key: cord-0994466-ahh8or3o
authors: Giovane, Richard A.; Rezai, Shadi; Cleland, Ellen; Henderson, Cassandra E.
title: Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID‐19) and the rationale for their utilization: A review
date: 2020-07-09
journal: Rev Med Virol
DOI: 10.1002/rmv.2136
sha: 0af692da4780be985c065060ad79f743da2fe91d
doc_id: 994466
cord_uid: ahh8or3o

SARS‐CoV‐2 has caused a pandemic which is putting strain on the health‐care system and global economy. There is much pressure to develop both preventative and curative therapies for SARS‐CoV‐2 as there is no evidence to support therapies to improve outcomes in patients with SARS‐CoV‐2. Medications that inhibit certain steps of virus life cycle that are currently used to treat other illnesses such as Malaria, Ebola, HIV and Hepatitis C are being studied for use against SARS‐CoV‐2. To date, data is limited for medications that facilitate clinical improvement of COVID‐19 infections.

Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 which causes coronavirus disease 2019 or COVID-19 was initially identified in Wuhan, China during December 2019; has spread worldwide, causing a pandemic. 1 Although the amount of reported cases is uncertain due to the variable sensitivity of testing and reported symptoms, it is estimated that over 1 million cases and 60 000 deaths have occurred. 1 Symptoms of COVID-19 vary and include fever, fatigue, dry cough and myalgia. Severity of the illness ranges from asymptomatic to severe with a fatality rate of at least 2.3%. 1 As this pandemic causes strain on global health-care, there has been an urgent need to establish standard therapies to improve outcomes. Moreover, there is no known effective prophylactic therapy against COVID-19 and so far, there are no medications that have undergone large clinical trials that demonstrate improved outcomes against SARS-CoV-2. 1 Currently, there are only recommendations against further spread through proper hand hygiene, respiratory hygiene, self-quarantine and person protective equipment [PPE] for health-care workers. 2 Vaccination using BCG against COVID-19 has been proposed, however human trials are still being conducted and limited data is available on their efficacy, safety and when they will be available to the general public. 3 Given the current pandemic of COVID-19, there has been proposed use of available medications to improve outcomes in patients with SARS-CoV-2. We present a review of proposed therapies for COVID-19, their mechanisms of action and their efficacy. with the spike protein being used for the viral entry into host cells by attaching onto angiotensin-converting enzyme 2 [ACE2]. 5, 6 Once bound, SARS-CoV-2 gains access to the cytosol of the host cell by cleavage of the S protein by TMPRRS2. 4, 6 Within the cytosol, SARS-CoV-2 begins the synthesis of replicase and other nonstructural proteins. Once this is complete, it begins the synthesis of its structural proteins through the use of its own RNA-dependent RNA polymerase. 4, 6 After assembly of the virus, it exits the cell and begins the process again. Although the exact pathogenesis of SARS-CoV-2 is poorly understood, one proponent of its pathogenesis is that it induces proinflammatory cytokines and chemokines such as IL-6, TNF α, IL-1B and GCSF which can lead to a cytokine storm and subsequent endothelial damage. 7 Understanding the replication cycle of SARS-CoV-2 can help researchers hypothesize potential medications agents that prevent the viral entry, protein synthesis and replication cycle [ Table 1 ].

Beginning with viral entry via the S-protein and ACE2 receptor, Umifenovir [Arbidol] targets the S-protein/ACE2 interaction which prevents viral entry into cells. It is currently being studied as both a treatment and prophylactic agent against SARS-CoV-2. 8 In a study done by Wang et al on the use of this medication, it showed to decrease mortality and increase discharge rate 8 ; however, there were many limitations with this study such as nonrandomization and there needs to be more data on this therapy to prove efficacy. Camostat mesylate is another agent being investigated to inhibit viral entry, as it inhibits TMPRSS2 which facilitates viral entry into the host cell. 9 Although in vitro, this medication inhibits viral entry into cells, human trials are still pending. 9 Chloroquine and Hydroxychloroquine are anti-malarial drugs are being studied as potential drugs of choice for SARS-CoV-2. These medications work by inhibiting membrane fusion, glycosylation of host receptors, endocytosis as well as decreasing cytokine production. 10 Despite its mechanism of action, there has been no study that shows clear benefit of using either agent. 11 Protease inhibitors used in HIV such as Lopinavir/Ritonavir had potential for SARS-CoV-2 therapy as it inhibits 3-chymotrypsin-like protease. 6 16 Of the patients that did receive Favipiravir, patients were found to have elevated uric acid and elevated transaminases; this again poses an issue due to SARS-CoV-2 as a potential cause of hepatic damage. 16 The study had many limitations; the most important being is that it was not peer reviewed.

Ribavirin, is another prodrug used to treat hepatitis C and hantavirus. It works by inhibiting RNA-dependent RNA polymerase via acting as a guanosine or adenosine analog that alters RNA-dependent replication and synthesis. 17 Efficacy is unknown for the use of Ribavirin against SARS-CoV-2 as many of the studies done have been inconclusive as researchers could not distinguish benefit of Ribavirin from that of standard therapy. 18 More importantly, patients that received

Ribavirin were more likely to develop hemolytic anemia and elevated transaminase. 18 Remdesivir, another prodrug that forms into an adenosine nucleotide analog that inhibits RNA-dependent RNA polymerase. 19 Data for the efficacy of Remdesivir in vitro studies is promising as Remdesivir has shown inhibitory effects for viral replication in human liver cells. 20 More importantly, in a study done by Grein . 24 The rationale behind using these medications is that there are similarities between HAPE and SARS-CoV-2; both have hypoxia, tachypnea, low PaCO2 levels, elevated fibrinogen levels and develop into ARDS. 24 Although similar, we must remember that the pathophysiology in which ARDS develops in each of these illnesses is different; with HAPE occurs due to elevated pulmonary artery pressure while SARS-CoV-2 is hypothesized to cause endothelial damage through pro-inflammatory cytokines. 7, 24 Moreover, the mechanism in which acetazolamide and nifedipine treat HAPE would have different consequences in a patient with SARS-CoV-2. Acetazolamide is a carbonic anhydrase inhibitor, this enzyme is used to acidify the urine and transport bicarbonate back to the body under normal conditions. 25 Inhibiting this enzyme leads to diuresis which will increase urinary bicarbonate and decreases blood pH, this will cause hyperventilation to increase oxygen levels and decrease carbon dioxide in order to compensate the decrease in blood pH. 26 Although this will help a patient with HAPE; decreasing blood volume through diuresis and decreasing blood pH would not be ideal for a patient with SARS-CoV-2. 26 Moreover, acetazolamide is contraindicated in patients with poor renal function, which is seen in patients with SARS-CoV-2. 26, 27 Nifedipine, a calcium channel blocker, works in a similar manner as it lowers blood pressure; although effective in HAPE, 24 this would not be ideal for someone with SARS-CoV-2 as it would alter their ventilation/perfusion ratio and lower their oxygenation. 28 3 | CONCLUSION SARS-CoV-2 has caused a pandemic that is creating a health-care crisis and economic strain worldwide. As more cases are reported each day, finding a standard therapy to SARS-CoV-2 that shows efficacy in large clinical trials during a pandemic poses an ongoing challenge to clinicians and researchers.

Use of antiviral drugs to reduce COVID-19 transmission

masks-in-the-community-during-home-care-and-in-healthcaresettings-in-the-context-of-the-novel-coronavirus-(2019-ncov)-outbreak

Coronaviruses: an overview of their replication and pathogenesis

Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical features of 69 cases with coronavirus disease

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Virological and clinical cure in covid-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis

Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics

A trial of Lopinavir-Ritonavir in adults hospitalized with severe covid-19

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study

Antiviral efficacy of Favipiravir against Ebola virus: a translational study in cynomolgus macaques

Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv. Preprint posted

Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis

SARS: systematic review of treatment effects

Coronavirus susceptibility to the antiviral Remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Compassionate use of Remdesivir for patients with severe Covid-19

Tocilizumab treatment in COVID-19: a single center experience

Effective treatment of severe COVID-19 patients with tocilizumab

Nifedipine and phosphodiesterase inhibitors: rationale for their utilization as adjunctive countermeasures in the treatment of coronavirus disease 2019 (COVID-19)

Mechanisms of action of acetazolamide in the prophylaxis andtreatment of acute mountain sickness

The kidney and acid-base regulation

Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT

Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID-19) and the rationale for their utilization: A review

The authors have no competing interest.

https://orcid.org/0000-0002-8547-2693Shadi Rezai https://orcid.org/0000-0001-8498-565X