key: cord-0928851-gsoxaso9 authors: Scavone, Cristina; Brusco, Simona; Bertini, Michele; Sportiello, Liberata; Rafaniello, Concetta; Zoccoli, Alice; Berrino, Liberato; Racagni, Giorgio; Rossi, Francesco; Capuano, Annalisa title: Current pharmacological treatments for COVID‐19: What's next? date: 2020-05-15 journal: Br J Pharmacol DOI: 10.1111/bph.15072 sha: e1e8154b24ac6d54850c09ba69fef6da7f1d911e doc_id: 928851 cord_uid: gsoxaso9 Since December 2019 SARS‐Cov‐2 was found responsible for the disease COVID‐19, which has spread worldwide. No specific therapies/vaccines are yet available for the treatment of COVID‐19. Drug repositioning may offer a strategy and a number of drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab. This paper describes the main pharmacological properties of such drugs administered to patients with COVID‐19, focusing on their antiviral, immune‐modulatory and/or anti‐inflammatory actions. Where available, data from clinical trials involving patients with COVID‐19 are reported. Preliminary clinical trials seem to support their benefit. However, such drugs in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. Nevertheless, while waiting for effective preventive measures i.e. vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. Their results will help us in defining the best way to treat COVID‐19 and reducing its symptoms and complications. outbreak a pandemic. According to current evidence, the epidemic started with animal to human transmission (Benvenuto et al., 2020) . A phylogenetic analysis has demonstrated that the new coronavirus significantly clustered with the sequence of bat SARS-like coronavirus (Benvenuto et al., 2020) . It has envelopes, and the particles are round or oval with diameter from 60 to 140 nm (National Health Commission & State Administration of Traditional Chinese Medicine, 2020). As for other coronaviruses, the replication of SARS-CoV-2 starts with the attachment to the host cell through interactions between the Spike protein (S protein) and its target protein. In this phase, the virus interacts with ACE2 enzyme, which is attached to the outer surface of the cell membrane, and a serine protease TMPRSS2. Once into the cell, replication and transcription phases start (Fehr & Perlman, 2015; Hoffmann et al., 2020) . The transmission among people occurs through respiratory droplets (Q. . In mild cases, SARS-Cov-2 infection can cause fever, fatigue and dry cough, while severe cases frequently cause pneumonia, respiratory and kidney failure. Apart from respiratory and flu-like symptoms, this infection may be complicated by lymphopaenia and interstitial pneumonia with high levels of proinflammatory cytokines, such as IL-1, IL-2, IL-6, granulocyte-colony stimulating factor (G-CSF), IP-10 (C-X-C motif chemokine 10; CXCL10) and TNF-α. This condition leads to the so-called cytokine storm which, in turn, can induce acute respiratory distress syndrome (ARDS), organ failure and sepsis, potentially progressing to patient's death . Patients with mild form of COVID-19 should be eligible for isolation and, sometimes, symptomatic treatments (mainly paracetamol for fever control). On the other hand, patients presenting severe pneumonia require hospitalizations and frequently access to intensive care units, where mechanical ventilation can be provided. For these patients, pharmacological treatments are strongly needed. At present, neither specific drugs nor vaccines are available for the treatment of COVID-19. Since there is no time to evaluate new drug therapies, drug repositioning may offer a strategy to efficiently control clinical course of the disease and the spread of pandemic (Kruse, 2020) . In this paper, we aim to provide an overview of treatments currently administered in patients with COVID-19, mainly focusing on antivirals and drugs with immune-modulatory and/or anti-inflammatory properties, their pharmacological features and achievement in term of patients' clinical outcomes. A close review of drugs that are currently under clinical development is provided as well. The mechanism of action, main safety concerns and drug-drug interactions of antiviral, immune-modulatory and anti-inflammatory agents currently used or under clinical development for the treatment of are reported in Table 1 . A large number of antiviral agents, many of which are used for the treatment of human immunodeficiency virus (HIV), hepatitis and flu symptoms, are currently administered off-label worldwide in patients with COVID-19 or are under clinical evaluation for the treatment of the disease. Here, we discuss the most used antivirals in terms of pharmacodynamics, potential for the treatment of COVID-19 and data from clinical studies where available. A brief analysis of antivirals less used is also presented. The combination lopinavir/ritonavir, which is indicated with other antiretroviral medicinal products for the treatment of HIV-1, has raised increasing interest for the treatment of COVID-19. Lopinavir is a protease inhibitor with high specificity for HIV-1 and HIV-2, while ritonavir increases lopinavir plasma concentration through the inhibition of cytochrome P450 (Soliman, 2011) . This combination was already tested in patients with SARS infection, demonstrating to be associated with favourable outcomes, and it is currently evaluated, in combination with IFN-β, in patients with MERS-CoV infection (Arabi et al., 2018; Arabi et al., 2020; Dayer, Taleb-Gassabi, & Dayer, 2017) . Cao et al. carried out a randomized, controlled, hospitalized patients with severe SARS-CoV-2 infection. Patients were randomized to receive the combination lopinavir/ritonavir plus standard care for 14 days or standard care alone. According to study's results, no differences between the combination treatment and the standard treatment, in terms of clinical improvement, mortality at 28 days and the percentages of patients with detectable viral RNA could be demonstrated Moreover, adverse events, especially gastrointestinal ones, were more common in the group of patients receiving the combination treatment, while serious adverse events were more common in the standard-care group. Authors concluded that in hospitalized patients with severe COVID-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care . Furthermore, an open-label, randomized clinical trial, which will compare the efficacy of lopinavir/ritonavir versus hydroxychloroquine in 150 patients with mild COVID-19, is currently ongoing in the Republic of Korea . Since clinical evidence on the efficacy and safety of the combination lopinavir/ritonavir in patients with COVID-19 is still limited and controversial, further studies are required to confirm a possible role of these drugs. Nevertheless, this combination is currently used in Italy in COVID-19 patients with less disease severity compared with patients evaluated in the study published on NEJM Agenzia Italiana del Farmaco a, 2020) Remdesivir has been recently recognized as a promising antiviral drug against a broad spectrum of RNA viruses (including MERS-CoV) infection in cultured cells (Sheahan et al., 2020) , mice and non-human primate models (De Wit et al., 2020) . It is a nucleotide analogue, able to inhibit RNA-dependent RNA polymerase (RdRp), proteins essential for viral replication. The drug was initially developed as a treatment for Ebola and Marburg infections but did not demonstrate clinical efficacy. However, antiviral activities were also demonstrated against single-stranded RNA viruses, including MERS and SARS-Cov (Agostini et al., 2018) . Recent results from a preclinical study indicated that, in vitro, the association remdesivir/chloroquine could be highly effective trial is evaluating the efficacy and safety of remdesivir in 1,600 patients with COVID-19; this study will end in May 2020 (Clinicaltrial. gov c, 2020) . Data from the Italian real clinical practice showed that the drug has already been used in patients with COVID-19 at the Spallanzani hospital in Rome and that it is currently being administered in 12 Italian clinical centres (Adnkronos, 2020) . Lastly, a case report highlighted promising results for this treatment in the first US patient with COVID-19 (Holshue et al., 2020) . Another group of antiviral agents are also being considered as potential treatments for SARS-Cov-2 infection. For these antivirals, a brief description is reported below. Among these, there is the combination darunavir/cobicistat, which is currently approved for the treatment of HIV-1 in association with other antivirals. Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease, while cobicistat is an inhibitor of cytochromes P450 that enhances darunavir plasma concentrations (Deeks, 2018 Indeed, compared to the control group, the treatment with meplazumab was earlier associated with improvement in pneumonia. These results, although preliminary, seem to confirm the involvement of CD147 in the penetration and replication of the virus in the body as well as in the development of inflammatory processes related to the infection (Clinicaltrial.gov h, 2020 As previously reported, the SARS-Cov-2 infection can be associated, especially in severe form, with the exaggerate activation of inflammatory processes and the development of cytokine storm. Based on this consideration, several drugs with immunomodulatory properties are currently evaluated in patients with COVID-19. These drugs include both synthetic and biological medicines that are able to modulate specific inflammatory pathways through the inhibition of human IL-6 receptor (IL-6R), of the metabolism, motility and chemotaxis of polymorphonuclear cells, of JAK or TNF-α production. tocilizumab. This is a monoclonal antibody that inhibits ligand binding to the IL-6R and that is authorized for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis (Scott, 2017) . Scientific evidence suggests that the IL-6 pathway plays a key role in guiding the inflammatory immune response at the level of pulmonary alveoli in patients affected by COVID-19. Indeed, this immune response produces damage to the lung parenchyma, which significantly reduces respiratory function (Mehta, 2020; Zhang et al., 2020) . The drug was first tested in China to reduce lung complications in 20 patients with severe SARS-CoV-2 infection (X. . The treatment was associated with a reduction of oxygen requirement, resolution of CT lesions, normalization of lymphocyte count, reduction of C-reactive protein levels and hospital discharge, with average hospitalization duration of 13.5 days. Given the achieved clinical outcomes, the drug is currently used in several Italian hospitals, including the Cotugno Hospital in Naples. Since tocilizumab seems able to prevent the hyperactivation of inflammatory pathway, its use can be expected also in early stages for patients with not severe COVID-19. Currently, three clinical studies, including one that was authorized by the AIFA, are ongoing (Clinicaltrial.gov i, 2020; Clinicaltrial.gov l, 2020) . Sarilumab belongs to the same drug class of tocilizumab, and three trials are underway to evaluate the efficacy and safety of this drug, alone or in combination with standard care, in almost 1,500 patients with COVID-19 (Clinicaltrial.gov m, 2020; Clinicaltrial.gov n, 2020; Clinicaltrial.gov o, 2020). Two other drugs, chloroquine and hydroxychloroquine, are offlabel used in Chinese and Italian clinical centres for the treatment of COVID-19 (Dong, Hu, & Gao, 2020) , and they were labelled as "miracle cure" in the USA (The Guardian, 2020). These compounds are authorized as antimalarial drugs and for the treatment of autoimmune diseases, including lupus and rheumatoid arthritis. Even though both drugs are considered to be safe with adverse events that are generally mild and transitory, they can be associated with cardiovascular disorders, including prolongation of QT that can be life-threatening (Frisk-Holmberg, Bergqvist, & Englund, 1983) . They may also induce retinal toxicity that was described with long-term use (Easterbrook, 1993; Mavrikakis, Papazoglou, Sfikakis, Vaiopoulos, & Rougas, 1996) . Furthermore, since the incidence of hepatic abnormalities significantly increases in patients with COVID-19, an impaired metabolism of both medications can be expected, leading to further increase in the risk of liver impairment (Rismanbaf & Zarei, 2020) . Some preclinical studies showed that chloroquine has antiviral activity against SARS coronavirus (Keyaerts, Vijgen, Maes, Neyts, & Ranst, 2004) , human coronavirus OC43 (Keyaerts et al., 2009 ) and influenza A H5N1 (Yan et al., 2013) , suggesting a possible role in SARS-Cov-2 infection (Gao, Tian, & Yang, 2020; Inglot, 1969 (Gbinigie & Frie, 2020) showed that there is limited evidence of in vitro activity of both drugs against SARS-CoV-2, while clinical data was derived from only two studies (J. Gautret et al., 2020) with small sample size (overall, 66 patients) and methodological limitations, with no data on medium or long-term follow-up. In conclusion, currently scientific evidence on the efficacy and safety of chloroquine and hydroxychloroquine in patients with COVID-19 are scarce. High-quality randomized clinical trials are strongly needed. Another drug able to reduce the cytokine storm is colchicine that is authorized for the treatment of acute attack of gouty arthritis and pericarditis. The drug reduces the inflammatory response through several mechanisms:-the inhibition of the metabolism, motility and chemotaxis of polymorphonuclear cells, the inhibition of the adhesion and recruitment of neutrophils and the modulation of leukocyte-mediated inflammatory activities (Andreu & Timasheff, 1982; Chia, Grainger, & Harper, 2009; Dalbeth & Lauterio, 2014; Z. Li, Davis, Mohr, Nain, & Gemsa, 1996; Martinon, Pétrilli, Mayor, Tardivel, & Tschopp, 2006) . On March 2020, a phase 3 clinical study (COLCORONA) began. This study will enrol 6,000 outpatients with COVID-19 with the following characteristics:age ≥ 40 years; diagnosis of COVID-19 in the past 24 h; at least one risk factor between age > 70 years, diabetes, uncontrolled hypertension, asthma or COPD, heart failure, fever ≥38.4 C in the last 48 h, dyspnoea, pancytopenia or high neutrophil count and low lymphocyte count and finally patients not of childbearing age or using contraception methods (Clinicaltrial.gov p, 2020) . Baricitinib is currently approved for the treatment of rheumatoid arthritis. It is a selective and reversible inhibitor of JAK1 and JAK2. (Clinicaltrial.gov q, 2020; Stebbing et al., 2020; Favalli et al., 2020; Bekerman et al., 2017) . Aviptadil is an analogue of vasoactive intestinal polypeptide (VIP). This drug is authorized for the treatment of erectile dysfunction, sarcoidosis and acute lung damage. The rationale for its use for the treatment of ARDS is based on the results from preclinical studies showing that the VIP is highly concentrated in the lung, where it prevents the activation of caspases NMDA-induced, inhibits IL-6 and TNF-α production and protects against HCl-induced pulmonary oedema (Leuchte et al., 2008; Petkov et al., 2003; Said, 2012) . In a clinical study, 7/8 patients with severe ARDS were successfully treated with ascending doses of the VIP (Clinicaltrial.gov r, 2020) . A phase II clinical trial based on patients with COVID-19 infection will begin shortly. Eculizumab is a monoclonal antibody approved for the treatment of atypical haemolytic uraemic syndrome, refractory generalized myasthenia gravis and neuromyelitis spectrum disorders. It is an inhibitor of the terminal portion of the complement cascade involved in the inflammatory response. Even though the role of complement cascade in the pathogenesis of SARS-CoV-2 infections is uncertain, many studies suggested that its inhibition might potentially work as a therapeutic approach (Gralinski et al., 2018; Ip et al., 2005; Yuan et al., 2005) . Based on these considerations, eculizumab will be tested in the SOLID-C19 clinical trial in the treatment of patients with severe SARS-CoV-2 and ARDS (Clinicaltrial.gov s, 2020) . A phase 2/3 randomized, open-label, study is investigating the efficacy and safety of emapalumab, a monoclonal antibody targeting IFN-γ, and anakinra, an antagonist of IL-1R, in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection (Clinicaltrial.gov t, 2020) . This study received the approval by the AIFA (Ministero della Salute, 2020). Finally, noteworthy is the use of corticosteroids. A recent document released by the WHO specified that these drugs are adjunctive therapies for COVID-19. Specifically, it has been reported that, according to the results of a systematic review of observational studies, the use of corticosteroids in patients with SARS was not associated with survival benefit (Stockman, Bellamy, & Garner, 2006) . Similarly, a further systematic review of observational studies found a higher risk of mortality and secondary infections with corticosteroids administered in patients with flu (Rodrigo, Leonardi-Bee, Nguyen-Van-Tam, & Lim, 2016) . However, this effect was not confirmed by a subsequent study (Delaney, 2016) . Therefore, the WHO recommend for patients with COVID-19 to use corticosteroids only if they are indicated for another reason such as exacerbation of asthma or COPD, septic shock (WHO a, 2020). Literature data support that corticosteroids do not add clinical benefits in the treatment of COVID-19 infection (Ling et al., 2020) . On the other hand, some studies reported improvements in SARS patients treated with methylprednisolone, also in terms of reduction of IL-8, monocyte chemo-attractant protein-1 and Th1 chemokine IFN-γ-inducible protein-10 (CXCL10; Sung et al., 2004; Wong et al., 2004) , while one case reports described positive effects of methylprednisolone on clinical outcomes of one patient with COVID-19 (L. . In conclusion, considering that evidence available is quite conflicting regarding to corticosteroids in patients with COVID-19, their use should undergo a case-by-case evaluation. Preclinical studies have demonstrated that the blockade of PD-1 or PD-L1 can prevent T cell death, regulate cytokine production and reduce organ dysfunction (Markham & Keam, 2019; X. D. Zhu & Sun, 2019) . The study was launched on February 2020 to verify its efficacy in combination with thymosin in 120 patients with severe pneumonia associated with lymphocytopenia (Clinicaltrial.gov u, 2020 (Jawhara, 2020) . In addition, human convalescent serum may represent a good option for the prevention and treatment of COVID-19 (Hopkins, 2020) . Despite high expectations for convalescent serum, related risks should be considered, including those associated with inadvertent infection, immunological reactions, the development of antibody-dependent enhancement of infection and the attenuation of the immune response that may be responsible for vulnerability to subsequent reinfection (Casadevall & Pirofski, 2020) . Finally, the development of a vaccine against SARS-CoV-2 is urgently needed. However, according to Shang, Yang, Rao, and Rao (2020) , (WHO b, 2020) . Researchers from the University of Pittsburgh School of Medicine announced a potential vaccine against SARS-CoV-2 that was tested in mice and produced antibodies specific to SARS-CoV-2 able to neutralize the virus (Science Daily, 2020). Furthermore, an experimental mRNA vaccine against the pandemic coronavirus was already administered to one person in the United States (Cohen, 2020) . Since the beginning of the outbreak, a large number of clinical studies have been registered worldwide, and several drugs were repurposed to face the new health emergency of COVID-19. We described pharmacological properties and available clinical data for several drugs, mainly antiviral, immune-modulatory and anti-inflammatory agents. For many of these drugs, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab, evidence from preliminary clinical trials seems to support their benefit in improving patients' clinical conditions. However, considering that adequate clinical trials are necessary to reach any firm conclusion on the efficacy profiles of these compounds, we believe that their use should be restricted to controlled environments and under adequate clinical studies. Considering that nowadays, no specific treatments are available for COVID-19, drugs repurposing is necessary, but it requires caution. Indeed, too many drugs that are currently tested in patients with COVID-19 have an unknown efficacy profile. On the other hand, those with proven efficacy have a peculiar safety profile, which calls for a strict monitoring of treated patients. Therefore, patients treated with such drugs should undergo a routine monitoring. Furthermore, as reported by The Liverpool Drug Interaction Group, particular attention should be given at adverse events deriving from drug-drug interactions, which could be very common in patients with COVID-19, given the huge amount of pharmacological therapies to which they are subjected to (The Liverpool Drug Interaction Group, 2020). Worldwide regulatory agencies are promoting many interventions to guarantee access to effective and safe medicines, though no proven specific therapies are available to prevent or treat COVID-19. In addition, on March 18, the EMA and the US FDA jointly chaired the first global regulatory meeting experts to support proceeding to firstin-human clinical studies (H. . Since SARS-Cov-2 is still an unknown virus, we are now learning its transmission mechanisms, clinical spectrum of disease, diagnostics and lethality. In conclusion, while waiting for the development of an effective vaccine, many clinical trials on different types of drugs are currently underway. Their results will certainly bring new knowledge and will help us in defining the best way to treat COVID-19 and reducing its symptoms and complications. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMA-COLOGY (Harding et al., 2018) are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 Alexander, Christopoulos, et al., 2019) . 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