Special Issue "COVID-19 in Pharmaceuticals"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Jean Jacques Vanden Eynde
E-Mail Website1 Website2
Guest Editor
Formerly head of the Department of Organic Chemistry (FS), University of Mons-UMONS, 7000 Mons, Belgium
Interests: heterocycles; microwave-induced synthesis; medicinal chemistry; green chemistry
Special Issues and Collections in MDPI journals
Dr. Annie Mayence
E-Mail Website
Guest Editor
Formerly professor at the Haute Ecole Provinciale de Hainaut-Condorcet, 7330 Saint-Ghislain, Belgium
Interests: medicinal chemistry; organic synthesis; parasitic diseases; orphan drugs
Special Issues and Collections in MDPI journals

Special Issue Information

COVID-19 (coronavirus disease 2019) is a global outbreak of pneumonia and acute respiratory distress syndrome. The exceptionally rapid spread of the disease, which affects every age group, is leading to an urgent need for prophylactic and curative treatments. Consequently, combatting the causal agent SARS-CoV-2 has emerged as a tremendous challenge, gathering efforts from academia, pharmaceutical companies, hospitals, international organizations, as well as governments and philanthropic associations.

This Special Issue covers any aspect of that quest for treatments and welcomes opinions, brief reports, communications, research articles, as well as reviews. 

Dr. Jean Jacques Vanden Eynde
Dr. Annie Mayence
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibodies
  • antiviral agent
  • convalescent serum
  • coronavirus
  • COVID-19
  • curative treatment
  • dietary supplement
  • immunity
  • inhibitors
  • plasma
  • PCR
  • prophylactic treatment
  • protein-based therapy
  • RNA
  • SARS-CoV-2
  • serological test
  • small molecules
  • traditional medicine
  • vaccine
  • 2019-nCoV

Published Papers (40 papers)

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Research

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Article
A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)
Pharmaceuticals 2021, 14(10), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100954 - 23 Sep 2021
Viewed by 1059
Abstract
Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to [...] Read more.
Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 μM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the μM range, supporting the in silico data. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor
Pharmaceuticals 2021, 14(6), 541; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060541 - 05 Jun 2021
Cited by 1 | Viewed by 1221
Abstract
The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, [...] Read more.
The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Identification of Anti-SARS-CoV-2 Compounds from Food Using QSAR-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Analysis
Pharmaceuticals 2021, 14(4), 357; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040357 - 13 Apr 2021
Cited by 2 | Viewed by 1465
Abstract
Due to the genetic similarity between SARS-CoV-2 and SARS-CoV, the present work endeavored to derive a balanced Quantitative Structure−Activity Relationship (QSAR) model, molecular docking, and molecular dynamics (MD) simulation studies to identify novel molecules having inhibitory potential against the main protease (Mpro) of [...] Read more.
Due to the genetic similarity between SARS-CoV-2 and SARS-CoV, the present work endeavored to derive a balanced Quantitative Structure−Activity Relationship (QSAR) model, molecular docking, and molecular dynamics (MD) simulation studies to identify novel molecules having inhibitory potential against the main protease (Mpro) of SARS-CoV-2. The QSAR analysis developed on multivariate GA–MLR (Genetic Algorithm–Multilinear Regression) model with acceptable statistical performance (R2 = 0.898, Q2loo = 0.859, etc.). QSAR analysis attributed the good correlation with different types of atoms like non-ring Carbons and Nitrogens, amide Nitrogen, sp2-hybridized Carbons, etc. Thus, the QSAR model has a good balance of qualitative and quantitative requirements (balanced QSAR model) and satisfies the Organisation for Economic Co-operation and Development (OECD) guidelines. After that, a QSAR-based virtual screening of 26,467 food compounds and 360 heterocyclic variants of molecule 1 (benzotriazole–indole hybrid molecule) helped to identify promising hits. Furthermore, the molecular docking and molecular dynamics (MD) simulations of Mpro with molecule 1 recognized the structural motifs with significant stability. Molecular docking and QSAR provided consensus and complementary results. The validated analyses are capable of optimizing a drug/lead candidate for better inhibitory activity against the main protease of SARS-CoV-2. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods
Pharmaceuticals 2021, 14(4), 332; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040332 - 06 Apr 2021
Cited by 2 | Viewed by 1412
Abstract
The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the [...] Read more.
The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out. As a result, five different potentially repurposable drugs interfering with viral entry—cepharantine, clofazimine, metergoline, imatinib and efloxate—have been identified. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study
Pharmaceuticals 2021, 14(3), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030226 - 07 Mar 2021
Cited by 3 | Viewed by 1221
Abstract
Given the current scarcity of curative treatment of COVID-19, the search for an effective treatment modality among all available medications has become a priority. This study aimed at investigating the role of functional inhibitors of acid sphingomyelinase (FIASMAs) on in-hospital COVID-19 mortality. In [...] Read more.
Given the current scarcity of curative treatment of COVID-19, the search for an effective treatment modality among all available medications has become a priority. This study aimed at investigating the role of functional inhibitors of acid sphingomyelinase (FIASMAs) on in-hospital COVID-19 mortality. In this retrospective cohort study, we included adult in-patients with laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged hospital or deceased) from Erasme Hospital (Brussels, Belgium). We used univariate and multivariate logistic regression models to explore the risk factors associated with in-hospital mortality. We included 350 patients (205 males, 145 females) with a mean age of 63.24 years (SD = 17.4, range: 21–96 years). Seventy-two patients died in the hospital and 278 were discharged. The four most common comorbidities were hypertension (184, 52.6%), chronic cardiac disease (110, 31.4%), obesity (96, 27.8%) and diabetes (95, 27.1%). Ninety-three participants (26.6%) received a long-term prescription for FIASMAs. Among these, 60 (64.5%) received amlodipine. For FIASMAs status, multivariable regression showed increasing odds ratio (OR) for in-hospital deaths associated with older age (OR 1.05, 95% CI: 1.02–1.07; p = 0.00015), and higher prevalence of malignant neoplasm (OR 2.09, 95% CI: 1.03–4.22; p = 0.039). Nonsignificant decreasing OR (0.53, 95% CI: 0.27–1.04; p = 0.064) was reported for FIASMA status. For amlodipine status, multivariable regression revealed increasing OR of in-hospital deaths associated with older age (OR 1.04, 95% CI: 1.02–1.07; p = 0.0009), higher prevalence of hypertension (OR 2.78, 95% CI: 1.33–5.79; p = 0.0062) and higher prevalence of malignant neoplasm (OR 2.71, 95% CI: 1.23–5.97; p = 0.013), then secondarily decreasing OR of in-hospital death associated with long-term treatment with amlodipine (OR 0.24, 95% CI: 0.09–0.62; p = 0.0031). Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in-patients. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Evaluation of the Antiviral Activity of Sitagliptin-Glatiramer Acetate Nano-Conjugates against SARS-CoV-2 Virus
Pharmaceuticals 2021, 14(3), 178; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030178 - 24 Feb 2021
Cited by 1 | Viewed by 907
Abstract
The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. There is a current race for developing strategies to treat and/or prevent COVID-19 worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that [...] Read more.
The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. There is a current race for developing strategies to treat and/or prevent COVID-19 worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes COVID-19. The aim of the present work was to evaluate the efficacy of the combined complex (nano-conjugates) of two FDA-approved drugs, sitagliptin (SIT) and glatiramer acetate (GA), against a human isolate of the SARS-CoV-2 virus. SIT-GA nano-conjugates were prepared according to a full three-factor bilevel (23) factorial design. The SIT concentration (mM, X1), GA concentration (mM, X2), and pH (X3) were selected as the factors. The particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for the Fourier-transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) was carried out. In addition, the half-maximal inhibitory concentration (IC50) in Vero-E6 epithelial cells previously infected with the virus was investigated. The results revealed that the optimized formula of the prepared complex was a 1:1 SIT:GA molar ratio at a pH of 10, which met the required criteria with a desirability value of 0.878 and had a particle size and zeta potential at values of 77.42 nm and 27.67 V, respectively. The SIT-GA nano-complex showed antiviral potential against an isolate of SARS-CoV-2 with IC50 values of 16.14, 14.09, and 8.52 µM for SIT, GA, and SIT-GA nano-conjugates, respectively. Molecular docking has shown that the formula’s components have a high binding affinity to the COVID 3CL protease, essential for coronavirus replication, paralleled by 3CL protease inhibition (IC50 = 2.87 µM). An optimized formulation of SIT-GA could guarantee both enhanced deliveries to target cells and improved cellular uptake. Further clinical studies are being carried out to validate the clinical efficacy of the optimized formulation against SARS-CoV-2. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach
Pharmaceuticals 2021, 14(2), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020087 - 25 Jan 2021
Cited by 1 | Viewed by 1313
Abstract
A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a [...] Read more.
A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID-19. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2
Pharmaceuticals 2020, 13(12), 443; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120443 - 04 Dec 2020
Cited by 20 | Viewed by 3512
Abstract
(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory [...] Read more.
(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory Food and Drug Administration (FDA)-approved drugs, commonly prescribed to relieve respiratory symptoms, against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the viral causative agent of the COVID-19 pandemic. (3) Results: Of these FDA-approved antimicrobial drugs, Azithromycin, Niclosamide, and Nitazoxanide showed a promising ability to hinder the replication of a SARS-CoV-2 isolate, with IC50 of 0.32, 0.16, and 1.29 µM, respectively. We provided evidence that several antihistamine and anti-inflammatory drugs could partially reduce SARS-CoV-2 replication in vitro. Furthermore, this study showed that Azithromycin can selectively impair SARS-CoV-2 replication, but not the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A virtual screening study illustrated that Azithromycin, Niclosamide, and Nitazoxanide bind to the main protease of SARS-CoV-2 (Protein data bank (PDB) ID: 6lu7) in binding mode similar to the reported co-crystalized ligand. Also, Niclosamide displayed hydrogen bond (HB) interaction with the key peptide moiety GLN: 493A of the spike glycoprotein active site. (4) Conclusions: The results suggest that Piroxicam should be prescribed in combination with Azithromycin for COVID-19 patients. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics
Pharmaceuticals 2020, 13(12), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120425 - 27 Nov 2020
Cited by 2 | Viewed by 1008
Abstract
The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered [...] Read more.
The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band > 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8–5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study
Pharmaceuticals 2020, 13(10), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100317 - 17 Oct 2020
Cited by 15 | Viewed by 1616
Abstract
Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO2 ≤ 96% despite O2-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective [...] Read more.
Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO2 ≤ 96% despite O2-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3–0.81), p-value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135–0.51, p = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis (p < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Squalene Emulsion Manufacturing Process Scale-Up for Enhanced Global Pandemic Response
Pharmaceuticals 2020, 13(8), 168; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080168 - 28 Jul 2020
Cited by 1 | Viewed by 1298
Abstract
Squalene emulsions are among the most widely employed vaccine adjuvant formulations. Among the demonstrated benefits of squalene emulsions is the ability to enable vaccine antigen dose sparing, an important consideration for pandemic response. In order to increase pandemic response capabilities, it is desirable [...] Read more.
Squalene emulsions are among the most widely employed vaccine adjuvant formulations. Among the demonstrated benefits of squalene emulsions is the ability to enable vaccine antigen dose sparing, an important consideration for pandemic response. In order to increase pandemic response capabilities, it is desirable to scale up adjuvant manufacturing processes. We describe innovative process enhancements that enabled the scale-up of bulk stable squalene emulsion (SE) manufacturing capacity from a 3000- to 5,000,000-dose batch size. Manufacture of concentrated bulk along with the accompanying viscosity change in the continuous phase resulted in a ≥25-fold process efficiency enhancement. Process streamlining and implementation of single-use biocontainers resulted in reduced space requirements, fewer unit operations, and minimization of cleaning requirements. Emulsion physicochemical characteristics were measured by dynamic light scattering, laser diffraction, and HPLC with charged aerosol detection. The newly developed full-scale process was demonstrated by producing two 5,000,000-dose batches of bulk concentrated SE. A scale-up of adjuvant manufacturing capacity through process innovation enables more efficient production capabilities for pandemic response. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Communication
Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection
Pharmaceuticals 2020, 13(6), 132; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13060132 - 25 Jun 2020
Cited by 21 | Viewed by 2103
Abstract
SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus [...] Read more.
SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Excess Ascorbate is a Chemical Stress Agent against Proteins and Cells
Pharmaceuticals 2020, 13(6), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13060107 - 27 May 2020
Cited by 3 | Viewed by 1743
Abstract
Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates [...] Read more.
Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates and metabolic activities of several leukocyte subsets implicated in the antiviral cellular immune response are also affected. Excess ascorbate is thus an unselective biological stress agent. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review

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Review
Pharmacology and Adverse Events of Emergency-Use Authorized Medication in Moderate to Severe COVID-19
Pharmaceuticals 2021, 14(10), 955; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100955 (registering DOI) - 23 Sep 2021
Viewed by 224
Abstract
Some effective drugs have been approved or issued an Emergency Use Authorization for the treatment of COVID-19 in hospitalized patients, but post-market surveillance is warranted to monitor adverse events. We reviewed clinical trials and case reports in patients with moderate-to-severe COVID-19 infection who [...] Read more.
Some effective drugs have been approved or issued an Emergency Use Authorization for the treatment of COVID-19 in hospitalized patients, but post-market surveillance is warranted to monitor adverse events. We reviewed clinical trials and case reports in patients with moderate-to-severe COVID-19 infection who received remdesivir, baricitinib, tocilizumab, or sarilumab. The drug-specific pharmacokinetics, toxicity, and drug interactions are summarized in this study. Remdesivir and baricitinib are small-molecule drugs that are mainly metabolized by the kidneys, while tocilizumab and sarilumab are monoclonal antibody drugs with metabolic pathways that are currently not fully understood. The most common adverse events of these drugs are alterations in liver function, but serious adverse events have rarely been attributed to them. Only a few studies have reported that remdesivir might be cardiotoxic and that baricitinib might cause thromboembolism. Biological agents such as baricitinib, tocilizumab, and sarilumab could inhibit the pathway of inflammatory processes, leading to immune dysregulation, so the risk of secondary infection should be assessed before prescribing. Further recognition of the pathogenic mechanism and risk factors of adverse events is essential for optimizing treatment strategies. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Neuropsychiatric Disorders and COVID-19: What We Know So Far
Pharmaceuticals 2021, 14(9), 933; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090933 - 17 Sep 2021
Viewed by 419
Abstract
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more [...] Read more.
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more common in patients with severe infection according to their respiratory status and divided into three categories: (1) CNS manifestations; (2) cranial and peripheral nervous system manifestations; and (3) skeletal muscle injury manifestations. Patients with pre-existing cerebrovascular disease are at a higher risk of admission to the intensive care unit (ICU) and mortality. The neurological manifestations associated with COVID-19 are of great importance, but when life-threatening abnormal vital signs occur in severely ill COVID-19 patients, neurological problems are usually not considered. It is crucial to search for new treatments for brain damage, as well as for alternative therapies that recover the damaged brain and reduce the inflammatory response and its consequences for other organs. In addition, there is a need to diagnose these manifestations as early as possible to limit long-term consequences. Therefore, much research is needed to explain the involvement of SARS-CoV-2 causing these neurological symptoms because scientists know zero about it. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Prevalence and Significance of Hypermetabolic Lymph Nodes Detected by 2-[18F]FDG PET/CT after COVID-19 Vaccination: A Systematic Review and a Meta-Analysis
Pharmaceuticals 2021, 14(8), 762; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080762 - 03 Aug 2021
Cited by 1 | Viewed by 922
Abstract
Recently, several articles reported incidental findings at 2-[18F]FDG PET/CT in patients who have received COVID-19 vaccinations, including hypermetabolic axillary lymph nodes (HALNs) ipsilateral to the COVID-19 vaccine injection site which may cause diagnostic dilemmas. The aim of our work was to [...] Read more.
Recently, several articles reported incidental findings at 2-[18F]FDG PET/CT in patients who have received COVID-19 vaccinations, including hypermetabolic axillary lymph nodes (HALNs) ipsilateral to the COVID-19 vaccine injection site which may cause diagnostic dilemmas. The aim of our work was to calculate the prevalence of this finding. A comprehensive computer literature search of PubMed/MEDLINE, Embase, and Cochrane library databases was performed to identify recently published articles that investigated the prevalence of HALNs detected by 2-[18F]FDG PET/CT after COVID-19 vaccination. Pooled prevalence of this finding was calculated through a meta-analytic approach. Nine recently published articles including 2354 patients undergoing 2-[18F]FDG PET/CT after recent COVID-19 vaccination have been included in the systematic review. Overall, HALNs ipsilateral to the vaccine injection site were frequent findings mainly due to vaccine-related immune response in most of the cases. The pooled prevalence of HALNs after COVID-19 vaccination was 37% (95% confidence interval: 27–47%) but with significant heterogeneity among the included studies. Physicians must be aware and recognize the significant frequency of HALNs at 2-[18F]FDG PET/CT related to immune response to vaccine injection. Larger studies are needed to confirm the findings of this systematic review and meta-analysis. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Current Status of Baricitinib as a Repurposed Therapy for COVID-19
Pharmaceuticals 2021, 14(7), 680; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070680 - 15 Jul 2021
Viewed by 1048
Abstract
The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of [...] Read more.
The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents
Pharmaceuticals 2021, 14(6), 546; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060546 - 07 Jun 2021
Cited by 1 | Viewed by 1048
Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 [...] Read more.
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Clinical Management of COVID-19: A Review of Pharmacological Treatment Options
Pharmaceuticals 2021, 14(6), 520; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060520 - 28 May 2021
Cited by 4 | Viewed by 2398
Abstract
Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the [...] Read more.
Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the public health strategy to reduce the burden of COVID-19, the management of this disease will continue to rely heavily on pharmacotherapy. This study aims to provide an updated review of pharmacological agents that have been developed and/or repurposed for the treatment of COVID-19. To this end, a comprehensive literature search was conducted using the PubMed, Google Scholar, and LitCovid databases. Relevant clinical studies on drugs used in the management of COVID-19 were identified and evaluated in terms of evidence of efficacy and safety. To date, the FDA has approved three therapies for the treatment of COVID-19 Emergency Use Authorization: convalescent plasma, remdesivir, and casirivimab/imdevimab (REGN-COV2). Drugs such as lopinavir/ritonavir, umifenovir, favipiravir, anakinra, chloroquine, hydroxychloroquine, tocilizumab, interferons, tissue plasminogen activator, intravenous immunoglobulins, and nafamosat have been used off-label with mixed therapeutic results. Adjunctive administration of corticosteroids is also very common. The clinical experience with these approved and repurposed drugs is limited, and data on efficacy for the new indication are not strong. Overall, the response of the global scientific community to the COVID-19 pandemic has been impressive, as evident from the volume of scientific literature elucidating the molecular biology and pathophysiology of SARS-CoV-2 and the approval of three new drugs for clinical management. Reviewed studies have shown mixed data on efficacy and safety of the currently utilized drugs. The lack of standard treatment for COVID-19 has made it difficult to interpret results from most of the published studies due to the risk of attribution error. The long-term effects of drugs can only be assessed after several years of clinical experience; therefore, the efficacy and safety of current COVID-19 therapeutics should continue to be rigorously monitored as part of post-marketing studies. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
New Approaches and Repurposed Antiviral Drugs for the Treatment of the SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(6), 503; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060503 - 25 May 2021
Cited by 1 | Viewed by 968
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). The outbreak of this coronavirus was first identified in Wuhan (Hubei, China) in December 2019, and it was declared as pandemic by the World Health Organization (WHO) [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). The outbreak of this coronavirus was first identified in Wuhan (Hubei, China) in December 2019, and it was declared as pandemic by the World Health Organization (WHO) in March 2020. Today, several vaccines against SARS-CoV-2 have been approved, and some neutralizing monoclonal antibodies are being tested as therapeutic approaches for COVID-19 but, one of the key questions is whether both vaccines and monoclonal antibodies could be effective against infections by new SARS-CoV-2 variants. Nevertheless, there are currently more than 1000 ongoing clinical trials focusing on the use and effectiveness of antiviral drugs as a possible therapeutic treatment. Among the classes of antiviral drugs are included 3CL protein inhibitors, RNA synthesis inhibitors and other small molecule drugs which target the ability of SARS-COV-2 to interact with host cells. Considering the need to find specific treatment to prevent the emergent outbreak, the aim of this review is to explain how some repurposed antiviral drugs, indicated for the treatment of other viral infections, could be potential candidates for the treatment of COVID-19. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection
Pharmaceuticals 2021, 14(5), 454; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050454 - 11 May 2021
Cited by 1 | Viewed by 1106 | Correction
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients
Pharmaceuticals 2021, 14(4), 336; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040336 - 06 Apr 2021
Cited by 5 | Viewed by 1190
Abstract
The Coronavirus Disease-19 (COVID-19) pandemic has caused more than 100,000,000 cases of coronavirus infection in the world in just a year, of which there were 2 million deaths. Its clinical picture is characterized by pulmonary involvement that culminates, in the most severe cases, [...] Read more.
The Coronavirus Disease-19 (COVID-19) pandemic has caused more than 100,000,000 cases of coronavirus infection in the world in just a year, of which there were 2 million deaths. Its clinical picture is characterized by pulmonary involvement that culminates, in the most severe cases, in acute respiratory distress syndrome (ARDS). However, COVID-19 affects other organs and systems, including cardiovascular, urinary, gastrointestinal, and nervous systems. Currently, unique-drug therapy is not supported by international guidelines. In this context, it is important to resort to adjuvant therapies in combination with traditional pharmacological treatments. Among natural bioactive compounds, palmitoylethanolamide (PEA) seems to have potentially beneficial effects. In fact, the Food and Drug Administration (FDA) authorized an ongoing clinical trial with ultramicronized (um)-PEA as an add-on therapy in the treatment of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. In support of this hypothesis, in vitro and in vivo studies have highlighted the immunomodulatory, anti-inflammatory, neuroprotective and pain-relieving effects of PEA, especially in its um form. The purpose of this review is to highlight the potential use of um-PEA as an adjuvant treatment in SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Rapamycin: Drug Repurposing in SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(3), 217; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030217 - 05 Mar 2021
Cited by 2 | Viewed by 870
Abstract
Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, [...] Read more.
Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world’s acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(1), 71; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010071 - 17 Jan 2021
Cited by 9 | Viewed by 3111
Abstract
In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute [...] Read more.
In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Inhibition of SARS-CoV-2 Entry into Host Cells Using Small Molecules
Pharmaceuticals 2020, 13(12), 447; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120447 - 08 Dec 2020
Cited by 5 | Viewed by 1527
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a virus belonging to the Coronavirus family, is now known to cause Coronavirus Disease (Covid-19) which was first recognized in December 2019. Covid-19 leads to respiratory illnesses ranging from mild infections to pneumonia and lung failure. [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a virus belonging to the Coronavirus family, is now known to cause Coronavirus Disease (Covid-19) which was first recognized in December 2019. Covid-19 leads to respiratory illnesses ranging from mild infections to pneumonia and lung failure. Strikingly, within a few months of its first report, Covid-19 has spread worldwide at an exceptionally high speed and it has caused enormous human casualties. As yet, there is no specific treatment for Covid-19. Designing inhibitory drugs that can interfere with the viral entry process constitutes one of the main preventative therapies that could combat SARS-CoV-2 infection at an early stage. In this review, we provide a brief introduction of the main features of coronaviruses, discuss the entering mechanism of SARS-CoV-2 into human host cells and review small molecules that inhibit SARS-CoV-2 entry into host cells. Specifically, we focus on small molecules, identified by experimental validation and/or computational prediction, that target the SARS-CoV-2 spike protein, human angiotensin converting enzyme 2 (ACE2) receptor and the different host cell proteases that activate viral fusion. Given the persistent rise in Covid-19 cases to date, efforts should be directed towards validating the therapeutic effectiveness of these identified small molecule inhibitors. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Role of 2-[18F]FDG as a Radiopharmaceutical for PET/CT in Patients with COVID-19: A Systematic Review
Pharmaceuticals 2020, 13(11), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110377 - 10 Nov 2020
Cited by 11 | Viewed by 1122
Abstract
Some recent studies evaluated the role of fluorine-18 fluorodeoxyglucose (2-[18F]FDG) as a radiopharmaceutical for positron emission tomography/computed tomography (PET/CT) imaging in patients with Coronavirus Disease (COVID-19). This article aims to perform a systematic review in this setting. A comprehensive computer literature [...] Read more.
Some recent studies evaluated the role of fluorine-18 fluorodeoxyglucose (2-[18F]FDG) as a radiopharmaceutical for positron emission tomography/computed tomography (PET/CT) imaging in patients with Coronavirus Disease (COVID-19). This article aims to perform a systematic review in this setting. A comprehensive computer literature search in PubMed/MEDLINE and Cochrane library databases regarding the role of 2-[18F]FDG PET/CT in patients with COVID-19 was carried out. This combination of key words was used: (A) “PET” OR “positron emission tomography” AND (B) “COVID” OR “SARS”. Only pertinent original articles were selected; case reports and very small case series were excluded. We have selected 11 original studies of 2-[18F]FDG PET/CT in patients with COVID-19. Evidence-based data showed first preliminary applications of this diagnostic tool in this clinical setting, with particular regard to the incidental detection of interstitial pneumonia suspected for COVID-19. To date, according to evidence-based data, 2-[18F]FDG PET/CT cannot substitute or integrate high-resolution CT to diagnose suspicious COVID-19 or for disease monitoring, but it can only be useful to incidentally detect suspicious COVID-19 lesions in patients performing this imaging method for standard oncological and non-oncological indications. Published data about the possible role of 2-[18F]FDG PET/CT in patients with COVID-19 are increasing, but larger studies are warranted. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Emerging Therapeutic Modalities against COVID-19
Pharmaceuticals 2020, 13(8), 188; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080188 - 08 Aug 2020
Cited by 6 | Viewed by 3769
Abstract
The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. [...] Read more.
The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence?
Pharmaceuticals 2020, 13(8), 166; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080166 - 26 Jul 2020
Cited by 6 | Viewed by 1579
Abstract
Dysregulation of the immune system undoubtedly plays an important and, perhaps, determining role in the COVID-19 pathogenesis. While the main treatment of the COVID-19 intoxication is focused on neutralizing the excessive inflammatory response, it is worth considering an equally significant problem of the [...] Read more.
Dysregulation of the immune system undoubtedly plays an important and, perhaps, determining role in the COVID-19 pathogenesis. While the main treatment of the COVID-19 intoxication is focused on neutralizing the excessive inflammatory response, it is worth considering an equally significant problem of the immunosuppressive conditions including immuno-paralysis, which lead to the secondary infection. Therefore, choosing a treatment strategy for the immune-mediated complications of coronavirus infection, one has to pass between Scylla and Charybdis, so that, in the fight against the “cytokine storm,” it is vital not to miss the point of the immune silence that turns into immuno-paralysis. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Substance Use Disorder in the COVID-19 Pandemic: A Systematic Review of Vulnerabilities and Complications
Pharmaceuticals 2020, 13(7), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13070155 - 18 Jul 2020
Cited by 19 | Viewed by 4421
Abstract
As the world endures the coronavirus disease 2019 (COVID-19) pandemic, the conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by [...] Read more.
As the world endures the coronavirus disease 2019 (COVID-19) pandemic, the conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
The Rationale for Potential Pharmacotherapy of COVID-19
Pharmaceuticals 2020, 13(5), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050096 - 14 May 2020
Cited by 22 | Viewed by 4253
Abstract
On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 [...] Read more.
On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Correction
Correction: Zanella et al. Tenofovir, Another Inexpensive, Well Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection. Pharmaceuticals 2021, 14, 454
Pharmaceuticals 2021, 14(8), 827; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080827 - 23 Aug 2021
Viewed by 450
Abstract
Text Correction [...] Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
Perspective
Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(7), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070691 - 18 Jul 2021
Cited by 1 | Viewed by 939
Abstract
The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been [...] Read more.
The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
Opinion
COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?
Pharmaceuticals 2021, 14(7), 664; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070664 - 11 Jul 2021
Viewed by 1020
Abstract
The DisCoVeRy clinical trial aimed at the evaluation of four treatments for patients suffering from severe to critical COVID-19: Hydroxychloroquine, eventually associated with azithromycin; the combination lopinavir/ritonavir; the combination with the addition of interferon β-1a; remdesivir. The trial was discontinued due to the [...] Read more.
The DisCoVeRy clinical trial aimed at the evaluation of four treatments for patients suffering from severe to critical COVID-19: Hydroxychloroquine, eventually associated with azithromycin; the combination lopinavir/ritonavir; the combination with the addition of interferon β-1a; remdesivir. The trial was discontinued due to the lack of positive results. Meanwhile, many other potential options have been considered either to target the virus itself, the interactions with the host cells, or the cytokine storm frequently observed during the infection. Several of those options are briefly reviewed. They include vaccines, small molecules, antibodies, and stem cells. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Perspective
Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19
Pharmaceuticals 2021, 14(1), 15; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010015 - 26 Dec 2020
Cited by 7 | Viewed by 1663
Abstract
COVID-19 has rapidly spread worldwide and incidences of hospitalisation from respiratory distress are significant. While a vaccine is in the pipeline, there is urgency for therapeutic options to address the immune dysregulation, hyperinflammation and oxidative stress that can lead to death. Given the [...] Read more.
COVID-19 has rapidly spread worldwide and incidences of hospitalisation from respiratory distress are significant. While a vaccine is in the pipeline, there is urgency for therapeutic options to address the immune dysregulation, hyperinflammation and oxidative stress that can lead to death. Given the shared pathogenesis of severe cases of COVID-19 with aspects of multiple sclerosis and psoriasis, we propose dimethyl fumarate as a viable treatment option. Currently approved for multiple sclerosis and psoriasis, dimethyl fumarate is an immunomodulatory, anti-inflammatory and anti-oxidative drug that could be rapidly implemented into the clinic to calm the cytokine storm which drives severe COVID-19. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Commentary
Emetine Is Not Ipecac: Considerations for Its Use as Treatment for SARS-CoV2
Pharmaceuticals 2020, 13(12), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120428 - 27 Nov 2020
Viewed by 1104
Abstract
Emetine is a potent antiviral that acts on many viruses in the low-nM range, with several studies in animals and humans demonstrating antiviral activity. Historically, emetine was used to treat patients with Spanish influenza, in the last stages of the pandemic in the [...] Read more.
Emetine is a potent antiviral that acts on many viruses in the low-nM range, with several studies in animals and humans demonstrating antiviral activity. Historically, emetine was used to treat patients with Spanish influenza, in the last stages of the pandemic in the early 1900s. Some of these patients were “black” with cyanosis. Emetine rapidly reversed the cyanosis and other symptoms of this disease in 12–24 h. However, emetine also has been shown to have anti-inflammatory properties and it appears it is these anti-inflammatory properties that were responsible for the effects seen in patients with Spanish influenza. Emetine, in the past, has also been used in 10s to 100s of millions of people at a dose of ~60 mg daily to treat amoebiasis. Based on viral inhibition data we can calculate a likely SARS-CoV2 antiviral dose of ~1/10th the amoebiasis dose, which should dramatically reduce the risk of any side effects. While there are no anti-inflammatory dose response data available, based on the potential mode of action, the anti-inflammatory actions may also occur at low doses. This paper also examines the toxicity of emetine seen in clinical practice and that seen in the laboratory, and discusses the methods of administration aimed at reducing side effects if higher doses were found to be necessary. While emetine is a “pure drug” as it is extracted from ipecac, some of the differences between emetine and ipecac are also discussed. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
Opinion
Can Nuclear Imaging of Activated Macrophages with Folic Acid-Based Radiotracers Serve as a Prognostic Means to Identify COVID-19 Patients at Risk?
Pharmaceuticals 2020, 13(9), 238; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090238 - 09 Sep 2020
Cited by 5 | Viewed by 1225
Abstract
Herein, we discuss the potential role of folic acid-based radiopharmaceuticals for macrophage imaging to support clinical decision-making in patients with COVID-19. Activated macrophages play an important role during coronavirus infections. Exuberant host responses, i.e., a cytokine storm with increase of macrophage-related cytokines, such [...] Read more.
Herein, we discuss the potential role of folic acid-based radiopharmaceuticals for macrophage imaging to support clinical decision-making in patients with COVID-19. Activated macrophages play an important role during coronavirus infections. Exuberant host responses, i.e., a cytokine storm with increase of macrophage-related cytokines, such as TNFα, IL-1β, and IL-6 can lead to life-threatening complications, such as acute respiratory distress syndrome (ARDS), which develops in approximately 20% of the patients. Diverse immune modulating therapies are currently being tested in clinical trials. In a preclinical proof-of-concept study in experimental interstitial lung disease, we showed the potential of 18F-AzaFol, an 18F-labeled folic acid-based radiotracer, as a specific novel imaging tool for the visualization and monitoring of macrophage-driven lung diseases. 18F-AzaFol binds to the folate receptor-beta (FRβ) that is expressed on activated macrophages involved in inflammatory conditions. In a recent multicenter cancer trial, 18F-AzaFol was successfully and safely applied (NCT03242993). It is supposed that the visualization of activated macrophage-related disease processes by folate radiotracer-based nuclear imaging can support clinical decision-making by identifying COVID-19 patients at risk of a severe disease progression with a potentially lethal outcome. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Opinion
Cancer Patients Have a Higher Risk Regarding COVID-19–and Vice Versa?
Pharmaceuticals 2020, 13(7), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13070143 - 06 Jul 2020
Cited by 4 | Viewed by 2003
Abstract
The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by [...] Read more.
The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. We offer lines of thought to provide ideas for urgently needed studies on the potential long-term effects of SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Opinion
COVID-19: An Update about the Discovery Clinical Trial
Pharmaceuticals 2020, 13(5), 98; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050098 - 14 May 2020
Cited by 8 | Viewed by 2712
Abstract
Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of [...] Read more.
Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of lopinavir/ritonavir, hydroxychloroquine, and chloroquine. Results recently published on the clinical evaluation of those drugs are compiled in this brief report, although complete data are still impatiently awaited. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Opinion
COVID-19: A Brief Overview of the Discovery Clinical Trial
Pharmaceuticals 2020, 13(4), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13040065 - 10 Apr 2020
Cited by 20 | Viewed by 5566
Abstract
The outbreak of COVID-19 is leading to a tremendous search for curative treatments. The urgency of the situation favors a repurposing of active drugs but not only antivirals. This short communication focuses on four treatments recommended by WHO and included in the first [...] Read more.
The outbreak of COVID-19 is leading to a tremendous search for curative treatments. The urgency of the situation favors a repurposing of active drugs but not only antivirals. This short communication focuses on four treatments recommended by WHO and included in the first clinical trial of the European Discovery project. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Commentary
Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses
Pharmaceuticals 2020, 13(3), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13030051 - 21 Mar 2020
Cited by 27 | Viewed by 3753
Abstract
The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine [...] Read more.
The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine had amongst the lowest reported half-maximal effective concentration (EC50) from over 290 agents screened for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses. While EC50 concentrations of emetine are achievable in the blood, studies show that concentrations of emetine can be almost 300 times higher in the lungs. Furthermore, based on the relative EC50s of emetine towards the coronaviruses compared with Entamoeba histolytica, emetine could be much more effective as an anti-coronavirus agent than it is against amoebiasis. This paper also discusses the known side effects of emetine and related compounds, how those side effects can be managed, and the optimal method of administration for the potential treatment of COVID-19. Given the serious and immediate threat that the COVID-19 coronavirus poses, our long history with emetine and the likely ability of emetine to reach therapeutic concentrations within the lungs, ipecac, emetine, and other analogues should be considered as potential treatment options, especially if in vitro studies confirm viral sensitivity. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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