Recent advances in management of COVID-19: A review.

Introduction

The COVID-19 pandemic first appeared as a case of pneumonia of unknown cause in December 2019 in Wuhan, China. Later, it evolved to a global outbreak and was declared a pandemic by the Word Health Organization (WHO) on March 11, 2020. The WHO reported over 94 million confirmed cases of COVID-19 including 2 million deaths, globally as of 2021 [1] . It is caused by a novel virus from the family of Coronavirus (CoV). This same family of virus caused the previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in 2003–4 and 2012, respectively. The WHO defines Coronavirus as “a large family of viruses that cause illness ranging from the common cold to more severe diseases” [2] . Coronaviruses are single-stranded RNA viruses. They are highly diverse due to their susceptibility to mutation and recombination. They mainly infect humans, mammals, and birds. The SARS-CoV-2 or COVID-19 virus is thought to have originated in bats then spread to humans, possibly by contaminated meat sold in China’s meat market. Symptoms of COVID-19 may involve multiple systems including respiratory, gastrointestinal, musculoskeletal, and neurologic. Respiratory symptoms can be manifested as dry cough, chest pain, rhinorrhoea and/or nasal congestion, sore throat and shortness of breath. Gastrointestinal symptoms can present as diarrhea, nausea, vomiting, haemoptysis and abdominal pain. Finally, patients could experience nonspecific symptoms such as fever, chills, fatigue, muscle ache, loss of taste and/or smell, headaches and confusion [3] .

The Coronavirus enters the host cell via a trimeric spike glycoprotein, or peplomers, which give the viruses their corona-like appearance. The spike is constituted of two subunits: S1 and S2. The top of S1 subunit termed RBD, binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of the host cell. S2 subunit fuses with the host cell membrane. As the S1 subunit binds to the receptor, a host transmembrane serine protease 2 (TMPRSS2) activates the spike and cleaves ACE2, by acting on S2 subunit. This cleavage facilitates the fusion of the virus with the cell membrane, as shown in Fig. 1 [4] . Beside the more common direct membrane fusion pathway, a second suggested mechanism for COVID-19 entry is the endocytic pathway, thought to be pH dependant [5] . Fig. 1 Mechanisms of COVID-19 entry into the host cell. COVID-19 can invade the host cell by two mechanism: direct fusion or through the endocytic pathway. Fig. 1

The viral RNA of coronavirus can be detected by polymerase chain reaction (real-time PCR). Since the outbreak of COVID-19, several treatment and prevention methods (i.e., vaccines) are under various phases of clinical trials. Some even got approved for Emergency Use Authorization (EUA) by the U.S Food and Drug Administration (FDA). Pharmacological agents could be classified into three classes according to the stage they tackle in COVID-19 infection. Stage I is the early infection phase during which the domination of upper respiratory tract symptoms is present. Management during this phase relies on supportive care to assist the immune system or prophylactic therapy possibly with ivermectin. Stage II is the pulmonary phase in which the patient develops pneumonia with all its associated symptoms. The aim during this stage is to inhibit viral entry or replication. In this class we mainly focused on famotidine, monoclonal antibodies, nanobodies, camostat mesylate and antiviral drugs. Stage III is the hyperinflammation phase, the most severe phase, in which the patient develops acute respiratory distress syndrome (ADRS), sepsis and multi-organ failure. Treatment during this phase aims to suppress the immune response. Drugs like dexamethasone, the monoclonal antibody tocilizumab, dexamethasone, repurposed selective serotonin reuptake inhibitors (SSRI), melatonin or other immunomodulatory agents are being investigated in halting the cytokine release syndrome. Some patients also developed disseminated intravascular coagulation, against which anticoagulants are given [6] .

The FDA issued EUA for three vaccines: Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccine. However recently, on April 13, 2021, the FDA and the Centers for Disease Control and prevention (CDC) recommended withholding Johnson & Johnson (Janssen) COVID-19 vaccine until further safety investigations. This decision came after six reported cases of blood clotting, namely cerebral venous sinus thrombosis [7] . In this review, we summarized the findings of selected pharmacological agents against COVID-19 in terms of mechanism of action, efficacy, safety and stage of development. Our aim is to shed light on promising drugs and identify gaps in knowledge.

Treatment of different phases of COVID-19

Early infection (phase I)

Phase I is identified by upper respiratory symptoms most commonly cough, malaise and headaches, with the absence of shortness of breath. Less commonly patients might also present with sore throat, arthralgia, chills, rhinorrhoea, nausea and vomiting or loss of taste and/or smell. During this phase, the virus is replicating in the upper respiratory tract, mainly the nasal passages. The patient shows no to mild symptoms, with a presentation that is very similar to a flu or common cold. The goal during this phase is to support the immune system and to provide symptomatic management according to patient’s presentation. Some patients are limited to this phase while others progress to the more severe stage II or III [8] , [9] .

Symptomatic treatment/supportive care

Symptomatic treatment involves the use of analgesics and antipyretics to relieve symptoms of headache, fever and myalgia. For cough or dyspnea, self-proning (patient with respiratory distress is placed on his stomach) provides symptomatic improvement. Education on breathing exercise is also important. For mild cases of COVID-19 infection, general supportive care is provided. This includes adequate hydration (especially when fever is present), rest, repositioning and ambulation [10] . Table 1 summarizes the symptomatic treatment and supportive care used during the mild phase (early infection). Table 1 Symptomatic treatment/supportive care during the mild phase of COVID-19. Table 1 Early infection (mild phase) Symptoms Treatment/ supportive care Headache, fever and myalgia • Adequate hydration • Acetaminophen • nonsteroidal anti-inflammatory drug (NSAID) Cough, and Dyspnea • Self-proning • Breathing exercises education Over the counter (OTC) medications: • Dextromethorphan Prescribed medication: • Benzonatate (100–200 mg three times daily)

Pulmonary phase (phase II): entry/fusion inhibition & antiviral agents

In phase II, the virus proceeds to infect the lungs triggering the innate immune response. As a result, patients develop pneumonia with its associated symptoms such as a worsened cough, fever, dyspnea and decreased oxygen levels. It is during this stage that most patients require hospitalization. Management during this phase is focused on preventing viral entry and invasion, in addition to limiting viral replication by antiviral therapy [11] , [12] , [13] , as indicated below:

Ivermectin

Ivermectin is approved by the FDA as an anti-parasite drug to treat onchocerciasis (river blindness), Malaria, head lice and scabies [14] , [15] . The class of Ivermectin is avermectins. Ivermectin has shown an antiviral activity towards many RNA and DNA viruses [16] . In recent studies, ivermectin has shown in vitro antiviral activity against COVID-19.

The use of 5 µM ivermectin reduced viral particle proliferation (5000-fold reduction in COVID-19 levels) within a 48-hour incubation period. The mechanism of action of ivermectin against COVID-19 is through inhibiting importin (IMP) α and β. IMP α and β are needed for the virus to gain access into the nucleus of the host cell [17] . Ivermectin was also found to antagonize transmembrane receptor CD147 [18] .

In clinical settings, a retrospective cohort study including ( n = 280) hospitalized patients infected with COVID-19 in South Florida hospital. 173 patients received ivermectin 200 mcg/kg orally and usual clinical care, while 107 patients received the usual clinical care only. Patients treated with ivermectin had significantly lower mortality rate (15.0% vs 25.2%) compared to conventional care only ( p = 0.03) [19] . Furthermore, in a cross-sectional study, 100 mild to moderate COVID-19 patients were treated with a combination of oral doxycycline 100 mg and ivermectin 0.2 mg/kg. Within 6 days, 83.5% tested negative for COVID-19 and had major improvement in symptoms ( p = 0.59). Additionally, no side effects or admission to intensive care was needed [20] . A case-control study conducted among healthcare workers in an Indian hospital, evaluated ivermectin as a prophylactic agent. Study subjects were health care workers that tested positive (case) or negative (control) for COVID-19. 77 of the control group and 38 of the case group, who took two doses of ivermectin prophylactically had 73% reduced risk of infection by COVID-19 [21] . It is not clear whether ivermectin should be used as treatment or prophylaxis and further studies are needed to establish ivermectin efficacy and mechanism against COVID-19.

Monoclonal antibodies

Antibodies are an important part of the host immune system and play a role in the eradication of pathogens including viruses. Monoclonal antibodies are synthetic proteins produced to mimic the natural immune response. As a result, they are very effective with vast applications. They are used in autoimmune diseases, asthma, oncology, neurology, radioimmunology and diagnostics [22] , [23] , [24] . Nonetheless, the FDA approved agents for viral infections are limited to Ebola and Respiratory Syncytial Virus (RSV) [25] , [26] . In comparison to other therapeutic agents, monoclonal antibodies are more specific, as they are designed to target a single protein.

There are many monoclonal antibodies developed or under development for treatment and/or prophylaxis of COVID-19. The majority target the S-spike protein, limiting viral attachment to the ACE2 receptor and further entry. Currently, the FDA permitted EUA for two combinations of monoclonal antibodies. REGEN-COV2 (casirivimab with imdevimab) approved in November 2020. While lately, in February 2021, the combination of bamlanivimab with etesevimab, by Eli Lilly and Company, was also approved [27] , [28] . Clinical trials that lead to FDA approval are provided in Table 2 . Bamlanivimab monotherapy was initially approved, but due to development of resistant, the decision was revoked by the FDA [29] . According to the FDA, monoclonal antibodies are indicated in mild to moderate COVID-19 infected adults or even children (12 years or older with a minimum body weight of 40 kg), at high risk (as defined in the FDA fact sheet) for developing severe disease [30] , [31] . Table 2 Clinical trials that resulted in FDA approved of three monoclonal antibodies. Table 2 Drug Name of Clinical trial Type of clinical trial Study subjects Dose Status BAMLANIVIMAB (LY-CoV555) BLAZE-1 interim data review from a Phase 2 randomized, double-blind, placebo controlled. n = 465 (ambulatory) Single IV infusion either 700 mg, 2800 mg, or 7000 mg REVOKED [29] BAMLANIVIMAB (LY-CoV555) AND ETESEVIMAB (LY-CoV016) BLAZE-1 Phase 2 randomized, double-blind, placebo controlled. n = 577 (ambulatory) Single IV infusion 700 mg + 1400 mg APPROVED EUA [33] Phase 3 randomized, double-blind, placebo controlled. n = 518 (ambulatory) Single IV infusion 2800 mg + 2800 mg CASIRIVIMAB AND IMDEVIMAB (REGN-COV2) R10933 –10987-COV-2067 phase 1/2 randomized, double-blind, placebo controlled. n = 799 (ambulatory) Single IV infusion 1200 mg + 1200 mg Or 4000 mg + 4000 mg APPROVED EUA [27]

Expressly, an IV infusion of monoclonal antibodies is given to patients that test positive for COVID-19 with no critical symptoms, but at risk of developing severe infection. Some of these risk factors include age > 65 years, obesity, immunodeficiency and others. According to several studies, early treatment with monoclonal antibodies in these patients would reduce viral load, hospitalization and death [32] . It is suggested that monoclonal antibodies possess antiviral effect by reducing viral replication in the nasopharynx. As hospitalized patients with more severe symptoms experienced no benefit, their use is possibly limited to early therapy. Although their ineffectiveness in later, more sever stages, could be related to the hyperinflammatory state that is of higher impact [33] .

Nanobodies

Despite advances in bioengineered monoclonal antibodies, as mentioned above, there are still some barriers to their use. Cost, heat sensitivity, and intravenous administration which requires patient hospitalization are all disadvantages of monoclonal antibodies. Additionally, in order to achieve effective alveolar concentration, a high dose must be injected which is associated with side effects. Their use was also linked with antibody-dependant enhancement of the disease (ADE), which could result in additional side effects [34] .

Nanobodies (Nbs) are a new class of recombinant antibodies that are derived from heavy-chain antibodies, found in sharks and camels [35] . Mammalian antibodies (also known as conventional or traditional) are heterotetrameric proteins consisting of one pair of heavy chains and another pair of light chains. Interestingly, camelid species including camels, lamas and alpacas have antibodies that are devoid of light chains, with only the two sets of heavy chains. The variable domain of the camelid antibody is called the VHH domain (illustrated in Fig. 2 ), more commonly known as nanobody [24] . Nbs are a rapidly growing filed in research with extensive evaluation in therapeutics and diagnostics. They have many advantages over conventional antibodies. To start, their small size (about 15 kDa) allows for good tissue penetration. Moreover, they have excellent aqueous solubility, stability, are easily bioengineer and suitable for large scale production assisted by yeast or bacteria. These outstanding biochemical properties possibly assists their administration by inhalation. Inhaled Nbs allow for lower doses, are more patient friendly and do not require hospitalization [36] , [37] . Finally, although attained from different species, their heavy chain is very alike to human antibodies, thus, is of low immunogenicity [38] , [39] , [40] , [41] . Caplacizumab is an FDA approved Nb for the management of thrombotic thrombocytopenia, supporting their therapeutic potential [42] . Although many Nbs have been bioengineered and successfully tested preclinically, their efficacy in humans is yet to be trialed [43] , [44] , [45] . Fig. 2 The structure of nanobodies (Nbs) and different multivalent nanobodies. Camelid species unlike conventional antibodies (IgG) only consist of two light chains. The variable domain highlighted is known as the VHH domain or more commonly nanobody. Nbs can be bioengineered as monovalent or multivalent. Multivalent Nbs can be further classified into bivalent (two identical Nbs), biparatropic (two different Nbs) or trivalent (three identical Nbs). Fig. 2

The main mechanism of action of Nbs against COVID-19 is by inhibiting spike protein-ACE2 binding interaction as shown in Fig. 3 . Schoof, et al., using yeast surface-display libraries, identified two classes of neutralizing Nbs. Class I Nbs such as Nb6 and Nb11 (the most potent member of class I), attached to RBD, while class II Nbs such as Nb3 attached to a different, unidentified epitope on spike proteins. The lateral class had less inhibitory effect against COVID-19. Cryo-electron microscopy (cryo-EM) was used to identify the binding site of the most potent class I Nb. Both Nb11 and Nb6 were found to bind the up and down conformation of RBD. Uniquely, the binding of Nb6 to the more stable down state, stabilized two nearby RBD in the down conformation. This was likely to facilitate binding of other Nb6 molecules. These findings were not manifested by Nb11, that only bound RBD. The mechanism of Nb6’s binding, influenced Schoof, M. and colleagues to design bivalent and trivalent forms of Nb6, that could possibly keep all RBD in the down state. Indeed, upon investigating the equilibrium dissociation constant (K D ) of bivalent and trivalent Nb6, more than 200,000-fold improvement in K D was noted. Furthermore, Nb6 was modified with the aim of enhancing potency. The matured (modified) Nb6 (mNb6) exhibited 500-fold augmentation in spike binding affinity. As mNb6 showed a similar binding mode to Nb6, engineered trivalent mNb6 were the most potent multivalent Nb in neutralizing COVID-19. The observed mNb6 neutralizing effect was by two mechanisms; blocking RBD-spike interaction and stabilizing RBD in inactive down-state (ACE2 receptor only binds to the up-state). Table 3 provides a summary of the monovalent and multivalent Nb affinities and neutralizing activities [46] . Fig. 3 Nanobodies inhibit the viral entry into the host cell. Nanobodies bind to viral spike proteins inhibiting spike-ACE2 binding. Fig. 3 Table 3 List of the different types of neutralizing nanobodies. Table 3 No. of study Nanobody type Mechanism of nanobody Nanobody name K D IC 50 References 1 Yeast surface displaced library using synthetic nanobody sequences Block the interaction of spike and RBD to ACE2 Nb6 41 nM 2.0 μM Schoof et al. [43] Nb6 trivalent N/A 1.2 nM Nb6 Redesign 0.56 nM 1.6 nM 2 Humanized antibody VHHs of llama Block the interaction of spike and RBD to ACE2 N/A 0.25 nM 1 nM Dong et al. [44] 3 Single domain nanobodies (sdNbs) Inhibitory effect against spike receptor-binding domain (RBD) of SARS-CoV-2 1E2 35.52 nM 18.8 nM Chi et al. [45] 2F2 5.175 nM 22.6 nM 3F11 3.349 nM 28.6 nM 4D8 6.028 nM 9.6 nM 5F8 0.996 nM 39.3 nM 4 Camelid nanobodies (one llama and one alpaca) Inhibitory effect against spike receptor-binding domain (RBD) of SARS-CoV-2 Single domain nanobody VHH E 2 nM 60 nM Koenig et al. [37] VHH U 21 nM 286 nM VHH V 9 nM 198 nM VHH W 22 nM 257 nM Multivalent nanobodies VHH EV N/A 2.9 nM VHH VE N/A 4.1 nM

In another study, a humanized llama VHH was used to examine the potency of Nbs against COVID-19. 91 high-affinity Nbs hit the spike protein binding site and 69 out of the 91 Nbs had a unique sequence. Upon further investigation of the 69 unique Nbs, 15S protein binders were discovered to block the spike protein-ACE2 receptor interaction, enhancing the neutralization effect against COVID-19 infection [47] . A Further study by Chi, et al., reported five single domain Nbs (sdNbs) that act against COVID-19 spikes. These monovalent Nbs had low affinity against pseudotyped particle of COVID-19. A successful attempt to improve the neutralizing activity of these sdNbs was noted upon fusion with human IgG Fc-domain. Fc-fused sdNbs showed 10-fold increase in activity compared to conventional sdNbs [48] . Although Fc-fused Nbs are more potent, they are more likely to be associated with ADE.

Koenig, et al., screened Nbs produced by immunized lama and alpaca. Out of 23 potential Nbs, four were the most potent VHH U, V, W and E in competing with COVID-19 for the RBD. VHH E had the highest activity (out of the four) with an IC50 (half maximal inhibitory concentration) of 60 nM. Surface plasmon resonance (SPR) assay identified two binding sites on RBD. One region that binds each of VHH U, V and W, while VHH E binds to a separate region. Based on this information, and those obtained from SPR, X-ray crystallography and cryo-EM, Koenig et al., engineered two types of Nbs. Multivalent Nb VHH EE and EEE, since VHH E was the most potent Nb. However, upon exposure, the virus rapidly developed resistance and was no longer recognized by the Nbs. To overcome or limit the resistance, bivalent biparatropic Nbs were developed that targeted two independent regions of the RBD (VHH E + U, VHH E + V, VHH E + W). Notwithstanding, it is speculated that bivalent biparatropic Nbs’ neutralizing mechanism enhances viral fusion as VHH E, U and W stabilized the RBD in the up conformation. Since the up conformation is the active conformation for COVID-19, it is believed that this triggers further conformational changes that eventually cause viral-membrane fusion. This observation is of interest as VHH E compared to VHH U and W target different binding sites, a phenomenon that was not observed in other coronaviruses. The exact mechanism is not clear and necessitates further investigation [37] . Table 3 provides a summary of the different Nbs’ mechanism of action, binding affinity and IC50.

To conclude, the use of Nbs that stabilize the RBD in the more stable down-confirmation, like the potent trivalent mNb6, might be of higher benefit. This would prevent possible Nb induced viral fusion. Also, they are devoid of ADE induced by Fc-fused sdNbs. Additionally, comparing potencies, mNb6 had the lowest IC50 versus each of VHH EV and VHH VE respectively. (1.6 nM vs 2.9 and 4.1 nM).

Famotidine

Famotidine is a Histamine-2 receptor (H2) antagonist, used in the treatment of peptic ulcer, mild reflux esophagitis and Zollinger-Ellison syndrome [49] . The potential mechanism of action of famotidine is being investigated. There are several studies that support the use of repurposed famotidine in COVID-19 patients.

In a case series, 10 non-hospitalized patients administered 80 mg famotidine three times daily for 11–21 days. All patients reported marked improvement in symptoms [50] . In a cohort retrospective study including a total of 1620 inpatients, 84 received a median dose of 136 mg famotidine for a duration of 5–8 days. On the other hand, 1566 patients were classified as control (did not receive famotidine). The results showed that the death/intubation ratio was (8/84). 10% of patients administered famotidine while 22% did not receive famotidine (332/1536). Results were statically significant ( p < 0.01) showing that famotidine administration was associated with an improved outcome in terms of need for intubation or death [51] . However, bases on these results alone, it cannot be confirmed that famotidine has a direct effect on COVID-19, because it was an observational study. In another retrospective cohort study, 110 hospitalized patients received a combination of famotidine 20 mg twice daily and cetirizine 10 mg (a histamine 1 (H1) receptor antagonist) twice daily. The results showed that the combination of both drugs together reduced the mortality rate by 26–45% compared to similar published reports [52] . Moreover, in a retrospective matched-observational cohort study, 83 out of 878 (9.5%) patients received 20 mg/day of famotidine within +/- 7 days of hospital admission. The remaining 4.8% of the cases received 40 mg/day famotidine. The primary outcomes in the famotidine group were, 12 (14.5%) patients died, 18 (21.7%) patients needed intubation and 6 (7.2%) patients had both death/intubation cases. In the Non-famotidine group 179 (26%) patients died, 221 (32.1%) patients needed intubation and 95 (13.8%) patients died and needed intubation. Famotidine was associated with lower mortality risk (odds ratio 0.366, 95% confidence interval (CI) 0.155–0.862, p = 0.021) [53] .

A hypothesis suggests that a high dose of famotidine could produce antiviral effect by inhibiting two COVID-19 proteases, papain-like protease and 3-chymotrypsin-like protease [50] , [54] . Nonetheless, in silico studies did not support this hypothesis. Loffredo et al., suggests that high dose famotidine is more likely to be involved in limiting the hyperinflammatory phase [55] . In summary, further studies are needed to identify famotidine’s mechanism of action and additional larger, multicentred studies are needed to confirm and support the effectiveness of famotidine towards COVID-19.

Other drugs

The following table summarizes other drugs that act against COVID-19 during the pulmonary phase ( Table 4 ). Camostat mesylate and baricitinib inhibit viral fusion while the other drugs inhibit viral replication. Table 4 Other drugs that act against SARS-CoV-2 during the pulmonary phase. Table 4 Viral life cycle target Drug name Pharmacological class Indication Mechanism of action against SARS-CoV-2 Concentration against SARS-CoV-2 ( μM) Phase of development Attachment and entry Baricitinib Janus kinase (JAK) 1/2 inhibitor Rheumatoid arthritis Dual effect: • Inhibition of kinase signaling that will prevent viral endocytosis • Inhibition of cytokine release by blocking the JAK 1&2 [53] NA Phase III [54] APROVED in japan [55] Camostat mesylate Protease inhibitor Pancreatitis Block TMPRSS2 involved in viral fusion [56] EC50: 1 Phase III [57] Proteolysis Boceprevir Protease inhibitors hepatitis C virus (HCV) NSP5 inhibitor (M pro / 3CL pro ), that cleaves viral proteins into the active form [58] EC50: 15.57 Preclinical screening [58] PF-07304814 Protease inhibitors / NSP5 inhibitor, (M pro / 3CL pro ). [59] NA Phase I [60] Translation of polyproteins Plitidepsin Didemnins Multiple myeloma Inhibitions of eEF1A, a protein needed for translation [61] IC90: 0.00176 Phase III [62] Zotatifin Anticancer NA Inhibition of protein biogenesis and blocks eIF4A, an enzyme needed to initiate translation [63] NA Phase I [64] RNA replication Remdesivir Adenosine analog (Antiviral) Filoviruses, pneumoviruses paramyxoviruses, and coronaviruses. Inhibits RNA-dependent RNA polymerase (RdRp) [65] EC50: 0.074 Phase III [66]

Hyperinflammatory phase III

During this phase, inflammation extends beyond the lungs into a systemic hyperinflammatory syndrome, also known as cytokine storm syndrome. As a result, patients can develop a range of complications mainly ARDS, sepsis or even multiorgan failure. It is characterized by an elevation in inflammatory mediators like IL-2, IL-6, IL-7, TNF- alpha, C- reactive protein and a decrease in T-cell count [56] .

Tocilizumab

Tocilizumab is a humanized monoclonal antibody that binds to interleukin 6 (IL-6) receptor. The approved use of tocilizumab is rheumatoid arthritis due to its anti-inflammatory effect. Tocilizumab can bind to both soluble IL-6 receptor and membrane bound receptor, antagonizing the effect of IL-6. IL-6 is an important pro-inflammatory mediator and its production is triggered by tissue injury and infection. Release of IL-6 into the circulation mobilizes B and T-cells. Targeting IL-6 receptor accordingly has a role in limiting the inflammatory and immune response [57] , [58] .

Unlike REGEN-COV2 and etesevimab used in selected mild to moderate COVID-19 outpatients, tocilizumab is investigated for more severe COVID-19 cases in hospitalized patients. COVID-19 intensive care unit (ICU) patients have high plasma levels of cytokines, known as cytokine storm. IL-6 particularly, was elevated in more severe COVID-19 cases or those requiring mechanical ventilation [57] . There are many studies that investigated the effect of tocilizumab as shown in Table 5 with conflicting findings. Thence, larger randomized clinical trials were conducted to delineate tocilizumab’s findings. Table 5 Clinical studies on tocilizumab. Table 5 Study no./name Study design Total number of patients Case Control Outcome Reference 1 Observational cohort study 44 n = 22 (Tocilizumab intravenous 600 mg) 22 • On day 14, lower respiratory rate in tocilizumab group (P = 0.03), and fewer required mechanical ventilation. • On day 7, a significant decrease in C-reactive protein levels (P = 0.04). Albertin et al. [74] 2 Retrospective cohort study 87 n = 29 (Tocilizumab 8 mg/kg) 58 • Significant reduction in hospital and ICU stay. • Mechanical ventilation had been reduced significantly at earlier time (P = 0.002) Eimer et al. [75] 3 Observational retrospective cohort study 544 n = 179 (16/88 received IV 8 mg/kg and 17–91 received 162 mg SC dose) 365 • 57/365 of the control group needed mechanical ventilation • 73/365 of the control group died • Tocilizumab group were having less death rates and invasive mechanical ventilation (P = 0.020) • 24/179 and 14/365 (P < 0.0001) had an acquired infection. Guaraldi et al. [76] 4 Multicentre cohort study 3924 n = 433 3491 • 1544 patients from control group died compared to 125 from tocilizumab arm. • 27 follow-up days, tocilizumab group had lower death rate compared to control group. • Estimated mortality rate after 30 days was 37.1% for control group and 27.5% tocilizumab group. Gupta et al. [77] EMPACTA Randomized, phase III, international controlled trial 389 n = 249 8 mg/kg IV 128 On day 28, 12% on the tocilizumab vs 19.3% died or needed mechanical ventilation (P = 0.04) Salama et al. [70] REMAP-CAP Global adaptive platform trial 803 n = 353 Tocilizumab (8 mg/kg) n = 48 Sarilumab (400 mg) 402 No dependence on organ support and improved survival. • REMAP-CAP Investigators [71] COVACTA Randomized, phase III trial 452 n = 294 Tocilizumab (8 mg/kg) 144 No improvement is survival or mortality. Rosas et al. [72]

Tocilizumab was part of the [RECOVERY] trial, a large randomized clinical trial that included all big hospitals in the United Kingdom. This trail aims to find potential treatment for severe COVID-19 hospitalized patients. Eligible patients had a positive COVID-19 test, hypoxia (defined as oxygen saturation < 92%) and systemic inflammatory C-reactive protein levels of ≥ 75 mg/L). Study participants were randomized to receive standard care only or standard care along with intravenous tocilizumab at a dose of 400–800 mg (according to weight). If patient’s condition did not improve, a second dose of tocilizumab was given, 12–24 h after the initial dose. 4116 adults were eligible according to the study criteria. Of those, 596 out of 2022 patient (29%) on the tocilizumab arm, were discharged after 28 days. Contrastingly, 694 out of 2094 subject (33%) who received the usual care, died ( p = 0.007). Overall, patients allocated to receive tocilizumab had 4% reduction in mortality and the need.

for invasive mechanical ventilation ( p = 0.0005) [59] . Comparable results were seen with EMPACTA (Evaluating Minority Patients with Actemra) in terms of reduced mortality and need for mechanical ventilation. EMPACTA is a phase III, international clinical trial. The aim of the study was to explore whether tocilizumab is safe and effective in COVID-19 hospitalized pneumonia patients, not on mechanical ventilation [60] . REMAP-CAP trial that recently published its results in New England Journal of Medicine ( NEJM ) also supported positive findings with tocilizumab when used in COVID-19 ICU patients that were not organ supported [61] . Finally, COVACTA trial involved 62 hospitals, and also published its results in NEJM , showed no major improvement in reducing mortality or survival [62] . Most studies reported no improvement in survival except the REMAP-CAP trial [63] .

Dexamethasone

One of the treatment approaches that has been widely implicated in the management of the hyperinflammatory phase is dexamethasone. Dexamethasone belongs to the Corticosteroids family, specifically; it is a glucocorticoid. Corticosteroids are used in several inflammatory conditions affecting a wide range of system, including dermatological, ophthalmic, rheumatologic, hematologic, gastroenterological and others. More importantly, they are commonly used in pulmonary infections like asthma, chronic obstructive pulmonary disease and viral pneumonias [64] , [65] . Dexamethasone is cheap, readily available and has a long half-life. In comparison to other corticosteroids, dexamethasone is 25 times more potent and has relatively no mineralocorticoid effect [66] , [67] .

Dexamethasone has both anti-inflammatory and immunomodulatory effect. These effects result from a genomic or non-genomic pathway depending on the dose. At a low dose, dexamethasone has a genomic effect, altering genes that code for proinflammatory cytokines and chemokines. The lipophilic nature of dexamethasone allows it to cross the cell membrane and bind to the glucocorticoid receptor in the cytoplasm. Upon binding, the complex relocates to the cell nucleus where it binds to glucocorticoid response elements. Glucocorticoid response elements modulate gene transcription of several inflammatory mediators like cytokines, macrophages, mast cells, lymphocytes and prostaglandins. Additionally, this binding upregulates anti-inflammatory mediators IL-10, annexin A1 and lipocortin-1. When a higher dose of dexamethasone is used, the anti-inflammatory and immunomodulatory effect result from a nongenomic pathway. Compared to the genomic pathway, it is faster but shorter in duration of action. Instead of binding intracellularly, dexamethasone binds either membrane-bound glucocorticoid receptor or cytosolic glucocorticoid receptor. A third mechanism is by a nonspecific cell membrane interaction, that alters certain signaling pathways [64] , [68] , [69] , [70] . Furthermore, based on computational molecular modeling, dexamethasone was found to inhibit the COVID-19M pro [71] .

A low dose of dexamethasone is indicated in severe cases of COVID-19, while no benefits were observed in mild to moderate cases. High doses are not recommended as they are associated with harmful effects [72] . According to the WHO and National Institutes of Health (NIH), corticosteroids are indicated as standard care for up to 10 days or until discharge in patients with COVID-19 pneumonia, requiring respiratory support [66] . These recommendations were largely shaped by the results of the RECOVERY trial. In the RECOVERY trial, hospitalized COVID-19 patients were allocated to receive dexamethasone along with usual care (n = 2104) or usual clinical care only (n = 4321). A dose of 6 mg dexamethasone was administered for up to 10 days or until discharge. Findings demonstrated that dexamethasone use is associated with lower mortality rate in patient on mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51–0.81) or oxygen therapy (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72–0.94) by day 28. Contrarily, no reduction in mortality was noted in patients not on respiratory support (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92–1.55) [73] .

Timing of initiating therapy is crucial. Early administration can aid viral replication and interfere with the adaptive immune response [64] . Evidence driven by current studies suggest maximum benefit from corticosteroid therapy when initiated in patients with persistent symptoms, beyond 7 days [74] . Although dexamethasone is mainly indicated in the hyperinflammatory phase, initiation during the pulmonary phase exclusively in hypoxic patients has also been advocated [56] . While guidelines were based on the results of the RECOVERY trial, the extend of secondary bacterial infections (seen with pervious viral pneumonias) was not assessed. Therefore, careful use is warranted particularly when administered with other immunosuppressants.

Selective Serotonin Reuptake inhibitors (SSRI)

Sigma-1 receptor (S1R) agonist

Sigma-1 receptor (S1R) is a transmembrane chaperon protein and function as a receptor for many ligands. It is located in the mitochondria-associated membrane that is found in many organ tissues, but mainly in the central nervous system. Mutations or polymorphism of the S1R can lead to neuronal degeneration, resulting in pathological conditions such as amyotrophic lateral sclerosis, Huntington’s diseases, Alzheimer’s and dementia [75] . S1R agonist used in animal models displayed neuroprotective actions [75] , [76] , [77] .

Interestingly, S1R is also involved in regulating oxidative stress in the endoplasmic reticulum. Specifically, inositol-requiring enzyme 1α (IRE1), a main stress sensor, promotes the release of inflammatory cytokines upon subjection to lipopolysaccharide (LPS). Unfortunately, IRE1 is difficult to target as it is involved in other important psychological conditions. For this reason, Rosen, et al., shifted their focus on S1R, suggesting the involvement of this receptor in IRE1-induced inflammation. The study assessed the effect of S1R-IRE1 pathway modification in mice after injection of LPS, or peritoneal administration of fecal slurry. Mice with deleted S1R had significant higher sepsis induced-mortality rates (higher tumor necrosis factor alpha (TNF-α) and IL-6 concentration p < 0.05). Oppositely, upregulation of S1R or suppression of IRE1 increased survival due to a decrease in inflammatory response (decrease in IL-8 concertation p < 0.05). These findings supported further assessment of the anti-inflammatory effect of fluvoxamine. Fluvoxamine is a SSRI but also a potent S1R agonist. Injection of fluvoxamine in septic animal models revealed positive improvement. The anti-inflammatory effect was reproducible in human cells as well [78] . These findings, although induced by LPS, are certainly promising. Sepsis is a lethal complication and a major cause of mortality in intensive care patients. Despite sepsis being more commonly bacterial, viral sepsis can be a complication of viral infection as well [79] , [80] . In a study by Chen et al., in (Wuhan, china), out of 99 cases admitted to the hospital, 4% had septic shock [81] . More importantly, TNF-α and IL-6 are two very important pro-inflammatory cytokines involved in COVID-19 associated cytokine storm. Cytokine storm is a major complication of COVID-19 resulting in multiorgan failure, ARDS or even death [82] .

A Double-blinded randomized study involved 152 mild PCR confirmed COVID-19 cases to receive either fluvoxamine (day 1 = 50 mg OD, day 2&3 = 100 mg twice daily, day 4–15 = 100 mg three times per day if tolerated) or placebo for 15 days. The objective was to assess the ability of fluvoxamine to halt disease progression and improve clinical outcome in symptomatic, non-hospitalized patients. The study was carried out remotely from patients’ home. None of the fluvoxamine arm subjects had deterioration in their condition compared to 8.3% of the placebo arm ( p < 0.09). Unfortunately, these finding cannot be considered statistically significant due to the limited sample size and the rather homogenous study subjects. It is also important to point out that since the study was conducted from distance, there is a higher chance of user bias [83] . Fluvoxamine does not require hospitalization, taken orally, readily available and relatively cheap in comparison to other COVID-19 used agents. Fluvoxamine is advantageous compared to other SSRI in that it does not cause QT-interval prolongation [84] .

Lysosomotropic agents

SSRI are also investigated as lysosomotropic agents. Specifically, sertraline and fluoxetine have been approved as lysosomotropic agents. Lysosomotropic agents are weak bases (pKa > 6, hydrophobic) that can penetrate endosomes or lysosomes in their unionized form. Once they cross, the acidic pH of endosomes or lysosomes causes protonation. Protonation traps the drug inside (ionized drugs cannot cross the membrane), neutralizing the acidic environment (increase in pH is represented in green Fig. 4 ). The acidic environment is crucial for the fusion of coronaviruses including COVID-19. Upon viral entry through the endocytic pathway, the decrease in endosomal pH allows the virus to attach vacuolar membrane and release the genetic material into the cytosol. This step is vital for viral replication and completion of its life cycle [85] . The closer the endosome gets to the nucleus, the higher the drop in pH (as shown in Fig. 5 ), which acts as a signal for the virus to exit the vacuole. Furthermore, the peptides needed for viral fusion are usually activated by endolysosomal proteases that require acidic pH for their function. Neutralizing the pH will thus inhibit this step. Fig. 4 Viral inhibition by Lysosomotropic agent. Lysosomotropism agents increase the endosomal/lysosomal pH (represented in green) which prevents viral vacuole escape into the cytosol. Fig. 4 Fig. 5 Ph-dependant viral release into the cytosol. The pH decreases gradually as the endosome gets closer to the nucleus (indicated by a more intense yellow color). The virus uses the increasing acidic environment as a signal to exit the endosome. Fig. 5

Other agents besides SSRI have also been investigated. Examples are chloroquine, hydroxychloroquine and sodium bicarbonate [86] , [87] , [88] . Chloroquine and hydroxychloroquine, although studied extensively as lysosomotropic agents, are largely limited by their toxicity, side effect profile, interpatient-variations and their long half-life (30–60 days). Fluoxetine on the other hand has a better side effect profile, is less toxic and has a notable faster elimination half-life (1–3 days) [88] . However, Schloer, et al., stated that complete inhibition of viral entry will only be achieved by inhibiting both pathways, the endocytic pathway as well as the direct fusion with the host plasma membrane [89] .

Functional inhibitors of Acid sphingomyelinase (FIASMA)

Functional inhibitions of Acid sphingomyelinase (FIASMA) is a pharmacological class with a wide range of therapeutic applications. Members of this class share the inhibitory effect on sphingomyelinase (SMA), the small size and general tolerability. The antidepressant fluoxetine belongs to this class.

In addition to the lysosomotropic effect of SSRI (mentioned above), Schloer, et al., also reported acid SMA inhibition (ASM), achieved with fluoxetine at higher concentration. ASM is a membrane bound lysosomal enzyme as indicated in Fig. 6 . During cellular stress ASM relocates to the cell membrane, where it catalyses the cleavage of sphingomyelin into lipophilic ceramide and hydrophilic phosphorylcholine head. Ceramide is involved in cell signaling that could lead to apoptosis [90] . Once fluoxetine crosses the lysosomal membrane, it disrupts ASM membrane binding and releases it into the lysosomal lumen. Detachment renders the enzyme inactive and further subjects it to proteolytic enzymes Fig. 6 [89] . In vitro studies showed that FIASMA can prevent the infection with influenza and Ebola virus. In a study by Carpinteiro et al., COVID-19 virus infected the cells by activation of SMA, therefore inactivation of SMA could limit viral infection [91] . Fig. 6 Functional inhibitors of Acid sphingomyelinase (FIASMA) by fluoxetine. ASM is a membrane bound enzyme. Fluoxetine displaces ASM which turns it into inactive. Displacement from the membrane also subjects it to proteolysis by proteolytic enzymes. Fig. 6

Fluoxetine also prevents efflux of cholesterol from the endosomes and lysosomes. As a result, less cholesterol is available for the plasma membrane and other cell functions. Cholesterol is particularly important for enveloped viruses as they form their envelopes from the host membrane. This mechanism is exhibited in influenza virus, through viral envelopes with decreased cholesterol content (crucial for viral survival) and less viral release. Indeed, 10 µM fluoxetine when used in a cell culture model of COVID-19, significantly reduced viral load. It was also noted that the inhibitory effect was dose-related [89] . In vitro and observational studies indicated that fluoxetine prevents COVID-19 infection at usual psychiatric doses [92] . The risk of mortality and intubation was reduced dramatically in COVID-19 patients receiving regular antidepressant doses of fluoxetine (20 mg), as documented by a retrospective clinical study [93] .

To summarize, SSRI can inhibit COVID-19 through several mechanism as shown in Table 6 S1R modulation, endolysosomal pH reduction and FIASMA. They have a good safety profile, are readily available, can be taken orally and are cost effective. This certainly makes them an attractive class for repurposing during this pandemic, when there are yet no definitive treatments available. However, their exact place of therapy is not yet clear, and further clinical trials need to be conducted. Table 6 SSRI Summary and comparison. Table 6 SSRI Classification Mechanisms related to COVID-19 Advantages Limitations Fluvoxamine Sigma-1 receptor agonist Anti-inflammatory effect by reducing important proinflammatory cytokines such as (TNF-α and IL-6). Thus, ameliorates sepsis and its complications No QT prolongation vs other SSRI Further investigation is needed. Sertraline & Fluoxetine Lysosomotropic agent Neuralization of endolysosomal pH, interfering with viral replication by: 1. Hindering viral release into the cytosol 2. Inactive fusion peptides Less toxic with a shorter half-life compared to chloroquine and hydroxychloroquine. Only inhibit the endocytic pathway, thus viral replication is not completely stopped. Not selective Fluoxetine Functional inhibitors of Acid sphingomyelinase 1. Degradation of acid sphingomyelinase, an important signaling enzyme. 2. Accumulation of cholesterol Generally, well tolerated. Reduced the risk of mortality and intubation. Drug interaction (inhibit CYP2C19 and CYP2D6)

Melatonin

There are several studies reporting the possible beneficial effect of melatonin, especially in elderly [94] . Melatonin biosynthesis has long been restricted to the pineal gland mainly at night. Nevertheless, increasing data indicate its release from the mitochondria. This means that most of the cells, including macrophages, synthesize melatonin. Melatonin possesses anti-inflammatory, antioxidant, immunomodulatory effect and preserves mitochondrial function during conditions of oxidative stress (see Table 7 ) [95] . Impressively, Veltri, et al., reported that the liver, heart and brain have the highest mitochondrial density. This means they would be most protected by melatonin during sepsis, which is a major cause of morbidity in COVID-19 patients [96] , [97] . Table 7 Melatonin mechanism against SARS-CoV-19. Table 7 Image 1

Suppression of the hyper-inflammatory state would ultimately also improve lung function. Especially when considering patients in the ICU that suffer additional pulmonary stress and inflammation due to mechanical ventilation [98] . However, melatonin has no documented direct antiviral activity and is therefore suggested as adjuvant therapy [94] , [99] .

It has been noticed that viruses can inhibit melatonin release both form the pineal gland and the mitochondria. Exogenous melatonin administration in several infections exhibited a protective effect and limited the intensity of the infection [100] . It is suspected that COVID-19 similarly inhibits melatonin synthesis, thus reducing melatonin plasma levels.

Administration of melatonin in COVID-19 patients would therefore reduce the cytokine storm and the generation of free radicals. Consequently, limiting not only alveolar damage, but also protect other vital organs. Several preclinical studies have demonstrated the positive effect of melatonin in reversing organ damage and increasing survival in septic shock [54] , [101] . Melatonin in several models successfully managed sepsis and restored vital organ function [102] .

The effect of melatonin is even more advantageous in the geriatric population. Upon aging, the body’s functions decline, and less melatonin is released, resulting in more severe cases. Both age and chronic conditions worsen prognosis and are associated with decreased melatonin levels [100] , [103] . This was evidenced by better response in aged rats, as reported by Escames, et al., [102] . In addition, supplemental melatonin administered to rodents delayed both aging and its associated chronic conditions [104] . Various clinical trials also confirm effectiveness. In one study, a dose of 60 mg/day parenteral melatonin, was administered to ICU COVID-19 patients. Melatonin reduced the severity of sepsis, improved discharge by 40% and abolished mortality rates [105] . These promising findings encouraged many researchers to conduct further clinical trials in hospitalized ICU COVID-19 infected patients [106] . As of 2021, there are two ongoing clinical trials, both approved by Spanish agency of medicine. Escames et al., (EudraCT, 2020-001808-42) aims to find an effective dose of melatonin against COVID-19 [105] . The second trial (EudraCT, 2020-001530-35) tests 2 mg of Circadin® (melatonin) as a prophylactic agent in high-risk individuals [107] .

Another important role of melatonin, especially in elderly, is its effect on the circadian rhythm [95] , [97] . Defective sleep patterns largely weaken the immune system and increase susceptibility to infection. This is further amplified by stress and lockdown [108] . This indicates that melatonin will not only assist in preventing infection, but also aim to regulate defective sleep patterns. Melatonin is safe even at high doses, readily available and can be taken orally. An oral dose of 50–100 mg half an hour before bedtime, has been suggested for the geriatric population [109] . However, firm guidelines on the use of melatonin in COVID-19 patients are lacking. Therefore, further investigations are needed to drive firm conclusions.

Conclusion

Despite the large number of clinical trials and available vaccines, cure against COVID-19 is still lacking. Patients with mild COVID-19 should be limited to supportive care and symptomatic treatment according to presentation. Selected monoclonal antibody combinations (casirivimab with imdevimab or bamlanivimab with etesevimab) are FDA approved for EUA in mild to moderate no-hospitalized COVID-19 patient at risk for clinical deterioration. Although inhaled neutralizing Nbs are almost certainly superior to monoclonal antibodies, they still lack clinical evidence for their efficacy. Ivermectin use as per WHO recommendations should be limited to clinical trials. For hospitalized COVID-19 patients that meet the WHO severity criteria, systemic corticosteroids or a combination of corticosteroids with an IL-6 blocker (tocilizumab or Sarilumab) is strongly recommended. While WHO only suggests the use of remdesivir and baricitinib in clinical trial, the NIH recommends the use of either remdesivir or baricitinib in combination with dexamethasone in hospitalized patients that require oxygen therapy. Other agents like camostat mesylate and plitidepsin seem promising, but still await the results of phase III clinical trials. Preliminary studies on repurposed melatonin and SSRI suggest their positive effect against COVID-19 in both outpatient and inpatient settings. Therefore, we suggest further investigations and larger clinical trials to determine their efficacy and place of therapy.

Although the fate of this pandemic is unpredictable, as the virus continues to mutate, history of previous coronavirus strains forecast that COVID-19 might end up similarly to influenza. Thus, even with the end of this pandemic, effective treatment will probably always be needed.

CRediT authorship contribution statement

Soraya Mouffak : Conceptualization, collection of data and original draft preparation Qamar Shubbar : Conceptualization, collection of data and original draft preparation Ekram Saleh : manuscript reviewing and editing Raafat El-Awady: Conceptualization, Supervision, manuscript reviewing and editing.

Conflict of interest statement

All authors declare that they have no conflict of interest.

References

1 Situational report. World Health organization 2021.

2 About the virus. World Health organization 2020.

3 Wu Y. Chen C. Chan Y. The outbreak of COVID-19: an overview J. Chin. Med. Assoc. 83 3 2020 217 220 32134861 10.1097/JCMA.0000000000000270 PMC7153464

4 Aronson J.K. Coronaviruses—A General Introduction 2020 Centre for Evidence-Based Medicine

5 Glebov O.O. Understanding SARS‐CoV‐2 endocytosis for COVID‐19 drug repurposing FEBS J. 287 17 2020 3664 3671 32428379 10.1111/febs.15369 PMC7276759

6 National Guidelines for Clinical Management and Treatment of COVID-19. 2020 1 June.

7 Coronavirus (COVID-19) vaccine. U.S. Food and Drug Administration 2021 April 13,.

8 Zhang J.J. Dong X. Cao Y.Y. Yuan Y.D. Yang Y.B. Yan Y.Q. Akdis C.A. Gao Y.D. Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China Allergy 75 7 2020 1730 1741 32077115 10.1111/all.14238

9 Xu X.W. Wu X.X. Jiang X.G. Xu K.J. Ying L.J. Ma C.L. Li S.B. Wang H.Y. Zhang S. Gao H.N. Sheng J.F. Cai H.L. Qiu Y.Q. Li L.J. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series Br. Med. J. 2020 m606 32075786 10.1136/bmj.m606 PMC7224340

10 Cohen P., Blau J., Bloom A. COVID-19: Outpatient evaluation and management of acute illness in adults.

11 Yufang S. Ying W. Changsun S. COVID-19 infection: the perspective on immune response Cell Death Differ. 27 2020 5 10.1038/s41418-020-0530-3 PMC7091918 32205856

12 Desai N. Neyaz A. Szabolcs A. Shih A.R. Chen J.H. Thapar V. Nieman L.T. Solovyov A. Mehta A. Lieb D.J. Kulkarni A.S. Jaicks C. Xu K.H. Raabe M.J. Pinto C.J. Juric D. Chebib I. Colvin R.B. Kim A.Y. Monroe R. Warren S.E. Danaher P. Reeves J.W. Gong J. Rueckert E.H. Greenbaum B.D. Hacohen N. Lagana S.M. Rivera M.N. Sholl L.M. Stone J.R. Ting D.T. Deshpande V. Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection Nat. Commun. 11 1 2020 1 15 33298930 10.1038/s41467-020-20139-7 PMC7725958

13 Tian W. Zhang N. Jin R. Feng Y. Wang S. Gao S. Gao R. Wu G. Tian D. Tan W. Chen Y. Gao G.F. Wong C. Immune suppression in the early stage of COVID-19 disease Nat. Commun. 11 1 2020 1 8 33203833 10.1038/s41467-020-19706-9 PMC7673112

14 Caly L. Druce J.D. Catton M.G. Jans D.A. Wagstaff K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Antivir. Res 178 2020 104787 10.1016/j.antiviral.2020.104787 PMC7129059 32251768

15 Juarez M. Schcolnik-Cabrera A. Dueñas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug Am. J. Cancer Res. 8 2 2018 317 331 29511601 PMC5835698

16 Heidary F. Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen J. Antibiot. 73 9 2020 593 602 10.1038/s41429-020-0336-z PMC7290143 32533071

17 Caly L. Druce J.D. Catton M.G. Jans D.A. Wagstaff K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Antivir. Res. 178 2020 104787 10.1016/j.antiviral.2020.104787 PMC7129059 32251768

18 Scheim D. Ivermectin for COVID-19 treatment: clinical response at quasi-threshold doses via hypothesized alleviation of CD147-mediated vascular occlusion. Available at SSRN 3636557 2020.

19 Rajter J.C. Sherman M.S. Fatteh N. Vogel F. Sacks J. Rajter J. Use of ivermectin is associated with lower mortality in hospitalized patients with Coronavirus Disease 2019: The ivermectin in COVID nineteen study Chest 159 1 2021 85 92 33065103 10.1016/j.chest.2020.10.009 PMC7550891

20 Rahman M.A. Iqbal S.A. Islam M.A. Niaz M.K. Hussain T. Siddiquee T.H. Comparison of viral clearance between ivermectin with doxycycline and hydroxychloroquine with azithromycin in COVID-19 patients J. Bangladesh Coll. Physicians Surg. 2020 5 9

21 Behera P., Patro BK, Singh AK, Chandanshive PD, Ravikumar SR, Pradhan SK, et al. Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: A matched case-control study. medRxiv 2020. 10.1371/journal.pone.0247163 PMC7886121 33592050

22 Gklinos P. Papadopoulou M. Stanulovic V. Mitsikostas D.D. Papadopoulos D. Monoclonal antibodies as neurological therapeutics Pharmaceuticals 14 2 2021 92 33530460 10.3390/ph14020092 PMC7912592

23 Berger M. Shankar V. Vafai A. Therapeutic applications of monoclonal antibodies Am. J. Med. Sci. 324 1 2002 14 30 12120821 10.1097/00000441-200207000-00004 PMC7093874

24 Bessalah S. Jebahi S. Mejri N. Salhi I. Khorchani T. Hammadi M. Perspective on therapeutic and diagnostic potential of camel nanobodies for coronavirus disease-19 (COVID-19) 3 Biotech 11 2 2021 1 14 10.1007/s13205-021-02647-5 PMC7820838 33500874

25 Marovich M. Mascola J.R. Cohen M.S. Monoclonal antibodies for prevention and treatment of COVID-19 J. Am. Med. Assoc. 324 2 2020 131 132 10.1001/jama.2020.10245 32539093

26 Monoclonal antibodies. COVID-19 Real-Time Learning Networking 2021.

27 Fact sheet got health care providers Emergency Use Authorization (EUA) casirivimab and imdevimab. Fda.gov. 2021.

28 Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19. 2021.

29 Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Monoclonal Antibody Bamlanivimab. Fda.gov. 2021 April 16,.

30 Fact sheet got health care providers Emergency Use Authorization (EUA) of bamlanivimab. Fda.gov. 2021.

31 FDA authorizes revisions to fact sheets to address SARS-CoV-2 variants for monoclonal antibody products under emergency use authorization. Fda.gov. 2021.

32 Lloyd E.C. Gandhi T.N. Petty L.A. Monoclonal Antibodies for COVID-19 J. Am. Med. Assoc. 325 10 2021 1015 10.1001/jama.2021.1225 33544136

33 Cohen M.S. Monoclonal antibodies to disrupt progression of early covid-19 infection N. Engl. J. Med. 384 2021 289 291 33471984 10.1056/NEJMe2034495 PMC7844860

34 Nevan J., Krogan;‡, Schoof. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike Downloaded from. QCRG Structural Biology Consortium 2020;13. 10.1126/science.abe3255 PMC7857409 33154106

35 Zare H. Rajabibazl M. Rasooli I. Ebrahimizadeh W. Bakherad H. Ardakani L.S. Gargari S.L. Production of nanobodies against prostate-specific membrane antigen (PSMA) recognizing LnCaP cells Int. J. Biol. Markers 29 2 2014 169 179 10.5301/jbm.5000063 24425321

36 Martinez-Delgado G. Inhaled nanobodies against COVID-19 Nat. Rev. Immunol. 20 10 2020 593 10.1038/s41577-020-00443-5 PMC7461751 32873887

37 Koenig P.A. Das H. Liu H. Kümmerer B.M. Gohr F.N. Jenster L.M. Schiffelers L. Tesfamariam Y.M. Uchima M. Wuerth J.D. Gatterdam K. Ruetalo N. Christensen M.H. Fandrey C.I. Normann S. Tödtmann J. Pritzl S. Hanke L. Boos J. Yuan M. Zhu X. Schmid-Burgk J.L. Kato H. Schindler M. Wilson I.A. Geyer M. Ludwig K.U. Hällberg B.M. Wu N.C. Schmidt F.I. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape Science 371 2021 6530 10.1126/science.abe6230 PMC7932109 33436526

38 Muyldermans S. Applications of nanobodies Annu. Rev. Anim. Biosci. 9 2021 401 421 33233943 10.1146/annurev-animal-021419-083831

39 Hassanzadeh-Ghassabeh G. Devoogdt N. De Pauw P. Vincke C. Muyldermans S. Nanobodies and their potential applications Nanomedicine 8 6 2013 1013 1026 23730699 10.2217/nnm.13.86

40 Huo J. Le Bas A. Ruza R.R. Duyvesteyn H. Mikolajek H. Malinauskas T. Tan T.K. Rijal P. Dumoux M. Ward P.N. Ren J. Zhou D. Harrison P.J. Weckener M. Clare D.K. Vogirala V.K. Radecke J. Moynié L. Zhao Y. Gilbert-Jaramillo J. Knight M.L. Tree J.A. Buttigieg K.R. Coombes N. Elmore M.J. Carroll M.W. Carrique L. Shah P. James W. Townsend A.R. Stuart D.I. Owens R.J. Naismith J.H. Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2 Nat. Struct. Mol. Biol. 27 9 2020 846 854 32661423 10.1038/s41594-020-0469-6

41 Xiang Y. Nambulli S. Xiao Z. Liu H. Sang Z. Duprex W.P. Schneidman-Duhovny D. Zhang C. Shi Y. Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2 Science 370 6523 2020 1479 1484 33154108 10.1126/science.abe4747 PMC7857400

42 Peyvandi F. Scully M. Kremer Hovinga J.A. Knöbl P. Cataland S. De Beuf K. Callewaert F. De Winter H. Zeldin R.K. Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura J. Thromb. Haemost. 15 7 2017 1448 1452 28445600 10.1111/jth.13716

43 Nambulli S. Xiang Y. Tilston-Lunel N.L. Rennick L.J. Sang Z. Klimstra W.B. Reed D.S. Crossland N.A. Shi Y. Duprex W.P. Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses Sci. Adv. 7 22 2021 eabh0319 34039613 10.1126/sciadv.abh0319 PMC8153718

44 Li T. Cai H. Yao H. Zhou B. Zhang N. van Vlissingen M.F. Kuiken T. Han W. GeurtsvanKessel C.H. Gong Y. Zhao Y. Shen Q. Qin W. Tian X.X. Peng C. Lai Y. Wang Y. Hutter C. Kuo S.M. Bao J. Liu C. Wang Y. Richard A.S. Raoul H. Lan J. Seeger M.A. Cong Y. Rockx B. Wong G. Bi Y. Lavillette D. Li D. A synthetic nanobody targeting RBD protects hamsters from SARS-CoV-2 infection Nat. Commun. 12 1 2021 1 13 34330908 10.1038/s41467-021-24905-z PMC8324831

45 Pymm P., Adair A., Chan L., Cooney JP, Mordant FL, Allison CC, et al. Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice. Proceedings of the National Academy of Sciences 2021;118(19). 10.1073/pnas.2101918118 PMC8126837 33893175

46 Schoof M. Faust B. Saunders R.A. Sangwan S. Rezelj V. Hoppe N. Boone M. Billesbølle C.B. Puchades C. Azumaya C.M. Kratochvil H.T. Zimanyi M. Deshpande I. Liang J. Dickinson S. Nguyen H.C. Chio C.M. Merz G.E. Thompson M.C. Diwanji D. Schaefer K. Anand A.A. Dobzinski N. Zha B.S. Simoneau C.R. Leon K. White K.M. Chio U.S. Gupta M. Jin M. Li F. Liu Y. Zhang K. Bulkley D. Sun M. Smith A.M. Rizo A.N. Moss F. Brilot A.F. Pourmal S. Trenker R. Pospiech T. Gupta S. Barsi-Rhyne B. Belyy V. Barile-Hill A.W. Nock S. Liu Y. Krogan N.J. Ralston C.Y. Swaney D.L. García-Sastre A. Ott M. Vignuzzi M. QCRG Structural Biology C. Walter P. Manglik A. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike Science 370 6523 2020 1473 1479 33154106 10.1126/science.abe3255 PMC7857409

47 Dong J. Huang B. Jia Z. Wang B. Gallolu Kankanamalage S. Titong A. Liu Y. Development of multi-specific humanized llama antibodies blocking SARS-CoV-2/ACE2 interaction with high affinity and avidity Emerg. Microbes Infect. 9 1 2020 1034 1036 32403995 10.1080/22221751.2020.1768806 PMC8284970

48 Chi X. Liu X. Wang C. Zhang X. Li X. Hou J. Ren L. Jin Q. Wang J. Yang W. Humanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain Nat. Commun. 11 1 2020 1 7 32913273 10.1038/s41467-020-18387-8 PMC7483421

49 Malone R.W. Tisdall P. Fremont-Smith P. Liu Y. Huang X.P. White K.M. Miorin L. Moreno E. Alon A. Delaforge E. Hennecker C.D. Wang G. Pottel J. Blair R.V. Roy C.J. Smith N. Hall J.M. Tomera K.M. Shapiro G. Mittermaier A. Kruse A.C. García-Sastre A. Roth B.L. Glasspool-Malone J. Ricke D.O. COVID-19: famotidine, histamine, mast cells, and mechanisms Front. Pharmacol. 12 2021 633680 10.3389/fphar.2021.633680 PMC8021898 33833683

50 Janowitz T. Gablenz E. Pattinson D. Wang T.C. Conigliaro J. Tracey K. Tuveson D. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series Gut 69 9 2020 1592 1597 32499303 10.1136/gutjnl-2020-321852 PMC7299656

51 Freedberg D.E. Conigliaro J. Wang T.C. Tracey K.J. Callahan M.V. Abrams J.A. Famotidine Research G. Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study Gastroenterology 159 3 2020 1129 1131. e3 32446698 10.1053/j.gastro.2020.05.053 PMC7242191

52 Hogan Ii R.B. Hogan Iii R.B. Cannon T. Rappai M. Studdard J. Paul D. Dooley T.P. Dual-histamine receptor blockade with cetirizine-famotidine reduces pulmonary symptoms in COVID-19 patients Pulm. Pharmacol. Ther. 63 2020 101942 10.1016/j.pupt.2020.101942 PMC7455799 32871242

53 Mather J.F. Seip R.L. McKay R.G. Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19 Am. J. Gastroenterol. 115 2020 1617 1623 32852338 10.14309/ajg.0000000000000832 PMC7473796

54 Wu C. Liu Y. Yang Y. Zhang P. Zhong W. Wang Y. Wang Q. Xu Y. Li M. Li X. Zheng M. Chen L. Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods Acta Pharm. Sin. B 10 5 2020 766 788 32292689 10.1016/j.apsb.2020.02.008 PMC7102550

55 Loffredo M., Lucero H., Chen D., O'Connell A., Bergqvist S., Munawar A., et al. The Effect of famotidine on SARS-CoV-2 proteases and virus replication. bioRxiv 2020. 10.1038/s41598-021-84782-w PMC7940615 33686143

56 Siddiqi H.K. Mehra M.R. COVID-19 illness in native and immunosuppressed states: a clinical–therapeutic staging proposal J. Heart Lung Transplant. 39 5 2020 405 407 32362390 10.1016/j.healun.2020.03.012 PMC7118652

57 Samaee H. Mohsenzadegan M. Ala S. Maroufi S.S. Moradimajd P. Tocilizumab for treatment patients with COVID-19: Recommended medication for novel disease Int. Immunopharmacol. 89 2020 107018 10.1016/j.intimp.2020.107018 PMC7494278 33045577

58 Tanaka T. Narazaki M. Kishimoto T. IL-6 in inflammation, immunity, and disease Cold Spring Harb. Perspect. Biol. 6 10 2014 016295 10.1101/cshperspect.a016295 PMC4176007 25190079

59 Horby PW, Pessoa-Amorim G., Peto L., Brightling CE, Sarkar R., Thomas K., et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. Medrxiv 2021.

60 Salama C. Han J. Yau L. Reiss W.G. Kramer B. Neidhart J.D. Criner G.J. Kaplan-Lewis E. Baden R. Pandit L. Cameron M.L. Garcia-Diaz J. Chávez V. Mekebeb-Reuter M. Lima de Menezes F. Shah R. González-Lara M.F. Assman B. Freedman J. Mohan S.V. Tocilizumab in patients hospitalized with Covid-19 pneumonia N. Engl. J. Med. 384 1 2021 20 30 33332779 10.1056/NEJMoa2030340 PMC7781101

61 A.C. Gordon, P.R. Mouncey, F. Al-Beidh, K.M. Rowan, A.D. Nichol, Y.M. Arabi, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19–Preliminary report. medRxiv 2021:2021.01. 07.21249390.

62 Rosas I.O. Bräu N. Waters M. Go R.C. Hunter B.D. Bhagani S. Skiest D. Aziz M.S. Cooper N. Douglas I.S. Savic S. Youngstein T. Del Sorbo L. Cubillo Gracian A. De La Zerda D.J. Ustianowski A. Bao M. Dimonaco S. Graham E. Matharu B. Spotswood H. Tsai L. Malhotra A. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia N. Engl. J. Med. 384 2021 1503 1516 33631066 10.1056/NEJMoa2028700 PMC7953459

63 Banerjee I. Mohabeer P. Shukla A. Kashyap A. Robinson J. COVID-19: recent advances in epidemiology, virology, etiopathogenesis, clinical trials and vaccine development J. Biomed. Sci. 7 1 2020 18 27

64 Ahmed M.H. Hassan A. Dexamethasone for the treatment of coronavirus disease (COVID-19): a review SN Compr. Clin. Med. 2020 1 10 10.1007/s42399-020-00610-8 PMC7599121 33163859

65 A. Hodgens, T. Sharman, Corticosteroids. StatPearls [Internet] 2020. 32119499

66 Johns M. George S. Taburyanskaya M. Poon Y.K. A review of the evidence for corticosteroids in COVID-19 J. Pharm. Pract. 2021 897190021998502 0897190021998502 10.1177/0897190021998502 33719698

67 Ahmed M.H. Hassan A. Dexamethasone for the treatment of coronavirus disease (COVID-19): a review SN Compr. Clin. Med. 2020 1 10 10.1007/s42399-020-00610-8 PMC7599121 33163859

68 Raju R. Prajith V. Biatris P.S. Therapeutic role of corticosteroids in COVID-19: a systematic review of registered clinical trials Fut. J. Pharm. Sci. 7 1 2021 1 18 10.1186/s43094-021-00217-3 PMC7968560 33754123

69 Annane D. Corticosteroids for COVID-19 J. Intensive Med. 1 2021 14 25 10.1016/j.jointm.2021.01.002 PMC7919540 36943816

70 Williams D.M. Clinical pharmacology of corticosteroids Respir. Care 63 6 2018 655 670 29794202 10.4187/respcare.06314

71 Khan S.U. Htar T. Deciphering the binding mechanism of Dexamethasone against SARS-CoV-2 main protease: computational molecular modelling approach ChemRxivorg 2020 10

72 Tomazini B.M. Maia I.S. Cavalcanti A.B. Berwanger O. Rosa R.G. Veiga V.C. Avezum A. Lopes R.D. Bueno F.R. Silva M. Baldassare F.P. Costa E. Moura R. Honorato M.O. Costa A.N. Damiani L.P. Lisboa T. Kawano-Dourado L. Zampieri F.G. Olivato G.B. Righy C. Amendola C.P. Roepke R. Freitas D. Forte D.N. Freitas F. Fernandes C. Melro L. Junior G. Morais D.C. Zung S. Machado F.R. Azevedo L. COALITION COVID- Brazil III I Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial J. Am. Med. Assoc. 324 13 2020 1307 1316 10.1001/jama.2020.17021 PMC7489411 32876695

73 Wootton D. Dexamethasone in hospitalized patients with COVID-19 N. Engl. J. Med. 384 8 2021 693 704 32678530 10.1056/NEJMoa2021436 PMC7383595

74 The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. NEJM 2021 Feb 25,;384:693–704. 10.1056/NEJMoa2021436 PMC7383595 32678530

75 Ryskamp D.A. Korban S. Zhemkov V. Kraskovskaya N. Bezprozvanny I. Neuronal sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases Front. Neurosci. 13 2019 862 31551669 10.3389/fnins.2019.00862 PMC6736580

76 Peviani M. Salvaneschi E. Bontempi L. Petese A. Manzo A. Rossi D. Salmona M. Collina S. Bigini P. Curti D. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation Neurobiol. Dis. 62 2014 218 232 24141020 10.1016/j.nbd.2013.10.010

77 Vela J.M. Repurposing sigma-1 receptor ligands for Covid-19 therapy? Front. Pharmacol. 11 2020 582310 10.3389/fphar.2020.582310 PMC7751758 33364957

78 Rosen D.A. Seki S.M. Fernández-Castañeda A. Beiter R.M. Eccles J.D. Woodfolk J.A. Gaultier A. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis Sci. Transl. Med. 11 2019 eaau5266 30728287 10.1126/scitranslmed.aau5266 PMC6936250

79 Colantuoni A. Martini R. Caprari P. Ballestri M. Capecchi P.L. Gnasso A. Lo Presti R. Marcoccia A. Rossi M. Caimi G. COVID-19 sepsis and microcirculation dysfunction Front. Physiol. 11 2020 747 32676039 10.3389/fphys.2020.00747 PMC7333313

80 Liu D. Wang Q. Zhang H. Cui L. Shen F. Chen Y. Sun J. Gan L. Sun J. Wang J. Zhang J. Cai Q. Deng J. Jiang J. Zeng L. Viral sepsis is a complication in patients with Novel Corona Virus Disease (COVID-19) Med. Drug Discov. 8 2020 100057 10.1016/j.medidd.2020.100057 PMC7378467 32838292

81 Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. Qiu Y. Wang J. Liu Y. Wei Y. Xia J. Yu T. Zhang X. Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Lancet 395 10223 2020 507 513 32007143 10.1016/S0140-6736(20)30211-7 PMC7135076

82 Ragab D. Salah Eldin H. Taeimah M. Khattab R. Salem R. The COVID-19 cytokine storm; what we know so far Front. Immunol. 11 2020 1446 32612617 10.3389/fimmu.2020.01446 PMC7308649

83 Lenze E.J. Mattar C. Zorumski C.F. Stevens A. Schweiger J. Nicol G.E. Miller J.P. Yang L. Yingling M. Avidan M.S. Reiersen A.M. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial J. Am. Med. Assoc. 324 22 2020 2292 2300 10.1001/jama.2020.22760 PMC7662481 33180097

84 Assimon M.M. Brookhart M.A. Flythe J.E. Comparative cardiac safety of selective serotonin reuptake inhibitors among individuals receiving maintenance hemodialysis J. Am. Soc. Nephrol. 30 4 2019 611 623 30885935 10.1681/ASN.2018101032 PMC6442344

85 Blaess M. Kaiser L. Sauer M. Csuk R. Deigner H. COVID-19/SARS-CoV-2 infection: lysosomes and lysosomotropism implicate new treatment strategies and personal risks Int. J. Mol. Sci. 21 14 2020 4953 32668803 10.3390/ijms21144953 PMC7404102

86 Khan N. Chen X. Geiger J.D. Role of endolysosomes in severe acute respiratory syndrome coronavirus-2 infection and coronavirus disease 2019 pathogenesis: implications for potential treatments Front. Pharmacol. 11 2020 595888 10.3389/fphar.2020.595888 PMC7723437 33324224

87 Mir M.A. Mansoor S. Bhat A. Rehman M.U. Ahmad A. Ahmad P. Lysosomotropic properties of sodium bicarbonate and covid-19 Farmacia 68 5 2020 771 778

88 Norinder U. Tuck A. Norgren K. Kos V.M. Existing highly accumulating lysosomotropic drugs with potential for repurposing to target COVID-19 Biomed. Pharmacother. = Biomed. Pharmacother. 130 2020 110582 10.1016/j.biopha.2020.110582 PMC7392152 32763818

89 Schloer S. Brunotte L. Goretzko J. Mecate-Zambrano A. Korthals N. Gerke V. Ludwig S. Rescher U. Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine Emerg. Microbes Infect. 9 1 2020 2245 2255 32975484 10.1080/22221751.2020.1829082 PMC7594754

90 Kornhuber J. Tripal P. Reichel M. Mühle C. Rhein C. Muehlbacher M. Groemer T.W. Gulbins E. Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications Cell. Physiol. Biochem. 26 1 2010 9 20 20502000 10.1159/000315101

91 Carpinteiro A. Edwards M.J. Hoffmann M. Kochs G. Gripp B. Weigang S. Adams C. Carpinteiro E. Gulbins A. Keitsch S. Sehl C. Soddemann M. Wilker B. Kamler M. Bertsch T. Lang K.S. Patel S. Wilson G.C. Walter S. Hengel H. Pöhlmann S. Lang P.A. Kornhuber J. Becker K.A. Ahmad S.A. Fassbender K. Gulbins E. Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells Cell Rep. Med. 1 8 2020 100142 10.1016/j.xcrm.2020.100142 PMC7598530 33163980

92 A.R. Eugene, Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers. medRxiv 2020.

93 N. Hoertel, M.S. Rico, R. Vernet, N. Beeker, A. Jannot, A. Neuraz, et al. Association between SSRI antidepressant use and reduced risk of intubation or death in hospitalized patients with coronavirus disease 2019: A multicenter retrospective observational study. MedRxiv 2020.

94 Zhang R. Wang X. Ni L. Di X. Ma B. Niu S. Liu C. Reiter R.J. COVID-19: melatonin as a potential adjuvant treatment Life Sci. 250 2020 117583 10.1016/j.lfs.2020.117583 PMC7102583 32217117

95 Anderson G.M. Fluvoxamine, melatonin and COVID-19 Psychopharmacology 238 2 2021 611 33392622 10.1007/s00213-020-05753-z PMC7779245

96 Veltri K.L. Espiritu M. Singh G. Distinct genomic copy number in mitochondria of different mammalian organs J. Cell Physiol. 143 1 1990 160 164 2318903 10.1002/jcp.1041430122

97 Biancatelli Ruben Manuel Luciano Colunga Berrill M. Mohammed Y.H. Marik P.E. Melatonin for the treatment of sepsis: the scientific rationale J. Thorac. Dis. 12 Suppl 1 2020 S54 S65 32148926 10.21037/jtd.2019.12.85 PMC7024751

98 Hardeland R. Tan D. Protection by melatonin in respiratory diseases: valuable information for the treatment of COVID-19 Melatonin Res. 3 3 2020 264 275

99 Sehirli A.O. Sayiner S. Serakinci N. Role of melatonin in the treatment of COVID-19; as an adjuvant through cluster differentiation 147 (CD147) Mol. Biol. Rep. 47 2020 8229 8233 32920757 10.1007/s11033-020-05830-8 PMC7486968

100 Reiter R.J. Abreu-Gonzalez P. Marik P.E. Dominguez-Rodriguez A. Therapeutic algorithm for use of melatonin in patients with COVID-19 Front. Med. 7 2020 226 10.3389/fmed.2020.00226 PMC7242729 32574327

101 Carrillo-Vico A. Lardone P.J. Naji L. Fernández-Santos J.M. Martín-Lacave I. Guerrero J.M. Calvo J.R. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro‐/anti‐inflammatory cytokine network, protection against oxidative damage and anti‐apoptotic effects J. Pineal Res. 39 4 2005 400 408 16207296 10.1111/j.1600-079X.2005.00265.x

102 Escames G. López L.C. Ortiz F. Ros E. Acuña-Castroviejo D. Age-dependent lipopolysaccharide-induced iNOS expression and multiorgan failure in rats: effects of melatonin treatment Exp. Gerontol. 41 11 2006 1165 1173 17049787 10.1016/j.exger.2006.09.002

103 Öztürk G. Akbulut K.G. Güney Ş. Melatonin, aging, and COVID-19: could melatonin be beneficial for COVID-19 treatment in the elderly? Turk. J. Med. Sci. 50 6 2020 1504 1512 32777902 10.3906/sag-2005-356 PMC7605095

104 Poeggeler B. Reiter R.J. Tan D. Chen L. Manchester L.C. Melatonin, hydroxyl radical‐mediated oxidative damage, and aging: a hypothesis J. Pineal Res. 14 4 1993 151 168 8102180 10.1111/j.1600-079x.1993.tb00498.x

105 Acuña‐Castroviejo D. Escames G. Figueira J.C. de la Oliva P. Borobia A.M. Acuña‐Fernández C. Clinical trial to test the efficacy of melatonin in COVID‐19 J. Pineal Res. 69 3 2020 12683 10.1111/jpi.12683 PMC7435535 32770854

106 Vlachou M. Siamidi A. Dedeloudi A. Konstantinidou S.K. Papanastasiou I.P. Pineal hormone melatonin as an adjuvant treatment for COVID 19 Int. J. Mol. Med. 47 4 2021 1 10.3892/ijmm.2021.4880 PMC7891824 33576451

107 Eudract_number: 2020 001530 35. EU Clinical Trials Register. 2020.

108 Morin C.M. Carrier J. Bastien C. Godbout R. Sleep and circadian rhythm in response to the COVID-19 pandemic Can. J. Public Health 111 5 2020 654 657 32700231 10.17269/s41997-020-00382-7 PMC7375451

109 Cardinali D.P. Brown G.M. Reiter R.J. Pandi-Perumal S.R. Elderly as a high-risk group during COVID-19 pandemic: effect of circadian misalignment, sleep dysregulation and melatonin administration Sleep Vigil. 2020 1 7 33015537 10.1007/s41782-020-00111-7 PMC7519696