Abbreviations
Absolute neutrophil count (ANC), adverse drug reaction (ADR), adverse
events (AEs), alanine aminotransferase (ALT), angiotensin receptor
blocker (ARB), antibody-dependent enhancement (ADE), AP2-associated
protein kinase 1 (AAK1), antigen-dependent enhancement (ADE), aspartate
transaminase (AST), chronic obstructive pulmonary disease (COPD),
cluster of differentiation 73 (CD73), cytochrome P450 (CYP), deep vein
thrombosis (DVT), disease-modifying anti-rheumatic drug (DMARD),
drug-drug interaction (DDI), drug-induced liver injury (DILI), Early
Access to Medicines Scheme (EAMS), exoribonuclease (ExoN),
favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP), human
coronavirus (HCoV), human immunodeficiency virus (HIV), intensive care
unit (ICU), interferon stimulated response element (ISRE), interferon
regulatory factor (IRF), main protease (Mpro), maximum serum
concentration (Cmax), Medicines and Healthcare products
Regulatory Agency (MHRA), Middle East respiratory syndrome coronavirus
(MERS-CoV), monocyte chemoattractant protein 1 (MCP1), Multicentric
Castleman’s disease (MCD), multiple sclerosis (MS), non-steroidal
anti-inflammatory drugs (NSAIDS), non-structural protein 14 (nsp14),
P-glycoprotein (P-gp), pharmacokinetic (PK), phosphate (P),
RNA-dependent RNA polymerase (RdRp), secondary haemophagocytic
lymphohistiocytosis (sHLH), Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), signal transducer and activator of
transcription proteins (STAT), sulfobutylether β-cyclodextrin sodium
(SBECD), thrombotic microangiopathy (TMA), tumour necrosis factor (TNF),
upper limit of normal (ULN), World Health Organization (WHO).
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly
pathogenic beta-coronavirus that emerged in Wuhan, Hubei Province, in
late December 2019 (X. Yang et al., 2020). SARS-CoV-2 is the seventh
human coronavirus (HCoV) to be identified and is the cause of the
disease known as COVID-19 which was declared by the World Health
Organization (WHO) as a “Public Health Emergency of International
Concern” on 30 January 2020 (T. Liu et al., 2020). The symptoms of
COVID-19 are non-specific and cover a broad clinical spectrum meaning
that clinical diagnosis without a test is challenging. Patients commonly
present with fever, cough and anosmia, although many patients are
asymptomatic. The virus can be transmitted by asymptomatic patients
alongside those in the symptomatic and pre-symptomatic phase of the
disease (D. Wu, Wu, Liu, & Yang, 2020; X. Yang et al., 2020). As of
6th June 2020, COVID-19 is responsible for 395,459
deaths worldwide (John Hopkins University and Medicine, 2020). As the
number of new cases continues to increase rapidly, many clinical and
preclinical studies have been initiated to identify viable treatment
options for COVID-19 patients. Many of these potential therapeutic
strategies are based upon the re-purposing of approved drugs or the
evaluation of those currently in the clinical stages of drug development
(figure 1). For this reason, much information already exists on the
pharmacology and toxicology of each prospective therapy. In order to
examine their potential for efficacy and safety against COVID-19, it is
essential to consider all of the available information in this extremely
fast-moving and critical research field. Therefore, it is important to
assess drug-specific safety parameters in the context of the
pathogenesis of the virus and its clinical features in order to begin to
evaluate the disease-specific harm-benefit ratio.
Therapeutic strategies for the treatment of COVID-19 span a range of
phases including prophylactic administration, through to early
infection, through to the more severe disease stage characterised by
pulmonary involvement requiring mechanical ventilation and
hyperinflammation in some instances (Siddiqi & Mehra, 2020). At the
time of writing, over 600 clinical trials have been initiated across the
globe, with the majority of these investigating the use of a drug(s)
already approved for treatment of another disease (Clinical Trials.gov,
2020b). In addition to their administration as a monotherapy,
combination therapy has also been utilised. In addition to repurposed
compounds, several candidates in preclinical or clinical development
stages are also under-investigation, as well as widely available
borderline substances such as ascorbic acid (Clinical Trials.gov,
2020d). However, it is important to note that the number of clinical
trials initiated should not be taken as an indicator of the ultimate
potential for success.
Our perspective will focus upon selected repurposed therapies
which are used in different phases of the disease (figure 1), and can
broadly be categorised by their mechanism of action as 1) viral entry
inhibitors; 2) disruption of cellular viral processing; 3) modulators of
the inflammatory phase and 4) compounds that stimulate the host’s
anti-viral response. Selections were based upon agents undergoing the
largest clinical trials at the time of writing, 6thJune 2020.