key: cord-0722134-02iftert
authors: Lam, Sarah; Lombardi, Andrew; Ouanounou, Aviv
title: COVID-19: A review of the proposed pharmacological treatments
date: 2020-08-06
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173451
sha: 6faa04c9f4e0cdad1e1374ba0ebb2cb20fd7f71c
doc_id: 722134
cord_uid: 02iftert

The emerging pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge for healthcare systems globally. The clinical course of COVID-19 and its ability to rapidly create widespread infection has major implications, warranting vigorous infection prevention and control measures. As the confirmed number of cases has surpassed 5.6 million worldwide and continues to grow, the potential severity of the disease and its deadly complications requires urgent development of novel therapeutic agents to both prevent and treat COVID-19. Although vaccines and specific drug therapies have yet to be discovered, ongoing research and clinical trials are being conducted to investigate the efficacy of repurposed drugs for treating COVID-19. In the present review, the drug candidates that have been suggested to treat COVID-19 will be discussed. These include anti-viral agents (remdesivir, ribavirin, lopinavir-ritonavir, favipiravir, chloroquine, hydroxychloroquine, oseltamivir, umifenovir), immunomodulatory agents (tocilizumab, interferons, plasma transfusions), and adjunctive agents (azithromycin, corticosteroids), among other miscellaneous agents. The mechanisms of action and further pharmacological properties will be explored, with a particular focus on the evidence-based safety and efficacy of each agent.

protein priming via host cell proteases (Hoffmann et al., 2020) . The primary target is human lung epithelial cells (Rothan and Byrareddy, 2020) . SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) receptors on the surface of human cells through its S-protein and, following this initial binding, 2 transmembrane serine protease (TMPRSS2) primes the S-protein, facilitating viral entry into the cell through endosomes (Fig. 1.) (Guzik et al., 2020; Hoffmann et al., 2020) . Once the virus has entered the human cell, it is capable of hijacking the host cell's machinery to undergo viral replication . The binding of S-proteins to ACE2 receptors is a critical step required for viral entry and is a potential target for pharmacotherapy that is being studied vigourously . Additionally, sequencing of the viral genome of SARS-CoV-2 has created opportunity for diagnostic testing, with hopes of developing effective preventive and therapeutic strategies (Sanders et al., 2020) . Researchers have discovered that the genome of SARS-CoV-2 is 76.6% similar to SARS-CoV . Although similar, subtle genetic differences may translate to significant differences in infectivity and severity.

Cytokine storm is an aberrant host immune response characterized by high concentrations of pro-inflammatory cytokines and chemokines, such as tumour necrosis factor-α (TNF-α) and various interleukins (IL), including IL-1 and IL-6 (Levi et al., 2020). TNF-α and IL-1 suppress endogenous anticoagulant pathways, while IL-6 aids in coagulation activation and thrombin generation (Levi et al., 2020) . The excessive release of cytokines results in excessive inflammation, contributing to the severity and pathogenesis of COVID-19.

There have been reports of cytokine storm associated hypercoagulopathy in patients with severe COVID-19. Characteristic findings include increased D-dimer concentration, prolonged J o u r n a l P r e -p r o o f prothrombin time, increased fibrin degradation products, and thrombocytopenia. Cohort studies have shown a 31% incidence of venous and arterial thrombotic complications, with the most common being potentially life-threatening pulmonary embolisms (Helms et al., 2020; Klok et al., 2020; Levi et al., 2020) . Although the pathogenesis of COVID-19-associated hypercoagulability is still unknown, systemic inflammation and hypoxia secondary to COVID-19 may increase inflammatory cytokine levels and subsequent coagulation pathway activation ("Antithrombotic Therapy | Coronavirus Disease COVID-19," CDC, 2020).

Identifying a drug that slows or kills SARS-CoV-2 requires a multi-factorial approach.

Successfully implemented pharmacotherapy has the potential to save severely ill patients and ease the burden of the pandemic on healthcare systems. Prophylactic treatment has been suggested, particularity to frontline workers and those at higher risk of susceptibility (Kupferschmidt, 2020) . As the detrimental consequences of COVID-19 continue to impact nations globally, the need for a safe and effective treatment is paramount. Currently, there is no vaccine or specific therapeutic drug to treat COVID-19, others than supportive care.

Pharmacotherapy has been aimed at alleviating symptoms, combined with various attempts to prevent the spread and complications of COVID-19. At present, repurposing of available medications has been the standard of care for treatment of SARS-CoV-2 patients (Kupferschmidt, 2020) . This includes unapproved agents that have demonstrated in vitro activity against SARS-CoV and MERS-CoV. Furthermore, many clinical trials are rapidly underway to develop potential therapeutic agents and vaccines.

J o u r n a l P r e -p r o o f Remdesivir was first developed during the peak of the Ebola virus outbreak in 2016, and has been shown to be the most promising therapy in treating COVID-19 (Ko et al., 2020; Sanders et al., 2020) . It is a broad-spectrum anti-viral agent that acts as an inhibitor of RNAdependent RNA polymerase, an enzyme needed for viral replication (Fig. 1.) (Kupferschmidt, 2020) . Although Remdesivir failed in clinical trials for treatment of Ebola in 2014, it is understood to be a safe drug. Similar to the doses used in the clinical trials to treat Ebola, remdesivir is administered as a 200mg loading dose on day 1, followed by a daily 100mg IV dose for nine days ( Table 2) .

The first randomized, placebo-controlled clinical trial by the National Institute of Allergy and Infectious Diseases (NIAID) demonstrated a significantly faster recovery time of 11 days (31% improvement) for 1,000 COVID-19 patients taking remdesivir, compared to 15 days in the placebo arm. However, there was no significant difference identified in the number of deaths between participants who received remdesivir versus those who did not. The mortality rate was 8% for patients receiving remdesivir compared to 11.6% in the control group ("Adaptive COVID-19 Treatment Trial (ACTT) ClinicalTrials.gov," 2020, "NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19," 2020; Ledford, 2020) . Gilead administration compared with standard of care, with results expected at the end of May ("Remdesivir Clinical Trials," 2020) . A randomized, double-blind, placebo-controlled multicentre phase III trial was conducted in China to evaluate the efficacy of remdesivir ("A Trial of Remdesivir in Adults With Severe COVID-19 ClinicalTrials.gov," 2020; Ko et al., 2020) . Severely ill COVID-19 patients (n = 237) were enrolled, and 158 were administered remdesivir while 79 were given placebo. Clinical improvements were defined as time to improvement (Y. . Statistically significant clinical improvements were not observed for patients taking remdesivir. The trial was ended prematurely due to lack of patient enrollment, as China's new case rate has dropped significantly.

Despite conflicting clinical results, the US Food and Drug Administration (FDA) approved an 'emergency use authorization' for hospital intravenous administration of Remdesivir to patients with severe COVID-19 on May 1, 2020 (Ledford, 2020).

Various clinical trials have reported serious adverse effects following administration of remdesivir, such as hepatoxicity (Table 1) ("Lexicomp for Dentistry,"). Additionally, over 10% of patients experienced nausea and acute respiratory failure in the Gilead clinical trial.

Ribavirin is a guanine analogue that inhibits viral RNA-dependent RNA polymerase ( Fig.  EC50=1 .13μM, respectively). The researchers concluded a decreased in vitro potency of ribavirin compared to its comparative therapeutic agents (M. . Furthermore, clinical studies of ribavirin for treatment of SARS-CoV have shown dose-dependent adverse drug reactions, including hematologic and liver toxicity ( Table 1 ) (Sanders et al., 2020) . This inconclusive research suggests that ribavirin has limited value in serving as a therapeutic agent against COVID-19. If used, combination therapy, such as with interferon-α or lopinavirritonavir, may provide improved clinical efficacy (Sanders et al., 2020; Yousefi et al., 2020; Zhong et al., 2020) .

Lopinavir-ritonavir is used as antiretroviral combination therapy to manage HIV positive patients. Lopinavir inhibits the HIV protease, an enzyme required for new viral assembly (Fig.   1.) . Due to its poor oral bioavailability and extensive biotransformation, lopinavir is coadministered with ritonavir in order to prolong levels in the human body and enhance its exposure ( 

The most common adverse effect of lopinavir-ritonavir includes gastrointestinal disturbance (up to 28%), most notably diarrhea and nausea. Hepatotoxicity (2-10%) has also been observed (Table 1 ) (Sanders et al., 2020; Wu et al., 2020) . In order to improve drug tolerability, reducing the current doses ( Table 2 ) from twice daily to once daily has been suggested (Baldelli, 2020). The addition of interferon β-1a to lopinavir-ritonavir has also been initiated in clinical trials (Kupferschmidt, 2020; McKee et al., 2020) .

Favipiravir was developed by Toyama Chemical in Japan in 2014. Favipiravir acts as a selective inhibitor of RNA-dependent RNA polymerase ( Fig. 1. ) (Coomes, 2020) . It is approved in some countries to treat influenza, Ebola, and norovirus (McKee et al., 2020; Wu et al., 2020) .

Preliminary clinical results indicate that favipiravir shows significantly greater improvement in chest imaging in COVID-19 patients compared to lopinavir-ritonavir (91.4% improvement with favipiravir, 62.2% improvement with lopinavir-ritonavir). Faster viral clearance (4 days versus 11 days) and fewer adverse events (11.4% versus 55.6%) were also observed in patients administered favipiravir compared to those taking lopinavir-ritonavir (Cai et al., 2020). A prospective randomized clinical trial conducted in China supports these results, demonstrating a significantly greater recovery rate in non-critical COVID-19 patients receiving favipiravir compared to umifenovir (71.4% versus 55.9%). In COVID-19 patients receiving favipiravir, fever, cough, and respiratory problems were reduced. It is important to note that this effect was not significant among critically ill COVID-19 patients (C. Chen et al., 2020) . These early results have led to further trials on the efficacy of favipiravir. Currently, favipiravir is being sent to 43 countries for clinical trial testing in COVID-19 patients.

J o u r n a l P r e -p r o o f Chloroquine and hydroxychloroquine are indicated for treatment of inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as well as prevention and treatment of malaria (Sanders et al., 2020) . These agents act to decrease the acidity in endosomes, inhibiting viral fusion and subsequent entry inside of the cell (Fig. 1. ) (Guzik et al., 2020) . The hydroxyl group found in hydroxychloroquine results in less toxicity than chloroquine, while maintaining similar anti-viral activity . Table 1 ) (Asensio et al., 2020; Bhimraj et al., 2020; Kalil, 2020; Rosenberg et al., 2020; Sanders et al., 2020) . This raises concerns as patients with cardiovascular comorbidities are already at higher risk of severe COVID-19 complications. This risk is then compounded by administration of potential COVID-19 therapeutic agents, increasing the risk of cardiac death (Kalil, 2020; Kupferschmidt, 2020) . Additional side effects documented include hepatitis, acute pancreatitis, neutropenia, and anaphylaxis (Table 1) (Kalil, 2020).

Oseltamivir is a neuraminidase inhibitor approved for the treatment of influenza A and B (Sanders et al., 2020; Wu et al., 2020) . Current research has indicated that oseltamivir is not effective for management of COVID-19, and is not recommended at this time (Yousefi et al., 2020) .

J o u r n a l P r e -p r o o f

Umifenovir inhibits membrane fusion of the viral envelope by targeting the interaction between viral S-proteins and ACE2 receptors (Fig. 1.) . In Russia and China, umifenovir is approved for prophylaxis and treatment of influenza A and B (Sanders et al., 2020; Wu et al., 2020) . Furthermore, it has demonstrated in vitro broad-spectrum antiviral activity against the The current data for umifenovir's role in COVID-19 treatment is inconclusive. Prospective, multicenter studies with larger sample sizes are needed to better determine its efficacy.

J o u r n a l P r e -p r o o f COVID-19 induces the release of pro-inflammatory cytokines, primarily IL-1β and IL-6, which mediate lung and tissue inflammation, fever, and fibrosis. Many inflammatory diseases, including viral infections, have been shown to benefit from suppression of IL-1β and IL-6 (Conti et al., 2020) . Recent studies have consistently found high levels of IL-6 and other proinflammatory cytokines in COVID-19 patients. Furthermore, high levels of IL-6 were found to be the main cause of cytokine storm (C. Zhang et al., 2020; S. Zhang et al., 2020) . Suppression of these pro-inflammatory cytokines may provide a therapeutic effect for treatment of cytokine storm induced by COVID-19 (Conti et al., 2020) .

Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody that binds to the IL-6 receptor with high affinity (Fig. 1.) . It is approved for treatment of cytokine release syndrome (CRS), rheumatic arthritis, and systemic juvenile idiopathic arthritis . At present, there is insufficient data to recommend either for or against its use in treating COVID-19. Retrospective studies have reported some efficacy in critically ill COVID-19 patients with significantly elevated levels of IL-6 (Luo et al., 2020; C. Zhang et al., 2020) . A preliminary observational study conducted by Xu et al. offers promising results for tocilizumab therapy. Of the 21 critically ill COVID-19 patients who received tocilizumab (4-8mg/kg body weight, 400mg through an intravenous drip to a maximum of 800mg), all patients experienced a rapid normalization of body temperature and a remarkable improvement of respiratory function with no reported adverse drug reactions. Researchers confirmed that 20 of the 21 patients fully recovered and were discharged within two weeks following tocilizumab treatment . Motivated by these results, Genentech announced on March 23, 2020, that the FDA approved a randomized, double-blind, placebo-J o u r n a l P r e -p r o o f controlled phase III clinical trial to evaluate the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. It plans to enroll 330 participants globally, with initial results by early summer of 2020 ("Genentech: Press Releases | Monday, Mar 23, 2020,"; Salvi and Patankar, 2020).

Type 1 interferons (IFN-1) are a group of cytokines with non-specific antiviral and immunomodulatory properties. They are comprised α and β subtypes, among others (ε, ω, κ) (Samuel, 2001) . Interferons -α (IFNα) and -β (IFNβ) have been suggested as candidates in COVID-19 pharmacotherapy (Belhadi et al., 2020; Martinez, 2020; Sallard et al., 2020) .

Interferons bind to interferon-alpha/beta receptors (IFNAR) on the cell membrane, which phosphorylate STAT1 and other transcription factors. STAT1 translocates to the nucleus, where it activates interferon-stimulated genes (ISGs). Activated ISGs lead to immunomodulatory effects and interfere with viral replication (Fig. 1., Table 1 ) (Sallard et al., 2020) . IFNα and IFNβ are commonly investigated as combination therapy with ribavirin and or lopinavir-ritonavir while SARS-CoV-2 has shown to be more sensitive (Menachery et al., 2014; Sheahan et al., 2020; Shen and Yang, 2020) . This was confirmed by in vitro pre-treatment with INF-1 (Lokugamage et al., 2020) . However, due to the lack of clinical trials investigating IFN-1 and the conflicting in vitro and animal studies, the use of interferons to treat COVID-19 is not currently recommended (Sanders et al., 2020; Totura and Bavari, 2019) . In China, ongoing trials of IFN-1 in COVID-19 treatment is expected to reveal additional findings once published.

Convalescent plasma has been widely used to improve the survival rate of patients during other coronavirus outbreaks, such as Influenza A, SARS-CoV, MERS-CoV, and Ebola virus (Rajendran et al., 2020; Rojas et al., 2020; Zhao and He, 2020) . Some blood centers have begun collecting plasma from patients who have recovered from COVID-19, with hopes that their plasma contains antibodies that are able to resolve the virus in infected individuals. Canadian Blood Services is taking part in CONCOR, a national trial aimed at testing the safety and efficacy of using COVID-19 convalescent plasma for treatment. To be eligible for donation, individuals must be younger than 67 years old, have a previously confirmed positive laboratory test for COVID-19, and be symptom free and fully recovered from the virus for at least 28 days ("COVID-19 and convalescent plasma," 2020). The therapeutic benefits of plasma transfusion therapy are suggested to be multifold, including the reduction of viremia, improvement of immune function in COVID-19 patients, and inhibition of cytokine storm formation (Brown and McCullough, 2020; . Although current data is limited, the available results are promising. Significant reductions in viral load, improvement of symptoms, and reduced mortality have all been demonstrated (Rajendran et al., 2020) . In a Chinese pilot study, nine J o u r n a l P r e -p r o o f patients who received convalescent plasma all showed improved clinical symptoms within three days. Increased amount of neutralizing antibody was found, with undetectable viral load in seven patients previously with viremia. No severe adverse effects were reported (Duan et al., 2020) . It is important to establish the timing of administration, as convalescent plasma may be most efficacious when used prophylactically or in the earlier stages of disease, shortly after symptom onset (Brown and McCullough, 2020; Zhao and He, 2020) . Additional considerations include transfusion-related adverse effects, such as chills, fever, and anaphylactic reactions (Zhao and He, 2020). Based on the available data, the use of plasma transfusion therapy has shown promise for treating COVID-19. Further evidence is needed to prove its safety and efficacy.

Azithromycin, a commonly used antibiotic, has been administered with hydroxychloroquine as a possible regimen to treat COVID-19. A multicentre retrospective cohort study of 1,438 hospitalized patients tested the efficacy and adverse events of hydroxychloroquine and azithromycin taken together, compared to hydroxychloroquine alone, azithromycin alone, and a placebo control group. Results showed no significant difference in the experimental groups compared to the control group. Furthermore, it was suggested that the risk of cardiac arrest may be significantly higher in patients receiving both hydroxychloroquine and azithromycin (OR=2.13) (Rosenberg et al., 2020) . In a similar observational study, there was no evidence that combination of hydroxychloroquine and azithromycin decreased risk of death in COVID-19 patients, and risk of death was higher in patients taking hydroxychloroquine alone (Magagnoli et al., 2020) . Due to the adverse cardiovascular effects observed in both hydroxychloroquine and azithromycin, clinical use of this combination requires baseline and follow-up ECG monitoring (Asensio et al., 2020; Bhimraj et al., 2020) . A large observational study of nearly 15,000 hospitalized COVID-19 patients conducted by Mehra et al. found that administration of chloroquine or hydroxychloroquine with or without the addition of azithromycin was associated with an increased risk of in-hospital mortality (1 in 6 patients versus 1 in 11 patients in the control group). Researchers also observed an increased frequency of ventricular arrythmias in the experimental group (8%) compared to the control arm (0.3%) (Mehra et al., 2020) . This study reveals a lack of benefit in treating COVID-19 patients with chloroquine or hydroxychloroquine either alone or in combination with azithromycin. Importantly, the study highlights the potential harms of administering these pharmacotherapies. There is an urgent need for data concluded from robust randomized clinical trials, as opposed to observational studies that have inherent bias and confounding variables (Geleris et al., 2020). Prospective randomized control trials of hydroxychloroquine with or without azithromycin are ongoing that will provide more definitive insight on its safety and efficacy in treating COVID-19 patients.

Corticosteroids, particularly methylprednisolone, has been suggested as an adjunctive agent in COVID-19 treatment. Corticosteroids have been widely used to treat severe pneumonia and prevent lung damage due their ability to suppress severe systemic inflammation (Yousefi et al., 2020; . There is limited data to support the use of corticosteroids as a therapeutic agent in treating COVID-19. Numerous observational studies and systematic reviews for viral pneumonias, including SARS-CoV and MERS-CoV, have shown inconclusive clinical evidence (Russell et al., 2020; Yang et al., 2020) . Furthermore, early administration of high dose corticosteroids may be potentially harmful, resulting in delayed viral clearance and increased mortality risk . High dose corticosteroids have also been associated with J o u r n a l P r e -p r o o f severe bacterial infection and hypokalemia (Table 1) . However, there is evidence that a specific subset of COVID-19 patients may benefit from corticosteroids. Low dose of corticosteroids may be therapeutic in patients with severe COVID-19 and other clinical indications, such as ARDS, sepsis, or septic shock . The lack of direct evidence warrants caution when considering corticosteroid use for COVID-19 patients.

Corticosteroid therapy should be evaluated on a case by case basis, with consideration of symptom severity, timing of intervention, dose, and duration of administration.

Camostat mesylate, known as Foipan, was first developed in the 1980s in Japan for treatment of pancreatitis, oral squamous cell carcinoma, and dystrophic epidermolysis (McKee et al., 2020; Sanders et al., 2020) . Camostat mesylate is a protease inhibitor, effective against trypsin, plasmin, kallikrein, and thrombin (Bittmann, 2020; Coote et al., 2009; Hoffmann et al., 2020) . It also inhibits the serine protease TMPRSS2 (Hoffmann et al., 2020; Uno, 2020) . Based on the current understanding of the SARS-CoV-2 infection mechanism, TMPRSS2 facilitates the activation of the viral S-protein and subsequent membrane fusion and entry (Hoffmann et al., 2020) . This makes camostat mesylate a potential pharmacological agent to inhibit SARS-CoV-2 entry into host lung cells, preventing initial infection (Fig. 1.) . Camostat mesylate is available as a crystalline solid that can be dissolved in organic solvents (Bittmann, 2020 

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