to receive most cases. The authors therefore suggest, in current and future studies,
tocilizumab compared to patients randomised to receive standard a fundamental core of data. The effectiveness of emapalumab, a
therapy (28.3% vs. 27.0%). No significant differences were observed in monoclonal anti-interferon gamma antibody, and anakinra, a receptor
the total number of ICU admissions (10.0% vs 7.9%) and 30-day mor­ antagonist for IL-1, are being evaluated in a phase 2/3, in a multi-centre
tality rate (3.3% vs 3.2%). The researchers therefore concluded that the study aimed at reducing hyperinflammation and respiratory distress in
early administration of tocilizumab in patients with COVID-19 pneu­ patients with the new coronavirus infection (U. S. National Library of
monia does not provide any relevant clinical benefit for patients. Medicine. ClinicalTrial.gov, 2020c).
Simultaneously, they stressed the need for further investigation to
evaluate the efficacy of the drug in specific patient subgroups. 2.3.2. Baricitinib
At the Azienda Socio Sanitaria Territoriale (ASST or Local Healthcare Richardson et al. (2020) suggest baricitinib as a possible therapy for
Area) Spedali Civili di Brescia, the data of 1525 patients with rheumatic acute respiratory disease caused by COVID-19. Baricitinib is an inhibitor
or musculoskeletal diseases were collected (Fredi et al., 2020): 117 (8%) of Janus kinases (enzymes involved in the transduction of the
presented symptoms compatible with COVID-19, of whom 65 returned a cytokine-mediated signal). The Italian Medicines Agency (Agenzia Ital­
positive SARS-CoV-2 swab, while 52 had a spectrum of symptoms iana del Farmaco, 2020a) authorised a clinical trial, which is currently in
indicative of COVID-19 but had not been tested with a swab. Patients progress, on the use of baricitinib as an add-on treatment in patients
with confirmed COVID-19 were older than those with suspected with COVID-19 compared to standard therapy. The primary objective is
COVID-19 (average age of 68 and 57 respectively) and were more likely to evaluate the effectiveness of baricitinib in decreasing the need for
to have high blood pressure (51% vs 27%) and be obese (17% vs 2%). invasive ventilation after 7 and 14 days of treatment. The secondary
There were no differences in rheumatologic disease or background objectives were to evaluate: the mortality rate 14 and 28 days after
therapy between confirmed and suspected COVID-19 patients. Of the 65 randomization; the invasive mechanical ventilation time; independence
patients with confirmed COVID-19, 47 (72%) developed pneumonia that from non-invasive mechanical ventilation; independence from oxygen
required hospitalisation. There were 12 (10%) deaths among the total therapy; improvement of oxygenation for at least 48 h; the length of
117 patients with confirmed or suspected COVID-19 (ten of them had hospital stay and stay in intensive care; the instrumental response
confirmed COVID-19 and two of them had suspected COVID-19). Pa­ (pulmonary ultrasound); and the description of the toxicity of bar­
tients who died with confirmed COVID-19 were older than patients who icitinib. Cantini et al. (2020) conducted an observational, retrospective,
survived. The case-control study included 26 patients with rheumatic longitudinal multi-centre study in 7 Italian hospitals with COVID-19
and musculoskeletal diseases and COVID-19 pneumonia and 62 corre­ moderate pneumonia patients to evaluate the 2-week effectiveness and
sponding controls. There was no significant difference between cases safety of baricitinib plus antivirals (lopinavir/ritonavir) compared with
and controls in the duration of COVID-19 symptoms before admission, the standard of care therapy. In this study, 113 patients were treated
the length of hospital stays or the Brescia-COVID Respiratory Severity with baricitinib and 78 were treated with usual care. The results showed
Scale score. Of 26 patients, glucocorticoids were used in 17 (65%) for that the 2-week case fatality rate was significantly lower in patients
severe respiratory manifestations related to lung involvement, while treated with baricitinib compared with controls. Moreover, as high­
tocilizumab was used in six (23%); thrombotic events occurred in four lighted by the authors, treatment with baricitinib was started in the
(15%) out of 26 cases. Four (15%) out of 26 cases and six (10%) out of 62 early phase of the COVID-19 disease (the median time was 7-days from
controls died during the study period. In patients with rheumatic and the onset of symptomatology), which may explain the low number of
musculoskeletal diseases, the poor prognosis was associated with older intensive care unit admissions and deaths.
age and the presence of comorbidities.
2.3.3. Corticosteroids
2.3.1. Anakinra COVID-19 patients over the age of 18 may be invited to participate in
A recent letter by Mehta et al. (2020) suggested that screening the UK’s randomised RECOVERY Trial (Randomised evaluation, 2020).
COVID-19 patients for hyper inflammation and subsequently treating The RECOVERY Trial aims to identify effective drugs in the treatment of
them with immunosuppressant drugs could improve mortality rates. adults hospitalised with COVID-19, particularly focusing on: low dosage
These include anakinra inhibitors IL-1α and IL-1β proinflammatory cy­ dexamethasone; lopinavir-ritonavir; hydroxychloroquine; azi­
tokines, which were administered with some benefit in the treatment of thromycin; and tocilizumab. The trial is designed to have the lowest
macrophage activation syndrome caused by various inflammatory con­ possible impact on the health service. The trial data are periodically
ditions and were also administered in several studies on patients with reviewed so that any effective treatment identified can be quickly made
COVID-19. King et al. (2020) support this scientific background for available to all patients. There are currently 170 centres and 6232 pa­
targeting hyperinflammation with anakinra in COVID-19 patients, tients involved in the United Kingdom. Preliminary results (Horby et al.,
emphasising several aspects of its use, patient selection, dosage and 2020) of the randomised RECOVERY clinical trial aimed at evaluating
outcome measures. Although it has been found that serum ferritin and the efficacy of potential treatments for COVID-19, including low-dose
IL-6 levels are highly associated with hyperinflammation, in the absence dexamethasone (corticosteroid), have recently been published. Alto­
of validated diagnostic criteria, recognition is often delayed. The authors gether, the study enrolled 11,500 patients from over 175 NHS hospitals
suggest a practical approach to patient selection dependent on the in the UK. In terms of the cohort referred for the use of dexamethasone,
investigation of the presence of severe COVID-19 and increased 2104 patients were randomly enrolled for the administration of

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dexamethasone 6 mg once a day (intravenously or orally) for ten days, inflammatory and coagulative parameters was observed, including
compared with a control group consisting of 4321 randomised patients increased levels of the fragments of degradation of fibrin such as D-
who were only administered ordinary treatments. Among patients un­ dimer, consumption of coagulation factors, thrombocytopenia, etc.
dergoing the ordinary care programme, 28-day mortality was higher or Therefore, in this stage, the goal should be the containment of hyper­
intermediate in those who needed ventilation or only oxygen, respec­ inflammation and its consequences (for example with biological drugs)
tively. In the dexamethasone group, mortality was one third lower in and therapeutic doses of non-fractionated LMWH or heparins, which are
ventilated patients and one fifth lower in oxygen-treated subjects. known for their anticoagulant properties (Agenzia Italiana del Farmaco,
Follow-up was completed for over 94% of the enrolled patients. 2020 a).
WHO suggests not to use corticosteroids in non-severe COVID-19 as Although not a specific drug for the treatment of COVID-19 patients,
the treatment brought no benefits (World Health Organization, 2020 b). based on results highlighted in some scientific studies, AIFA included
Based on the research conducted so far, monoclonal antibodies low-molecular-weight heparins among the drugs that can be used in the
against specific cytokines and corticosteroids are useful to counteract treatment of this pathology, providing useful elements to guide clini­
and prevent the cytokine storm, and they appear to improve clinical cians when prescribing (Agenzia Italiana del Farmaco, 2020a). More­
outcomes in patients with critical stage COVID-19 (Fig. 1). over, as part of the COVID-19 emergency, the evaluation of all clinical
trials on drugs has been entrusted to AIFA (Italian Care Law Decree Art.
2.3.4. Chloroquine and hydroxychloroquine 17).
Chloroquine and hydroxychloroquine are drugs with antiviral ac­ A retrospective analysis (Tang et al., 2020) of 415 consecutive cases
tivity that both also have immunomodulatory activity that could syn­ of severe COVID-19 pneumonia patients in Wuhan hospital suggests that
ergistically enhance the antiviral effect in vivo. As with other drugs, in patients in whom coagulation activation is demonstrated, adminis­
even in this case, the current state of emergency has meant that the tration of heparin for at least 7 days may result in an advantage in terms
aminocholine chloroquine and hydroxychloroquine, widely used for of survival. LMWH can be used in the initial stage of the disease when
malaria and rheumatic disease treatment, were also used on COVID-19 pneumonia is present and the patient suffers hypomobility at bedtime,
due to the anti-inflammatory and antiviral effects of both. An interna­ as prophylaxis of venous thromboembolism, or in the more advanced
tional multi-centre analysis, subsequently retracted (Mehra et al., 2020), stage, in hospitalised patients with thrombotic phenomena starting from
investigated the use of hydroxychloroquine or chloroquine with or the pulmonary circulation as a consequence of hyperinflammation.
without macrolides (azithromycin and clarithromycin, which are anti­ To the best of our knowledge, in the context of the management of
biotics with immunomodulatory and anti-inflammatory effects) for the critically ill patients with COVID-19, it seems of fundamental impor­
treatment of COVID-19. The study included data from 671 hospitals on tance to prevent the complication of venous thromboembolism through
six continents. Hospitalised patients with positive laboratory results for pharmacological prophylaxis (Fig. 1).
SARS-CoV-2 between December 20, 2019 and April 14, 2020 were
included. Overall, the data covered 96,032 patients (average age of 53.8 2.3.6. Therapeutic antibodies
years and 46.3% women) with COVID-19 who were hospitalised during Antibodies taken from the blood of recovered patients serve as a
the study period and met the inclusion criteria. The results of this large therapeutic alternative that is presently under study. It is estimated that
multi-centre observational analysis showed that each of the pharmaco­ the dose of antibodies critical for treating a person affected with SARS-
logical regimens examined (chloroquine or hydroxychloroquine alone CoV-2 requires the removal of antibodies from at least three patients
or in combination with a macrolide) were associated with an increased who have recovered from the SARS-CoV-2 infection. The short period
risk of the (clinically significant) onset of arrhythmias ventricular and between the pandemic and the treatment under consideration means
increased risk of in-hospital death. This result was associated with the that few pieces of evidence are currently available on the safety and
cardiovascular toxicity of chloroquine and hydroxychloroquine, partic­ efficacy of the use of plasma and hyperimmune immunoglobulins in the
ularly because of their known relationship with electrical instability treatment of patients with SARS-CoV-2 infections. One of the first
characterised by the prolongation of the QT interval (this interval ex­ studies on the use of plasma in the treatment of patients with SARS-CoV-
presses the time it takes for the ventricular myocardium to depolarise 2 infections was conducted on 5 COVID-19 patients (Shen et al., 2020),
and repolarise). This propensity is greater in subjects with cardiovas­ which was then followed by many other studies, mostly on a small
cular problems and heart injuries. As this was an observational study, number of patients. The main results of the studies conducted so far
the authors highlight the presence of numerous biases. However, the reported clinical and survival improvement in all patients after the end
results indicate that these treatments should not be used outside of of the additional intervention with plasma and hyperimmune immu­
clinical trials and that they require “urgent” confirmation through noglobulins. These findings need to be confirmed through some rando­
randomised clinical trials. On June 17, 2020, the World Health Orga­ mised clinical trials (RCTs). In this regard, the review by Valk et al.
nization (WHO) announced that the hydroxychloroquine arm of the (2020) examined both studies conducted on a limited number of patients
Solidarity trial project to find an effective COVID-19 treatment was and more complex research designs such as still ongoing RCTs. Among
being stopped (WHO, 2020). On April 23, 2020, AIFA had already these, the recent trial of Bennett-Guerrero et al. (U. S. National Library of
published the communication of the European Medicines Agency (EMA) Medicine. ClinicalTrial.gov, 2020d) (process identification number on
on its website. This communication drew attention to the risk of serious Trials. gov: NCT04344535) evaluates if the blood plasma transfusion
side effects from the use of chloroquine and hydroxychloroquine in containing antibodies to COVID-19 (anti-SARS-CoV-2), donated by pa­
treating COVID-19 patients, such as heart rhythm disturbances, which tients recovered from the infection, is safe and can be effective in the
can be aggravated if treatment is combined with other medicines, and treatment of hospitalised patients with COVID-19. This study involved
antibiotic azithromycin (Agenzia Italiana del Farmaco, 2020 e). On May 500 patients with a control group. In the United States (FDA NEWS
29, 2020, pending obtaining more solid evidence from ongoing clinical RELEASE, 2020), the Food and Drug Administration (FDA) indicates 3
trials in Italy and other countries, AIFA suspended the authorisation to regulatory pathways that allow access to the plasma of convalescents for
use hydroxychloroquine and chloroquine for the treatment of COVID-19 the therapy of COVID-19 to determine, through clinical studies, the ef­
outside of authorised clinical trials (Agenzia Italiana del Farmaco, 2020 ficacy and administration of the plasma: access treatment through
f). AIFA supports this decision based on a critical review of the latest participation in the clinical trial; extended access (which provides pa­
literary evidence (Agenzia Italiana del Farmaco, 2020 g). tients with a serious or fatal disease the opportunity to obtain trial
medical treatment outside the clinical trial, in the absence of available
2.3.5. Anticoagulants alternative treatments); new emergency investigative drug (the clinician
In the advanced stage of COVID-19, a progressive alteration of some may request this for a single patient if they believe that treatment may

7
C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

be urgently needed for the serious or life-threatening conditions they are 3. In case of acceptance of the manuscript the copyright will be trans­
experiencing). The position paper (Accorsi et al., 2020) of the Italian ferred to European Journal of Pharmacology.
Society for Transfusion Medicine and Immunohematology (SIMTI) and 4. The authors have no conflicts of interest to disclose.
of the Italian Society of Hemapheresis and Cell Manipulation (SidEM)
described the requirements that donors must have, the plasma collection
methods, the times for administration and possible adverse events. The Declaration of competing interest
main focus is patients with a SARS-CoV-2 documented infection who
voluntarily offer, after informed consent, to undergo apheresis proced­ The authors have no conflicts of interest to disclose.
ures for the collection of specific plasma for the treatment of serious
SARS-CoV-2 infections, according to all the directives in force on a na­ References
tional level. According to these indications, a subject with previous
SARS-CoV-2 infection can donate at least 14 days after their clinical Accorsi, P., Berti, P., de Angelis, V., De Silvestro, G., Mascaretti, L., Ostuni, A., 2020.
recovery (no symptoms) and after at least two NAT tests (Nucleic Acid ”Position paper” sulla produzione di plasma iperimmune da utilizzare nella terapia
della malattia da SARS-CoV2. Available at: http://www.emaferesi.it/wp-co
Test, a test that identifies the possible presence of the virus) with ntent/uploads/2020/03/Convalescent-Plasma-SIMTI_SIDEM-1.pdf.
negative results on the nasopharyngeal swab and serum/plasma, per­ Agenzia Italiana del Farmaco, 2020d. BARICIVID-19 study: MultiCentre, randomised,
formed after 24 h, after recovery or before discharge if hospitalised. An Phase IIa clinical trial evaluating efficacy and tolerability of Baricitinib as add-on
treatment of patients with COVID-19 compared to standard therapy.
additional negative NAT test, performed 14 days after the first, is not Sperimentazioni cliniche. https://www.aifa.gov.it/sperimentazioni-cliniche
mandatory (and not required by most protocols in place). An adequate -covid-19.
serum titre of specific neutralising antibodies is required (>160 with the Agenzia Italiana del Farmaco, 2020 b. COVID-19 - AIFA autorizza nuovo studio clinico
con tocilizumab. https://www.aifa.gov.it/web/guest/-/covid-19-aifa-autorizza-nuo
EIA method or with other equivalent methods). These people are vo-studio-clinico-con-tocilizumab. (Accessed 3 April 2020).
selected to donate hyperimmune plasma because they are COVID-19 Agenzia Italiana del Farmaco, 2020 c. Studio randomizzato multicentrico in aperto
convalescent patients. The authors of the position paper point out that sull’efficacia della somministrazione precoce del Tocilizumab in pazienti affetti da
polmonite da COVID-19. https://www.aifa.gov.it/documents/20142/1123276/stud
a large number of people who have recovered from asymptomatic
io_RE_Toci_17.06.2020.pdf/c32ed144-ce26-d673-6e4d-11d5d0d84836. (Accessed
infection (or from a disease with minor clinical signs) may become a 17 June 2020).
relevant source of hyperimmune plasma after demonstrating the pres­ Agenzia Italiana del Farmaco, 2020 h. Plasma: ISS e AIFA, studio nazionale per valutarne
l’efficacia. https://www.aifa.gov.it/-/plasma-iss-e-aifa-studio-nazionale-per-valuta
ence of an antibody titre of >160 with the EIA method (or equivalent
rne-l-efficacia. (Accessed 7 May 2020).
with other methods) with serological tests. Since they are regular blood Agenzia Italiana del Farmaco, 2020a. Eparine a basso peso molecolare nei pazienti adulti
donors, they fully comply with the selection criteria for plasma donation con COVID-19. https://www.aifa.gov.it/documents/20142/1123276/Eparine_Bass
after an adequate interval (28 days) has passed from symptom resolu­ o_Peso_Molecolare_11.04.2020.pdf/e30686fb-3f5e-32c9-7c5c-951cc40872f7.
(Accessed 3 April 2020).
tion. Their recruitment could easily be performed by screening for Agenzia Italiana del Farmaco, 2020e. COVID-19 - comunicazione EMA su clorochina e
SARS-CoV-2 (possibly followed by an antibody titration) in the donor idrossiclorochina. https://www.aifa.gov.it/-/covid-19-comunicazione-ema-su-clo
population at the time of donation. This would also allow for an rochina-e-idrossiclorochina. (Accessed 23 April 2020).
Agenzia Italiana del Farmaco, 2020f. AIFA sospende l’autorizzazione all’utilizzo di
epidemiological picture outside the context of a serious clinical disease idrossiclorochina per il trattamento del COVID-19 al di fuori degli studi clinici. https
leading to hospitalisation (Accorsi et al., 2020). To evaluate the efficacy ://www.aifa.gov.it/web/guest/-/aifa-sospende-l-autorizzazione-all-utilizzo-di-id
and role of plasma obtained from patients cured of COVID-19 with a rossiclorochina-per-il-trattamento-del-covid-19-al-di-fuori-degli-studi-clinici.
(Accessed 26 May 2020).
unique and standardised method, the National Institute of Health and Agenzia Italiana del Farmaco, 2020g. Idrossiclorochina nella terapia dei pazienti adulti
AIFA launched a randomised and controlled national multi-centre study con COVID-19. https://www.aifa.gov.it/documents/20142/1123276/idrossicloroch
(Agenzia Italiana del Farmaco, 2020h). ina_29.05.2020.pdf/3958aea0-5a5f-2d05-b1f6-034dbe28ce2a. (Accessed 29 May
2020).
In our view, the plasma of convalescents for the therapy of COVID-19
Beigel, J.H., Tomashek, K.M., Dodd, L.E., Mehta, A.K., Zingman, B.S., Kalil, A.C.,
represents an experimental and emergency therapy already utilised for Hohmann, E., Chu, H.Y., Luetkemeyer, A., Kline, S., Lopez de Castilla, D., Finberg, R.
other diseases. W., Dierberg, K., Tapson, V., Hsieh, L., Patterson, T.F., Paredes, R., Sweeney, D.A.,
Short, W.R., Touloumi, G., Lye, D.C., Ohmagari, N., Oh, M.D., Ruiz-Palacios, G.M.,
Benfield, T., Fätkenheuer, G., Kortepeter, M.G., Atmar, R.L., Creech, C.B.,
3. Conclusions Lundgren, J., Babiker, A.G., Pett, S., Neaton, J.D., Burgess, T.H., Bonnett, T.,
Green, M., Makowski, M., Osinusi, A., Nayak, S., Lane, H.C., ACTT-1 Study Group
Antiviral agents are useful to inhibit the clinical progression and Members, 2020. Remdesivir for the treatment of Covid-19 - preliminary report.
N. Engl. J. Med., NEJMoa2007764 https://doi.org/10.1056/NEJMoa2007764.
complications of COVID-19. Future studies are needed to identify spe­ Cantini, F., Niccoli, L., Nannini, C., Matarrese, D., Natale, M.E.D., Lotti, P., Aquilini, D.,
cific targets that inhibit the life cycle of SARS-COV-2 to prevent its Landini, G., Cimolato, B., Pietro, M.A.D., Trezzi, M., Stobbione, P., Frausini, G.,
replication and that, if used early, could avoid the characteristic com­ Navarra, A., Nicastri, E., Sotgiu, G., Goletti, D.J., 2020. Beneficial impact of
Baricitinib in COVID-19 moderate pneumonia; multicentre study. J. Infect.
plications of COVID-19. Clinical and survival improvement was found in S0163–4453 (20) https://doi.org/10.1016/j.jinf.2020.06.052, 30433-3.
patients treated with plasma and hyperimmune immunoglobulins. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M.,
Inflammation inhibitors (in particular anti-IL6, anti-IL1, inhibitors of Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., Yuan, Y.,
Chen, H., Li, H., Huang, H., Tu, S., Gong, F., Liu, Y., Wei, Y., Dong, C., Zhou, F.,
Janus kinases) are valuable candidates for the treatment of COVID-19 in Gu, X., Xu, J., Liu, Z., Zhang, Y., Li, H., Shang, L., Wang, K., Li, K., Zhou, X., Dong, X.,
its advanced stages. The ongoing clinical trials should confirm safety and Qu, Z., Lu, S., Hu, X., Ruan, S., Luo, S., Wu, J., Peng, L., Cheng, F., Pan, L., Zou, J.,
efficacy, and determine the COVID-19 stage in which these treatments Jia, C., Wang, J., Liu, X., Wang, S., Wu, X., Ge, Q., He, J., Zhan, H., Qiu, F., Guo, L.,
Huang, C., Jaki, T., Hayden, F.G., Horby, P.W., Zhang, D., Wang, C., 2020. A trial of
have the greatest benefit in terms of disease regression.
lopinavir-ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 382,
1787–1799. https://doi.org/10.1056/NEJMoa2001282.
Statements Dai, W., Zhang, B., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., Li, C., Li, Y.,
Bai, F., Wang, H., Cheng, X., Cen, X., Hu, S., Yang, X., Wang, J., Liu, X., Xiao, G.,
Jiang, H., Rao, Z., Zhang, L.K., Xu, Y., Yang, H., Liu, H., 2020. Structure-based design
The submitted manuscript “TREATMENT FOR COVID-19: AN of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science,
OVERVIEW” by Stasi et al., submitted for possible publication in the eabb4489. https://doi.org/10.1126/science.abb4489.
European Journal of Pharmacology. Documents - AIFA, 2020. Adaptive Randomized trial for therapy of Corona virus disease
2019 at home with oral antivirals (ARCO-Home study). https://www.aifa.gov.it/
documents/20142/1131319/covid-19_sperimentazioni_in_corso_09.05.2020.pdf/9
1. Has not been published previously, and is not under consideration d46f533-7406-8f7c-5e34-c119f7087d65. Accessed 7 May.
for publication elsewhere. Executive summary – Agenzia Italiana del Farmaco., 2020. https://www.aifa.gov.it/d
ocuments/20142/1127901/executive_summary_Toci_Nazionale.pdf.
2. The submitted manuscript is approved by all Authors. FDA News Release, 2020. Coronavirus (COVID-19) update: FDA coordinates national
effort to develop blood-related therapies for COVID-19. https://www.fda.gov/news-

8
C. Stasi et al. European Journal of Pharmacology 889 (2020) 173644

events/press-announcements/coronavirus-covid-19-update-fda-coordinates-nationa Long, Q.X., Li, Y., Peng, J., Huang, Y., Xu, D., 2020. Antibody responses to SARS-CoV-2 in
l-effort-develop-blood-related-therapies-covid-19. (Accessed 3 April 2020). patients with COVID-19. Nat. Med. 26, 845–848. https://doi.org/10.1038/s41591-
Fredi, M., Cavazzana, I., Moschetti, L., Andreoli, L., Franceschini, F., on behalf of the 020-0897-1.
Brescia Rheumatology COVID-19 Study Group, 2020. COVID-19 in patients with Matricardi, P., Dal Negro, R., Nisini, R., 2020. The first, holistic immunological model of
rheumatic diseases in northern Italy: a single-centre observational and case–control COVID-19: implications for prevention, diagnosis, and public health measures.
study. https://www.thelancet.com/action/showPdf?pii=S2665-9913%2820%293 Paediatric Allergy and Immunology. https://doi.org/10.1111/pai.13271, 10.1111/
0169-7, 18 June 2020. pai.13271.
Goldman, J.D., Lye, D.C.B., Hui, D.S., Marks, K.M., Bruno, R., Montejano, R., Spinner, C. Mehra, M.R., Desai, S.S., Ruschitzka, F., Patel, A.N., 2020. RETRACTED:
D., Galli, M., Ahn, M.Y., Nahass, R.G., Chen, Y.S., SenGupta, D., Hyland, R.H., hydroxychloroquine or chloroquine with or without a macrolide for treatment of
Osinusi, A.O., Cao, H., Blair, C., Wei, X., Gaggar, A., Brainard, D.M., Towner, W.J., COVID-19: a multinational registry analysis. Lancet S0140–6736 (20),
Muñoz, J., Mullane, K.M., Marty, F.M., Tashima, K.T., Diaz, G., Subramanian, A., GS- 31180–31186. https://doi.org/10.1016/S0140-6736(20)31180-6.
US-540-5773 Investigators, 2020. Remdesivir for 5 or 10 Days in patients with Mehta, P., McAuley, D.F., Brown, M., Sanchez, E., Tattersall, R.S., Manson, J.J., on behalf
severe Covid-19. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2015301, 2020, of the HLH Across Speciality Collaboration, UK, 2020. COVID-19: consider cytokine
10.1056/NEJMoa2015301. storm syndromes and immunosuppression. Lancet 395, 1033–1034. https://doi.org/
Grein, J., Ohmagari, N., Shin, D., Diaz, G., Asperges, E., Castagna, A., Feldt, T., Green, G., 10.1016/S0140-6736(20)30628-0.
Green, M.L., Lescure, F.X., Nicastri, E., Oda, R., Yo, K., Quiros-Roldan, E., Randomised evaluation of COVID-19 therapy. Available at: https://www.recoverytrial.
Studemeister, A., Redinski, J., Ahmed, S., Bernett, J., Chelliah, D., Chen, D., net/.
Chihara, S., Cohen, S.H., Cunningham, J., D’Arminio Monforte, A., Ismail, S., Richardson, P., Griffin, I., Tucker, C., Smith, D., Oechsle, O., Phelan, A., Rawling, M.,
Kato, H., Lapadula, G., L’Her, E., Maeno, T., Majumder, S., Massari, M., Mora- Savory, E., Stebbing, J., 2020. Baricitinib as potential treatment for 2019-nCoV acute
Rillo, M., Mutoh, Y., Nguyen, D., Verweij, E., Zoufaly, A., Osinusi, A.O., DeZure, A., respiratory disease. Lancet 395, e30–e31. https://doi.org/10.1016/S0140-6736(20)
Zhao, Y., Zhong, L., Chokkalingam, A., Elboudwarej, E., Telep, L., Timbs, L., 30304-4.
Henne, I., Sellers, S., Cao, H., Tan, S.K., Winterbourne, L., Desai, P., Mera, R., Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., Wang, F., Li, D., Yang, M., Xing, L.,
Gaggar, A., Myers, R.P., Brainard, D.M., Childs, R., Flanigan, T., 2020. Wei, J., Xiao, H., Yang, Y., Qu, J., Qing, L., Chen, L., Xu, Z., Peng, L., Li, Y.,
Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med. Zheng, H., Chen, F., Huang, K., Jiang, Y., Liu, D., Zhang, Z., Liu, Y., Liu, L., 2020.
382, 2327–2336. https://doi.org/10.1056/NEJMoa2007016. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma.
Guaraldi, G., Meschiari, M., Cozzi-Lepri, A., Milic, J., Tonelli, R., Menozzi, M., J. Am. Med. Assoc. 323, 1582–1589. https://doi.org/10.1001/jama.2020.4783.
Franceschini, E., Cuomo, G., Orlando, G., Borghi, V., Santoro, A., Di Gaetano, M., Tang, N., Bai, H., Chen, X., Gong, J., Li, D., Sun, Z., 2020. Anticoagulant treatment is
Puzzolante, C., Carli, F., Bedini, A., Corradi, L., Fantini, R., Castaniere, I., Tabbì, L., associated with decreased mortality in severe coronavirus disease 2019 patients with
Girardis, M., Tedeschi, S., Giannella, M., Bartoletti, M., Pascale, R., Dolci, G., coagulopathy. J. Thromb. Haemostasis 18, 1094–1099. https://doi.org/10.1111/
Brugioni, L., Pietrangelo, A., Cossarizza, A., Pea, F., Clini, E., Salvarani, C., jth.14817.
Massari, M., Viale, P.L., Mussini, C., 2020. Tocilizumab in patients with severe U. S. National Library of Medicine. ClinicalTrial.gov, 2020a. FLARE: favipiravir +/-
COVID-19: a retrospective cohort study. Lancet Rheumatol 2, e474–e484. https:// lopinavir: a RCT of early antivirals (FLARE). https://clinicaltrials.gov/ct2/show/NC
doi.org/10.1016/S2665-9913(20)30173-9. T04499677.
Gul, M.H., Htun, Z.M., Shaukat, N., Imran, M., Khan, A., 2020. Potential specific U. S. National Library of Medicine. ClinicalTrial.gov, 2020b. Trial of Early Therapies
therapies in COVID-19. Ther. Adv. Respir. Dis. 14 https://doi.org/10.1177/ During Non-hospitalized Outpatient Window for COVID-19 (TREATNOW).
1753466620926853, 1753466620926853. https://clinicaltrials.gov/ct2/show/NCT04372628?term=antiviral+agents%2C+ea
RECOVERY Collaborative Group, Horby, P., Lim, W.S., Emberson, J.R., Mafham, M., rly+phase&cond=Covid19&draw=6.
Bell, J.L., Linsell, L., Staplin, N., Brightling, C., Ustianowski, A., Elmahi, E., U. S. National Library of Medicine. ClinicalTrial.gov, 2020c. Efficacy and safety of
Prudon, B., Green, C., Felton, T., Chadwick, D., Rege, K., Fegan, C., Chappell, L.C., emapalumab and anakinra in reducing hyperinflammation and respiratory distress
Faust, S.N., Jaki, T., Jeffery, K., Montgomery, A., Rowan, K., Juszczak, E., Baillie, J. in patients with COVID-19 infection. https://clinicaltrials.gov/ct2/show/
K., Haynes, R., Landray, M.J., 2020 Jul 17. Dexamethasone in Hospitalized Patients NCT043240. (Accessed 27 March 2020).
with Covid-19 - Preliminary Report. N Engl J Med. https://doi.org/10.1056/ U. S. National Library of Medicine. ClinicalTrial.gov, 2020d. Convalescent plasma vs.
NEJMoa2021436. NEJMoa2021436, Epub ahead of print. PMID: 32678530; PMCID: Standard plasma for COVID-19. https://clinicaltrials.gov/ct2/show/NCT04344535?
PMC7383595. cond=NCT04344535&draw=2&rank=1. (Accessed 17 July 2020).
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., 2020. Clinical features of patients Valk, S.J., Piechotta, V., Chai, K.L., Doree, C., Monsef, I., Wood, E.M., Lamikanra, A.,
infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. Kimber, C., McQuilten, Z., So-Osman, C., Estcourt, L.J., Skoetz, N., 2020.
https://doi.org/10.1016/S0140-6736(20)30183-5. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a
Isidori, A.M., Arnaldi, G., Boscaro, M., Falorni, A., Giordano, C., Giordano, R., rapid review. Cochrane Database Syst. Rev. 5, CD013600. https://doi.org/10.1002/
Pivonello, R., Pofi, R., Hasenmajer, V., Venneri, M.A., Sbardella, E., Simeoli, C., 14651858.CD013600.
Scaroni, C., Lenzi, A., 2020. COVID-19 infection and glucocorticoids: update from World Health Organization. Solidarity, 2020. clinical trial for COVID-19 treatments. htt
the Italian Society of Endocrinology Expert Opinion on steroid replacement in ps://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-rese
adrenal insufficiency. J. Endocrinol. Invest. 43, 1141–1147. https://doi.org/ arch-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatme
10.1007/s40618-020-01266-w. nts.
King, A., Vail, A., O’Leary, C., Hannan, C., Brough, D., Patel, H., Galea, J., World Health Organization, 2020 b. WHO updates clinical care guidance with
Ogungberno, K., Wright, M., Pathmanaban, O., Hulme, S., Allan, S., 2020. Anakinra corticosteroid recommendations. https://www.who.int/news-room/feature-stories
in COVID-19: important considerations for clinical trials. Lancet Rheumatol 2, /detail/who-updates-clinical-care-guidance-with-corticosteroid-recommendations.
e379–381. https://doi.org/10.1016/S2665-9913(20)30160-0.