Pharmaceuticals

Research

20 pages, 4529 KiB

Open AccessArticle

Plant Metabolites as SARS-CoV-2 Inhibitors Candidates: In Silico and In Vitro Studies

by Alberto Jorge Oliveira Lopes, Gustavo Pereira Calado, Yuri Nascimento Fróes, Sandra Alves de Araújo, Lucas Martins França, Antonio Marcus de Andrade Paes, Sebastião Vieira de Morais, Cláudia Quintino da Rocha and Cleydlenne Costa Vasconcelos

Pharmaceuticals 2022, 15(9), 1045; https://doi.org/10.3390/ph15091045 - 24 Aug 2022

Cited by 15 | Viewed by 2696

Abstract

Since it acquired pandemic status, SARS-CoV-2 has been causing all kinds of damage all over the world. More than 6.3 million people have died, and many cases of sequelae are in survivors. Currently, the only products available to most of the world’s population [...] Read more.

Since it acquired pandemic status, SARS-CoV-2 has been causing all kinds of damage all over the world. More than 6.3 million people have died, and many cases of sequelae are in survivors. Currently, the only products available to most of the world’s population to fight the pandemic are vaccines, which still need improvement since the number of new cases, admissions into intensive care units, and deaths are again reaching worrying rates, which makes it essential to compounds that can be used during infection, reducing the impacts of the disease. Plant metabolites are recognized sources of diverse biological activities and are the safest way to research anti-SARS-CoV-2 compounds. The present study computationally evaluated 55 plant compounds in five SARS-CoV-2 targets such Main Protease (Mpro or 3CL or MainPro), RNA-dependent RNA polymerase (RdRp), Papain-Like Protease (PLpro), NSP15 Endoribonuclease, Spike Protein (Protein S or Spro) and human Angiotensin-converting enzyme 2 (ACE-2) followed by in vitro evaluation of their potential for the inhibition of the interaction of the SARS-CoV-2 Spro with human ACE-2. The in silico results indicated that, in general, amentoflavone, 7-O-galloylquercetin, kaempferitrin, and gallagic acid were the compounds with the strongest electronic interaction parameters with the selected targets. Through the data obtained, we can demonstrate that although the indication of individual interaction of plant metabolites with both Spro and ACE-2, the metabolites evaluated were not able to inhibit the interaction between these two structures in the in vitro test. Despite this, these molecules still must be considered in the research of therapeutic agents for treatment of patients affected by COVID-19 since the activity on other targets and influence on the dynamics of viral infection during the interaction Spro x ACE-2 should be investigated. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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21 pages, 4022 KiB

Open AccessArticle

Efficacy of Kan Jang^® in Patients with Mild COVID-19: Interim Analysis of a Randomized, Quadruple-Blind, Placebo-Controlled Trial

by Levan Ratiani, Elene Pachkoria, Nato Mamageishvili, Ramaz Shengelia, Areg Hovhannisyan and Alexander Panossian

Pharmaceuticals 2022, 15(8), 1013; https://doi.org/10.3390/ph15081013 - 17 Aug 2022

Cited by 6 | Viewed by 3584

Abstract

Kan Jang^®, the fixed combination of Andrographis paniculata (Burm. F.) Wall. ex. Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim extracts, is a herbal medicinal product for relieving symptoms of upper respiratory tract infections. This study aimed to assess the efficacy [...] Read more.

Kan Jang^®, the fixed combination of Andrographis paniculata (Burm. F.) Wall. ex. Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim extracts, is a herbal medicinal product for relieving symptoms of upper respiratory tract infections. This study aimed to assess the efficacy of Kan Jang^®/Nergecov® on duration and the relief of inflammatory symptoms in adults with mild COVID-19. 86 patients with laboratory-confirmed COVID-19 and mild symptoms for one to three days received supportive treatment (paracetamol) and six Kan Jang^® (daily dose of andrographolides—90 mg) or placebo capsules a day for 14 consecutive days in this randomized, quadruple-blinded, placebo-controlled, two-parallel-group study. The primary efficacy outcomes were the decrease in the acute-phase duration and the severity of symptoms score (sore throat, runny nose, cough, headache, fatigue, loss of smell, taste, pain in muscles), an increase in cognitive functions, physical performance, quality of life, and decrease in IL-6, c-reactive protein, and D-dimer in blood. Kan Jang^®/Nergecov^® was effective in reducing the risk of progression to severe COVID-19, decreasing the disease progression rate by almost 2.5-fold compared to placebo. Absolute risk reduction by Kan Jang treatment is 14%, the relative risk reduction is 243.9%, and the number Needed to Treat is 7.14. Kan Jang^®/Nergecov^® reduces the duration of disease, virus clearance, and days of hospitalization and accelerates recovery of patients, relief of sore throat, muscle pain, runny nose, and normalization of body temperature. Kan Jang^®/Nergecov^® significantly relieves the severity of inflammatory symptoms such as sore throat, runny nose, and muscle pain, decreases pro-inflammatory cytokine IL-6 level in the blood, and increases patients’ physical performance (workout) compared to placebo. In this study, for the first time we demonstrate that Kan Jang^®/Nergecov^® is effective in treating mild COVID-19. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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16 pages, 6112 KiB

Open AccessArticle

Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach

by Manuel I. Osorio, Osvaldo Yáñez, Mauricio Gallardo, Matías Zuñiga-Bustos, Jorge Mulia-Rodríguez, Roberto López-Rendón, Olimpo García-Beltrán, Fernando González-Nilo and José M. Pérez-Donoso

Pharmaceuticals 2022, 15(8), 986; https://doi.org/10.3390/ph15080986 - 11 Aug 2022

Cited by 4 | Viewed by 2271

Abstract

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 [...] Read more.

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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15 pages, 1898 KiB

Open AccessArticle

Optimization of 2-Aminoquinazolin-4-(3H)-one Derivatives as Potent Inhibitors of SARS-CoV-2: Improved Synthesis and Pharmacokinetic Properties

by Young Sup Shin, Jun Young Lee, Sangeun Jeon, Jung-Eun Cho, Subeen Myung, Min Seong Jang, Seungtaek Kim, Jong Hwan Song, Hyoung Rae Kim, Hyeung-geun Park, Lak Shin Jeong and Chul Min Park

Pharmaceuticals 2022, 15(7), 831; https://doi.org/10.3390/ph15070831 - 4 Jul 2022

Cited by 5 | Viewed by 2682

Abstract

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3H)-one 1, which shows significant activity (IC₅₀ = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo [...] Read more.

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3H)-one 1, which shows significant activity (IC₅₀ = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound 1 because its area under the curve (AUC) and maximum plasma concentration are low. Here, we designed and synthesized N-substituted quinazolinone derivatives that had good pharmacokinetics and that retained their inhibitory activity against SARS-CoV-2. These compounds were conveniently prepared on a large scale through a one-pot reaction using Dimroth rearrangement as a key step. The synthesized compounds showed potent inhibitory activity, low binding to hERG channels, and good microsomal stability. In vivo pharmacokinetic studies showed that compound 2b had the highest exposure (AUC_24h = 41.57 μg∙h/mL) of the synthesized compounds. An in vivo single-dose toxicity evaluation of compound 2b at 250 and 500 mg/kg in rats resulted in no deaths and an approximate lethal dose greater than 500 mg/kg. This study shows that N-acetyl 2-aminoquinazolin-4-(3H)-one 2b is a promising lead compound for developing anti-SARS-CoV-2 agents. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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17 pages, 31961 KiB

Open AccessArticle

The Potential Complementary Role of Using Chinese Herbal Medicine with Western Medicine in Treating COVID-19 Patients: Pharmacology Network Analysis

by Yi-Chin Lu, Liang-Wei Tseng, Yu-Chieh Huang, Ching-Wei Yang, Yu-Chun Chen and Hsing-Yu Chen

Pharmaceuticals 2022, 15(7), 794; https://doi.org/10.3390/ph15070794 - 26 Jun 2022

Cited by 8 | Viewed by 3616

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic in 2019—coronavirus disease (COVID-19). More and more Western medicine (WM) and Chinese herbal medicine (CHM) treatments have been used to treat COVID-19 patients, especially among Asian populations. However, the interactions between [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic in 2019—coronavirus disease (COVID-19). More and more Western medicine (WM) and Chinese herbal medicine (CHM) treatments have been used to treat COVID-19 patients, especially among Asian populations. However, the interactions between WM and CHM have not been studied. This study aims at using the network pharmacology approach to explore the potential complementary effects among commonly used CHM and WM in a clinical setting from a biomolecular perspective. Three well-published and widely used CHM formulas (National Research Institute of Chinese Medicine 101 (NRICM101), Qing-Fei-Pai-Du-Tang (QFPDT), Hua-Shi-Bai-Du-Formula (HSBDF)) and six categories of WM (Dexamethasone, Janus kinase inhibitors (JAKi), Anti-Interleukin-6 (Anti-IL6), anticoagulants, non-vitamin K antagonist oral anticoagulants (NOAC), and Aspirin) were included in the network pharmacology analysis. The target proteins on which these CHM and WM had direct effects were acquired from the STITCH database, and the potential molecular pathways were found in the REACTOME database. The COVID-19-related target proteins were obtained from the TTD database. For the three CHM formulas, QFPDT covered the most proteins (714), and 27 of them were COVID-19-related, while HSBDF and NRICM101 covered 624 (24 COVID-19-related) and 568 (25 COVID-19-related) proteins, respectively. On the other hand, WM covered COVID-19-related proteins more precisely and seemed different from CHM. The network pharmacology showed CHM formulas affected several inflammation-related proteins for COVID-19, including IL-10, TNF-α, IL-6, TLR3, and IL-8, in which Dexamethasone and Aspirin covered only IL-10 and TNF-α. JAK and IL-6 receptors were only inhibited by WM. The molecular pathways covered by CHM and WM also seemed mutually exclusive. WM had advantages in cytokine signaling, while CHM had an add-on effect on innate and adaptive immunity, including neutrophil regulation. WM and CHM could be used together to strengthen the anti-inflammation effects for COVID-19 from different pathways, and the combination of WM and CHM may achieve more promising results. These findings warrant further clinical studies about CHM and WM use for COVID-19 and other diseases. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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12 pages, 2902 KiB

Open AccessArticle

Analgesics Induce Alterations in the Expression of SARS-CoV-2 Entry and Arachidonic-Acid-Metabolizing Genes in the Mouse Lungs

by Fatima Khirfan, Yazun Jarrar, Tariq Al-Qirim, Khang Wen Goh, Qais Jarrar, Chrismawan Ardianto, Mohammad Awad, Hamzeh J. Al-Ameer, Wajdy Al-Awaida, Said Moshawih and Long Chiau Ming

Pharmaceuticals 2022, 15(6), 696; https://doi.org/10.3390/ph15060696 - 1 Jun 2022

Cited by 6 | Viewed by 3152

Abstract

Paracetamol and nonsteroidal anti-inflammatory drugs are widely used in the management of respiratory viral infections. This study aimed to determine the effects of the most commonly used analgesics (paracetamol, ibuprofen, and diclofenac) on the mRNA expression of severe acute respiratory syndrome coronavirus 2 [...] Read more.

Paracetamol and nonsteroidal anti-inflammatory drugs are widely used in the management of respiratory viral infections. This study aimed to determine the effects of the most commonly used analgesics (paracetamol, ibuprofen, and diclofenac) on the mRNA expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and arachidonic-acid-metabolizing genes in mouse lungs. A total of twenty eight Balb/c mice were divided into four groups and treated separately with vehicle, paracetamol, ibuprofen, and diclofenac in clinically equivalent doses for 14 days. Then, the expressions of SARS-CoV-2 entry, ACE2, TMPRSS2, and Ctsl genes, in addition to the arachidonic-acid-metabolizing cyp450, cox, and alox genes, were analyzed using real-time PCR. Paracetamol increased the expressions of TMPRSS2 and Ctsl genes by 8.5 and 5.6 folds, respectively, while ibuprofen and diclofenac significantly decreased the expression of the ACE2 gene by more than 2.5 folds. In addition, all tested drugs downregulated (p < 0.05) cox2 gene expression, and paracetamol reduced the mRNA levels of cyp4a12 and 2j5. These molecular alterations in diclofenac and ibuprofen were associated with pathohistological alterations, where both analgesics induced the infiltration of inflammatory cells and airway wall thickening. It is concluded that analgesics such as paracetamol, ibuprofen, and diclofenac alter the expression of SARS-CoV-2 entry and arachidonic-acid-metabolizing genes in mouse lungs. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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16 pages, 2126 KiB

Open AccessArticle

Accurate Mass Identification of an Interfering Water Adduct and Strategies in Development and Validation of an LC-MS/MS Method for Quantification of MPI8, a Potent SARS-CoV-2 Main Protease Inhibitor, in Rat Plasma in Pharmacokinetic Studies

by Yang Wang, Huan Xie, Yugendar R. Alugubelli, Yuying Ma, Shiqing Xu, Jing Ma, Wenshe R. Liu and Dong Liang

Pharmaceuticals 2022, 15(6), 676; https://doi.org/10.3390/ph15060676 - 27 May 2022

Cited by 1 | Viewed by 2782

Abstract

MPI8, a peptidyl aldehyde, is a potent antiviral agent against coronavirus. Due to unique tri-peptide bonds and the formyl functional group, the bioassay of MPI8 in plasma was challenged by a strong interference from water MPI8. Using QTOF LC-MS/MS, we identified MPI8•H₂ [...] Read more.

MPI8, a peptidyl aldehyde, is a potent antiviral agent against coronavirus. Due to unique tri-peptide bonds and the formyl functional group, the bioassay of MPI8 in plasma was challenged by a strong interference from water MPI8. Using QTOF LC-MS/MS, we identified MPI8•H₂O as the major interference form that co-existed with MPI8 in aqueous and biological media. To avoid the resolution of MPI8 and MPI8•H₂O observed on reverse phase columns, we found that a Kinetex hydrophilic interaction liquid chromatography (HILIC) column provided co-elution of both MPI8 and MPI8•H₂O with a good single chromatographic peak and column retention of MPI8 which is suitable for quantification. Thus, a sensitive, specific, and reproducible LC-MS/MS method for the quantification of MPI8 in rat plasma was developed and validated using a triple QUAD LC-MS/MS. The chromatographic separation was achieved on a Kinetex HILIC column with a flow rate of 0.4 mL/min under gradient elution. The calibration curves were linear (r² > 0.99) over MPI8 concentrations from 0.5–500 ng/mL. The accuracy and precision are within acceptable guidance levels. The mean matrix effect and recovery were 139% and 73%, respectively. No significant degradation of MPI8 occurred under the experimental conditions. The method was successfully applied to a pharmacokinetic study of MPI8 after administration of MPI8 sulfonate in rats. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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13 pages, 4656 KiB

Open AccessArticle

Discovery of Natural Lead Compound from Dendrobium sp. against SARS-CoV-2 Infection

by Jutamas Jiaranaikulwanitch, Wipawadee Yooin, Nopporn Chutiwitoonchai, Worathat Thitikornpong, Boonchoo Sritularak, Pornchai Rojsitthisak and Opa Vajragupta

Pharmaceuticals 2022, 15(5), 620; https://doi.org/10.3390/ph15050620 - 18 May 2022

Cited by 5 | Viewed by 2568

Abstract

Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to [...] Read more.

Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to be one choice to alleviate symptoms and reduce mortality during drug shortages. Dendrobium extract is one of the traditional medicines used for COVID-19 infection. Several compounds in Dendrobium sp. had been reported to exert pharmacological activities to treat common COVID-19-related symptoms. Herein, in silico screening of 83 compounds from Dendrobium sp. by using the SARS-CoV-2 spike protein receptor-binding domain (RBD) as a drug target was performed in searching for a new lead compound against SARS-CoV-2 infection. Four hit compounds showing good binding affinity were evaluated for antiviral infection activity. The new lead compound DB36, 5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone, was identified with the IC₅₀ value of 6.87 ± 3.07 µM. The binding mode revealed that DB36 bound with the spike protein at the host receptor, angiotensin-converting enzyme 2 (ACE2) binding motif, resulted in antiviral activity. This study substantiated the use of Dendrobium extract for the treatment of SARS-CoV-2 infection and has identified new potential chemical scaffolds for further drug development of SARS-CoV-2 entry inhibitors. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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20 pages, 4569 KiB

Open AccessArticle

Design of D-Amino Acids SARS-CoV-2 Main Protease Inhibitors Using the Cationic Peptide from Rattlesnake Venom as a Scaffold

by Raphael J. Eberle, Ian Gering, Markus Tusche, Philipp N. Ostermann, Lisa Müller, Ortwin Adams, Heiner Schaal, Danilo S. Olivier, Marcos S. Amaral, Raghuvir K. Arni, Dieter Willbold and Mônika A. Coronado

Pharmaceuticals 2022, 15(5), 540; https://doi.org/10.3390/ph15050540 - 27 Apr 2022

Cited by 13 | Viewed by 3418

Abstract

The C30 endopeptidase (3C-like protease; 3CL^pro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, is a promising drug target. Molecules isolated from animals, insects, [...] Read more.

The C30 endopeptidase (3C-like protease; 3CL^pro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, is a promising drug target. Molecules isolated from animals, insects, plants, or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus, has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial, and hemolytic activities. The crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low µM range were examined since they are susceptible to proteolytic degradation; we explored the utility of their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP as a promising prototype for a D-peptide-based drug. We also found that the D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CL^pro. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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25 pages, 2081 KiB

Open AccessArticle

Hypericum perforatum and Its Ingredients Hypericin and Pseudohypericin Demonstrate an Antiviral Activity against SARS-CoV-2

by Fakry F. Mohamed, Darisuren Anhlan, Michael Schöfbänker, André Schreiber, Nica Classen, Andreas Hensel, Georg Hempel, Wolfgang Scholz, Joachim Kühn, Eike R. Hrincius and Stephan Ludwig

Pharmaceuticals 2022, 15(5), 530; https://doi.org/10.3390/ph15050530 - 25 Apr 2022

Cited by 29 | Viewed by 8524

Abstract

For almost two years, the COVID-19 pandemic has constituted a major challenge to human health, particularly due to the lack of efficient antivirals to be used against the virus during routine treatment interventions. Multiple treatment options have been investigated for their potential inhibitory [...] Read more.

For almost two years, the COVID-19 pandemic has constituted a major challenge to human health, particularly due to the lack of efficient antivirals to be used against the virus during routine treatment interventions. Multiple treatment options have been investigated for their potential inhibitory effect on SARS-CoV-2. Natural products, such as plant extracts, may be a promising option, as they have shown an antiviral activity against other viruses in the past. Here, a quantified extract of Hypericum perforatum was tested and found to possess a potent antiviral activity against SARS-CoV-2. The antiviral potency of the extract could be attributed to the naphtodianthrones hypericin and pseudohypericin, in contrast to other tested ingredients of the plant material, which did not show any antiviral activity. Hypericum perforatum and its main active ingredient hypericin were also effective against different SARS-CoV-2 variants (Alpha, Beta, Delta, and Omicron). Concerning its mechanism of action, evidence was obtained that Hypericum perforatum and hypericin may hold a direct virus-blocking effect against SARS-CoV-2 virus particles. Taken together, the presented data clearly emphasize the promising antiviral activity of Hypericum perforatum and its active ingredients against SARS-CoV-2 infections. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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22 pages, 5112 KiB

Open AccessArticle

Use of Early Donated COVID-19 Convalescent Plasma Is Optimal to Preserve the Integrity of Lymphatic Endothelial Cells

by Nada Amri, Rémi Bégin, Nolwenn Tessier, Laurent Vachon, Louis Villeneuve, Philippe Bégin, Renée Bazin, Lionel Loubaki and Catherine Martel

Pharmaceuticals 2022, 15(3), 365; https://doi.org/10.3390/ph15030365 - 17 Mar 2022

Cited by 5 | Viewed by 3428

Abstract

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune [...] Read more.

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune response and the resolution of inflammation from peripheral tissues, including the artery wall. As vascular complications are a key pathogenic mechanism in COVID-19, leading to inflammation and multiple organ failure, we believe that sustaining lymphatic vessel function should be considered to define optimal CPT. We herein sought to determine what specific COVID-19 convalescent plasma (CCP) characteristics should be considered to limit inflammation-driven lymphatic endothelial cells (LEC) dysfunction. CCP donated 16 to 100 days after the last day of symptoms was characterized and incubated on inflammation-elicited adult human dermal LEC (aHDLEC). Plasma analysis revealed that late donation correlates with higher concentration of circulating pro-inflammatory cytokines. Conversely, extracellular vesicles (EVs) derived from LEC are more abundant in early donated plasma (r = −0.413, p = 0.004). Thus, secretion of LEC-EVs by an impaired endothelium could be an alarm signal that instigate the self-defense of peripheral lymphatic vessels against an excessive inflammation. Indeed, in vitro experiments suggest that CCP obtained rapidly following the onset of symptoms does not damage the aHDLEC junctions as much as late-donated plasma. We identified a particular signature of CCP that would counteract the effects of an excessive inflammation on the lymphatic endothelium. Accordingly, an easy and efficient selection of convalescent plasma based on time of donation would be essential to promote the preservation of the lymphatic and immune system of infected patients. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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18 pages, 7756 KiB

Open AccessArticle

Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial

by Irina Karosanidze, Ushangi Kiladze, Nino Kirtadze, Mikhail Giorgadze, Nana Amashukeli, Nino Parulava, Neli Iluridze, Nana Kikabidze, Nana Gudavadze, Lali Gelashvili, Vazha Koberidze, Eka Gigashvili, Natela Jajanidze, Naira Latsabidze, Nato Mamageishvili, Ramaz Shengelia, Areg Hovhannisyan and Alexander Panossian

Pharmaceuticals 2022, 15(3), 345; https://doi.org/10.3390/ph15030345 - 11 Mar 2022

Cited by 19 | Viewed by 7977

Abstract

Currently, no effective treatment of comorbid complications or COVID-19 long-haulers during convalescence is known. This randomized, quadruple-blind, placebo-controlled trial aimed to assess the efficacy of adaptogens on the recovery of patients with Long COVID symptoms. One hundred patients with confirmed positive SARS-CoV-2 test, [...] Read more.

Currently, no effective treatment of comorbid complications or COVID-19 long-haulers during convalescence is known. This randomized, quadruple-blind, placebo-controlled trial aimed to assess the efficacy of adaptogens on the recovery of patients with Long COVID symptoms. One hundred patients with confirmed positive SARS-CoV-2 test, discharged from COVID Hotel isolation, Intensive Care Unit (ICU), or Online Clinics, and who experienced at least three of nine Long COVID symptoms (fatigue, headache, respiratory insufficiency, cognitive performance, mood disorders, loss of smell, taste, and hair, sweatiness, cough, pain in joints, muscles, and chest) in the 30 days before randomization were included in the study of the efficacy of Chisan^®/ADAPT-232 (a fixed combination of adaptogens Rhodiola, Eleutherococcus, and Schisandra) supplementation for two weeks. Chisan^® decreased the duration of fatigue and pain for one and two days, respectively, in 50% of patients. The number of patients with lack of fatigue and pain symptoms was significantly less in the Chisan^® treatment group than in the placebo group on Days 9 (39% vs. 57%, pain relief, p = 0.0019) and 11 (28% vs. 43%, relief of fatigue, * p = 0.0157). Significant relief of severity of all Long COVID symptoms over the time of treatment and the follow-up period was observed in both groups of patients, notably decreasing the level of anxiety and depression from mild and moderate to normal, as well as increasing cognitive performance in patients in the d2 test for attention and increasing their physical activity and workout (daily walk time). However, the significant difference between placebo and Chisan^® treatment was observed only with a workout (daily walk time) and relieving respiratory insufficiency (cough). A clinical assessment of blood markers of the inflammatory response (C-reactive protein) and blood coagulation (D-dimer) did not reveal any significant difference over time between treatment groups except significantly lower IL-6 in the Chisan^® treatment group. Furthermore, a significant difference between the placebo and Chisan^® treatment was observed for creatinine: Chisan^® significantly decreased blood creatinine compared to the placebo, suggesting prevention of renal failure progression in Long COVID. In this study, we, for the first time, demonstrate that adaptogens can increase physical performance in Long COVID and reduce the duration of fatigue and chronic pain. It also suggests that Chisan^®/ADAPT-232 might be useful for preventing the progression of renal failure associated with increasing creatinine. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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16 pages, 2246 KiB

Open AccessArticle

Mineralocorticoid Receptor Antagonist (Potassium Canrenoate) Does Not Influence Outcome in the Treatment of COVID-19-Associated Pneumonia and Fibrosis—A Randomized Placebo Controlled Clinical Trial

by Katarzyna Kotfis, Igor Karolak, Kacper Lechowicz, Małgorzata Zegan-Barańska, Agnieszka Pikulska, Paulina Niedźwiedzka-Rystwej, Miłosz Kawa, Jerzy Sieńko, Aleksandra Szylińska and Magda Wiśniewska

Pharmaceuticals 2022, 15(2), 200; https://doi.org/10.3390/ph15020200 - 5 Feb 2022

Cited by 5 | Viewed by 2515

Abstract

In December 2019 the SARS-CoV-2 virus appeared in the world, mainly presenting as an acute infection of the lower respiratory tract, namely pneumonia. Nearly 10% of all patients show significant pulmonary fibrotic changes after the infection. The aim of this study was to [...] Read more.

In December 2019 the SARS-CoV-2 virus appeared in the world, mainly presenting as an acute infection of the lower respiratory tract, namely pneumonia. Nearly 10% of all patients show significant pulmonary fibrotic changes after the infection. The aim of this study was to evaluate the effectiveness and safety of potassium canrenoate in the treatment of COVID-19-associated pneumonia and pulmonary fibrosis. We performed a randomized clinical trial (RCT) of potassium canrenoate vs placebo. A total of 55 patients were randomized and 49 were included in the final analysis (24 allocated to the intervention group and 25 allocated to the control group). Patients were assessed by physical examination, lung ultrasound, CT imaging and blood samples that underwent biochemical analysis. This RCT has shown that the administration of potassium canrenoate to patients with COVID-19 induced pneumonia was not associated with shorter mechanical ventilation time, shorter passive oxygenation, shorter length of hospitalization or less fibrotic changes on CT imaging. The overall mortality rate was not significantly different between the two groups. Adverse events recorded in this study were not significantly increased by the administration of potassium canrenoate. The negative outcome of the study may be associated with the relatively small number of patients included. Any possible benefits from the use of potassium canrenoate as an antifibrotic drug in COVID-19 patients require further investigation. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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14 pages, 6398 KiB

Open AccessArticle

Novel Small-Molecule Inhibitors of the SARS-CoV-2 Spike Protein Binding to Neuropilin 1

by Anja Kolarič, Marko Jukič and Urban Bren

Pharmaceuticals 2022, 15(2), 165; https://doi.org/10.3390/ph15020165 - 28 Jan 2022

Cited by 22 | Viewed by 4976

Abstract

Furin cleavage of the SARS-CoV-2 spike protein results in a polybasic terminal sequence termed the C-end rule (CendR), which is responsible for the binding to neuropilin 1 (NRP1), enhancing viral infectivity and entry into the cell. Here we report the identification of 20 [...] Read more.

Furin cleavage of the SARS-CoV-2 spike protein results in a polybasic terminal sequence termed the C-end rule (CendR), which is responsible for the binding to neuropilin 1 (NRP1), enhancing viral infectivity and entry into the cell. Here we report the identification of 20 small-molecule inhibitors that emerged from a virtual screening of nearly 950,000 drug-like compounds that bind with high probability to the CendR-binding pocket of NRP1. In a spike NRP1 binding assay, two of these compounds displayed a stronger inhibition of spike protein binding to NRP1 than the known NRP1 antagonist EG00229, for which the inhibition of the CendR peptide binding to NRP1 was also experimentally confirmed. These compounds present a good starting point for the design of small-molecule antagonists against the SARS-CoV-2 viral entry. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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14 pages, 2457 KiB

Open AccessArticle

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 M^pro, Impairing Variants Replication In Vitro and In Vivo

by Otávio Augusto Chaves, Carolina Q. Sacramento, André C. Ferreira, Mayara Mattos, Natalia Fintelman-Rodrigues, Jairo R. Temerozo, Leonardo Vazquez, Douglas Pereira Pinto, Gabriel P. E. da Silveira, Laís Bastos da Fonseca, Heliana Martins Pereira, Aluana Santana Carlos, Joana C. d’Avila, João P. B. Viola, Robson Q. Monteiro, Patrícia T. Bozza, Hugo Caire Castro-Faria-Neto and Thiago Moreno L. Souza

Pharmaceuticals 2022, 15(1), 21; https://doi.org/10.3390/ph15010021 - 24 Dec 2021

Cited by 25 | Viewed by 4855

Abstract

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, [...] Read more.

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (M^pro) was inhibited by ATV, with Morrison’s inhibitory constant (K_i) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H₂O_cat) content. ATV was a competitive inhibitor, increasing the M^pro’s Michaelis–Menten (K_m) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the M^pro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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15 pages, 1281 KiB

Open AccessArticle

Quality Assessment of Investigational Medicinal Products in COVID-19 Clinical Trials: One Year of Activity at the Clinical Trials Office

by Diego Alejandro Dri, Giulia Praticò, Elisa Gaucci, Carlotta Marianecci and Donatella Gramaglia

Pharmaceuticals 2021, 14(12), 1321; https://doi.org/10.3390/ph14121321 - 17 Dec 2021

Cited by 2 | Viewed by 3040

Abstract

One year after the spread of the pandemic, we analyzed the assessment results of the quality documentation submitted to the Clinical Trials Office of the Italian Medicines Agency as part of the request for authorization of clinical trials with a COVID-19 indication. In [...] Read more.

One year after the spread of the pandemic, we analyzed the assessment results of the quality documentation submitted to the Clinical Trials Office of the Italian Medicines Agency as part of the request for authorization of clinical trials with a COVID-19 indication. In this article, we report the classification of the documentation type, an overview of the assessment results, and the related issues focusing on the most frequently detected ones. Relevant data regarding the Investigational Medicinal Products (IMPs) tested in COVID-19 clinical trials and their quality profiles are provided in the perspective of increasing transparency and availability of information. Some criticalities that have been exacerbated by the management of clinical trials during the emergency period are highlighted. Results confirm that IMPs tested in authorized COVID-19 clinical trials are developed in agreement with the same legal requirements for quality, safety, and efficacy as for any other medicinal product in the European Union (EU). The same strong regulatory framework applies, and there is no lowering in the safety profile due to the pandemic; authorized IMPs meet the highest standards of quality. The regulatory network should capitalize on lessons learned from the emergency setting. Some take-home messages are provided that could support the regulatory framework to expand its boundaries by innovating and evolving even though remaining strong and effective. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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28 pages, 4744 KiB

Open AccessArticle

Promising Antiviral Activity of Agrimonia pilosa Phytochemicals against Severe Acute Respiratory Syndrome Coronavirus 2 Supported with In Vivo Mice Study

by Nashwah G. M. Attallah, Aya H. El-Kadem, Walaa A. Negm, Engy Elekhnawy, Thanaa A. El-Masry, Elshaymaa I. Elmongy, Najla Altwaijry, Ashwag S. Alanazi, Gadah Abdulaziz Al-Hamoud and Amany E. Ragab

Pharmaceuticals 2021, 14(12), 1313; https://doi.org/10.3390/ph14121313 - 16 Dec 2021

Cited by 31 | Viewed by 3841

Abstract

The global emergence of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused the entire world’s attention toward searching for a potential remedy for this disease. Thus, we investigated the antiviral activity of Agrimonia pilosa ethanol extract (APEE) [...] Read more.

The global emergence of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused the entire world’s attention toward searching for a potential remedy for this disease. Thus, we investigated the antiviral activity of Agrimonia pilosa ethanol extract (APEE) against SARS-CoV-2 and it exhibited a potent antiviral activity with IC₅₀ of 1.1 ± 0.03 µg/mL. Its mechanism of action was elucidated, and it exhibited a virucidal activity and an inhibition of viral adsorption. Moreover, it presented an immunomodulatory activity as it decreased the upregulation of gene expression of COX-2, iNOS, IL-6, TNF-α, and NF-κB in lipopolysaccharide (LPS)-induced peripheral blood mononuclear cells. A comprehensive analysis of the phytochemical fingerprint of APEE was conducted using LC-ESI-MS/MS technique for the first time. We detected 81 compounds and most of them belong to the flavonoid and coumarin classes. Interestingly, isoflavonoids, procyanidins, and anthocyanins were detected for the first time in A. pilosa. Moreover, the antioxidant activity was evidenced in DPPH (IC₅₀ 62.80 µg/mL) and ABTS (201.49 mg Trolox equivalents (TE)/mg) radical scavenging, FRAP (60.84 mg TE/mg), and ORAC (306.54 mg TE/g) assays. Furthermore, the protective effect of APEE was investigated in Lipopolysaccharides (LPS)-induced acute lung injury (ALI) in mice. Lung W/D ratio, serum IL-6, IL-18, IL-1β, HO-1, Caspase-1, caspase-3, TLR-4 expression, TAC, NO, MPO activity, and histopathological examination of lung tissues were assessed. APEE induced a marked downregulation in all inflammation, oxidative stress, apoptosis markers, and TLR-4 expression. In addition, it alleviated all histopathological abnormalities confirming the beneficial effects of APEE in ALI. Therefore, APEE could be a potential source for therapeutic compounds that could be investigated, in future preclinical and clinical trials, in the treatment of patients with COVID-19. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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15 pages, 1252 KiB

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In Vitro Effect of Taraxacum officinale Leaf Aqueous Extract on the Interaction between ACE2 Cell Surface Receptor and SARS-CoV-2 Spike Protein D614 and Four Mutants

by Hoai Thi Thu Tran, Michael Gigl, Nguyen Phan Khoi Le, Corinna Dawid and Evelyn Lamy

Pharmaceuticals 2021, 14(10), 1055; https://doi.org/10.3390/ph14101055 - 17 Oct 2021

Cited by 15 | Viewed by 31677

Abstract

To date, there have been rapidly spreading new SARS-CoV-2 “variants of concern”. They all contain multiple mutations in the ACE2 receptor recognition site of the spike protein, compared to the original Wuhan sequence, which is of great concern, because of their potential for [...] Read more.

To date, there have been rapidly spreading new SARS-CoV-2 “variants of concern”. They all contain multiple mutations in the ACE2 receptor recognition site of the spike protein, compared to the original Wuhan sequence, which is of great concern, because of their potential for immune escape. Here we report on the efficacy of common dandelion (Taraxacum officinale) to block protein–protein interaction of SARS-COV-2 spike to the human ACE2 receptor. This could be shown for the wild type and mutant forms (D614G, N501Y, and a mix of K417N, E484K, and N501Y) in human HEK293-hACE2 kidney and A549-hACE2-TMPRSS2 lung cells. High-molecular-weight compounds in the water-based extract account for this effect. Infection of the lung cells using SARS-CoV-2 spike D614 and spike Delta (B.1.617.2) variant pseudotyped lentivirus particles was efficiently prevented by the extract and so was virus-triggered pro-inflammatory interleukin 6 secretion. Modern herbal monographs consider the usage of this medicinal plant as safe. Thus, the in vitro results reported here should encourage further research on the clinical relevance and applicability of the extract as prevention strategy for SARS-CoV-2 infection in terms of a non-invasive, oral post-exposure prophylaxis. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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19 pages, 4584 KiB

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SARS-CoV-2 Fears Green: The Chlorophyll Catabolite Pheophorbide A Is a Potent Antiviral

by Guillermo H. Jimenez-Aleman, Victoria Castro, Addis Londaitsbehere, Marta Gutierrez-Rodríguez, Urtzi Garaigorta, Roberto Solano and Pablo Gastaminza

Pharmaceuticals 2021, 14(10), 1048; https://doi.org/10.3390/ph14101048 - 15 Oct 2021

Cited by 15 | Viewed by 6673

Abstract

SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against COVID-19. Thus, despite the international efforts, [...] Read more.

SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against COVID-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here, we exploited the enormous potential of plant metabolism using the bryophyte Marchantia polymorpha L. and identified a potent SARS-CoV-2 antiviral, following a bioactivity-guided fractionation and mass-spectrometry approach. We found that the chlorophyll derivative Pheophorbide a (PheoA), a porphyrin compound similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2, preventing infection of cultured monkey and human cells, without noticeable cytotoxicity. We also show that PheoA targets the viral particle, interfering with its infectivity in a dose- and time-dependent manner. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against enveloped RNA viral pathogens such as HCV, West Nile, and other coronaviruses. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, which together with its previous use in photoactivable cancer therapy in humans, suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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13 pages, 3311 KiB

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A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

by Paolo Coghi, Li Jun Yang, Jerome P. L. Ng, Richard K. Haynes, Maurizio Memo, Alessandra Gianoncelli, Vincent Kam Wai Wong and Giovanni Ribaudo

Pharmaceuticals 2021, 14(10), 954; https://doi.org/10.3390/ph14100954 - 23 Sep 2021

Cited by 17 | Viewed by 4834

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 (K_D = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (K_D = 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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14 pages, 3419 KiB

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Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M^Pro Inhibitor

by Hani A. Alhadrami, Ahmed M. Sayed, Heba Al-Khatabi, Nabil A. Alhakamy and Mostafa E. Rateb

Pharmaceuticals 2021, 14(6), 541; https://doi.org/10.3390/ph14060541 - 5 Jun 2021

Cited by 20 | Viewed by 4709

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 K_i = 3.22 µM) of one of the viral key enzymes (i.e., M^Pro). 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 M^Pro 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 M^Pro testing, was 4.5 times more potent (IC₅₀ = 1.1 µM and K_i = 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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20 pages, 8798 KiB

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Identification of Anti-SARS-CoV-2 Compounds from Food Using QSAR-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Analysis

by Magdi E. A. Zaki, Sami A. Al-Hussain, Vijay H. Masand, Siddhartha Akasapu, Sumit O. Bajaj, Nahed N. E. El-Sayed, Arabinda Ghosh and Israa Lewaa

Pharmaceuticals 2021, 14(4), 357; https://doi.org/10.3390/ph14040357 - 13 Apr 2021

Cited by 26 | Viewed by 4926

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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18 pages, 2934 KiB

Open AccessArticle

Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods

by Tiziana Ginex, Urtzi Garaigorta, David Ramírez, Victoria Castro, Vanesa Nozal, Inés Maestro, Javier García-Cárceles, Nuria E. Campillo, Ana Martinez, Pablo Gastaminza and Carmen Gil

Pharmaceuticals 2021, 14(4), 332; https://doi.org/10.3390/ph14040332 - 6 Apr 2021

Cited by 23 | Viewed by 6028

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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11 pages, 1131 KiB

Open AccessArticle

Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study

by Gil Darquennes, Pascal Le Corre, Olivier Le Moine and Gwenolé Loas

Pharmaceuticals 2021, 14(3), 226; https://doi.org/10.3390/ph14030226 - 7 Mar 2021

Cited by 24 | Viewed by 4259

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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15 pages, 3533 KiB

Open AccessArticle

Evaluation of the Antiviral Activity of Sitagliptin-Glatiramer Acetate Nano-Conjugates against SARS-CoV-2 Virus

by Nabil A. Alhakamy, Osama A. A. Ahmed, Tarek S. Ibrahim, Hibah M. Aldawsari, Khalid Eljaaly, Usama A. Fahmy, Ahmed L. Alaofi, Filippo Caraci and Giuseppe Caruso

Pharmaceuticals 2021, 14(3), 178; https://doi.org/10.3390/ph14030178 - 24 Feb 2021

Cited by 14 | Viewed by 3676

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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17 pages, 1443 KiB

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Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

by Andrea Gelemanović, Tinka Vidović, Višnja Stepanić and Katarina Trajković

Pharmaceuticals 2021, 14(2), 87; https://doi.org/10.3390/ph14020087 - 25 Jan 2021

Cited by 5 | Viewed by 4478

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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24 pages, 3883 KiB

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FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2

by Ahmed Mostafa, Ahmed Kandeil, Yaseen A. M. M. Elshaier, Omnia Kutkat, Yassmin Moatasim, Adel A. Rashad, Mahmoud Shehata, Mokhtar R. Gomaa, Noura Mahrous, Sara H. Mahmoud, Mohamed GabAllah, Hisham Abbas, Ahmed El Taweel, Ahmed E. Kayed, Mina Nabil Kamel, Mohamed El Sayes, Dina B. Mahmoud, Rabeh El-Shesheny, Ghazi Kayali and Mohamed A. Ali

Pharmaceuticals 2020, 13(12), 443; https://doi.org/10.3390/ph13120443 - 4 Dec 2020

Cited by 119 | Viewed by 12244

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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13 pages, 1279 KiB

Open AccessArticle

Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics

by Anna Maria Piras, Ylenia Zambito, Maurizio Lugli, Baldassare Ferro, Paolo Roncucci, Filippo Mori, Alfonso Salvatore, Ester Ascione, Marta Bellini and Roberto Crea

Pharmaceuticals 2020, 13(12), 425; https://doi.org/10.3390/ph13120425 - 27 Nov 2020

Cited by 4 | Viewed by 3168

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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11 pages, 1861 KiB

Open AccessFeature PaperArticle

Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study

by Benjamin Rossi, Lee S. Nguyen, Philippe Zimmermann, Faiza Boucenna, Louis Dubret, Louise Baucher, Helene Guillot, Marie-Anne Bouldouyre, Yves Allenbach, Joe-Elie Salem, Paul Barsoum, Arezki Oufella and Helene Gros

Pharmaceuticals 2020, 13(10), 317; https://doi.org/10.3390/ph13100317 - 17 Oct 2020

Cited by 32 | Viewed by 4632

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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14 pages, 1460 KiB

Open AccessArticle

Squalene Emulsion Manufacturing Process Scale-Up for Enhanced Global Pandemic Response

by Tony Phan, Christian Devine, Erik D. Laursen, Adrian Simpson, Aaron Kahn, Amit P. Khandhar, Steven Mesite, Brad Besse, Ken J. Mabery, Elizabeth I. Flanagan and Christopher B. Fox

Pharmaceuticals 2020, 13(8), 168; https://doi.org/10.3390/ph13080168 - 28 Jul 2020

Cited by 6 | Viewed by 7720

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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13 pages, 1520 KiB

Open AccessCommunication

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

by Andreia Palmeira, Emília Sousa, Aylin Köseler, Ramazan Sabirli, Tarık Gören, İbrahim Türkçüer, Özgür Kurt, Madalena M. Pinto and M. Helena Vasconcelos

Pharmaceuticals 2020, 13(6), 132; https://doi.org/10.3390/ph13060132 - 25 Jun 2020

Cited by 52 | Viewed by 6712 | Correction

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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10 pages, 2523 KiB

Open AccessArticle

Excess Ascorbate is a Chemical Stress Agent against Proteins and Cells

by Maria Lehene, Eva Fischer-Fodor, Florina Scurtu, Niculina D. Hădade, Emese Gal, Augustin C. Mot, Alina Matei and Radu Silaghi-Dumitrescu

Pharmaceuticals 2020, 13(6), 107; https://doi.org/10.3390/ph13060107 - 27 May 2020

Cited by 7 | Viewed by 4989

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

Jump to: Research, Other

18 pages, 1067 KiB

Open AccessReview

Repurposing Potential of the Antiparasitic Agent Ivermectin for the Treatment and/or Prophylaxis of COVID-19

by Hoda Awad, Basmala Hassan, Sara Dweek, Yasmeen Aboelata, Mutasem Rawas-Qalaji and Iman Saad Ahmed

Pharmaceuticals 2022, 15(9), 1068; https://doi.org/10.3390/ph15091068 - 27 Aug 2022

Cited by 3 | Viewed by 7039 | Correction

Abstract

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in [...] Read more.

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials, novel nasal formulations of IVM were explored with the hope of an improved optimized effect. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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17 pages, 1429 KiB

Open AccessReview

Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative?

by Yadira Palacios and Leslie Chavez-Galan

Pharmaceuticals 2022, 15(5), 616; https://doi.org/10.3390/ph15050616 - 17 May 2022

Cited by 8 | Viewed by 5833

Abstract

The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the [...] Read more.

The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the options proposed for emergency treatment. One of the cytokines that requires a more exhaustive review is the tumor necrosis factor (TNF) and its receptors (TNFRs) as increased values of soluble formats for both TNFR1 and TNFR2 have been identified. TNF is a versatile cytokine with different impacts at the cellular level depending on the action form (transmembrane or soluble) and the receptor to which it is associated. In that sense, the triggered mechanisms can be diversified. Furthermore, there is the possibility of the joint action provided by synergism between one or more cytokines with TNF, where the detonation of combined cellular processes has been suggested. This review aims to discuss some roles of TNF and its receptors in the pro-inflammatory stage of COVID-19, understand its ways of action, and let to reposition this cytokine or some of its receptors as therapeutic targets. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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13 pages, 335 KiB

Open AccessReview

COVID-19 and Seasonal Influenza Vaccination: Cross-Protection, Co-Administration, Combination Vaccines, and Hesitancy

by Alexander Domnich, Andrea Orsi, Carlo-Simone Trombetta, Giulia Guarona, Donatella Panatto and Giancarlo Icardi

Pharmaceuticals 2022, 15(3), 322; https://doi.org/10.3390/ph15030322 - 8 Mar 2022

Cited by 36 | Viewed by 6454

Abstract

SARS-CoV-2 and influenza are the main respiratory viruses for which effective vaccines are currently available. Strategies in which COVID-19 and influenza vaccines are administered simultaneously or combined into a single preparation are advantageous and may increase vaccination uptake. Here, we comprehensively review the [...] Read more.

SARS-CoV-2 and influenza are the main respiratory viruses for which effective vaccines are currently available. Strategies in which COVID-19 and influenza vaccines are administered simultaneously or combined into a single preparation are advantageous and may increase vaccination uptake. Here, we comprehensively review the available evidence on COVID-19/influenza vaccine co-administration and combination vaccine candidates from the standpoints of safety, immunogenicity, efficacy, policy and public acceptance. While several observational studies have shown that the trained immunity induced by influenza vaccines can protect against some COVID-19-related endpoints, it is not yet understood whether co-administration or combination vaccines can exert additive effects on relevant outcomes. In randomized controlled trials, co-administration has proved safe, with a reactogenicity profile similar to that of either vaccine administered alone. From the immunogenicity standpoint, the immune response towards four influenza strains and the SARS-CoV-2 spike protein in co-administration groups is generally non-inferior to that seen in groups receiving either vaccine alone. Several public health authorities have advocated co-administration. Different combination vaccine candidates are in (pre)-clinical development. The hesitancy towards vaccine co-administration or combination vaccines is a multifaceted phenomenon and may be higher than the acceptance of either vaccine administered separately. Public health implications are discussed. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

17 pages, 662 KiB

Open AccessEditor’s ChoiceReview

Monoclonal Antibodies against SARS-CoV-2: Current Scenario and Future Perspectives

by Eugenia Quiros-Roldan, Silvia Amadasi, Isabella Zanella, Melania Degli Antoni, Samuele Storti, Giorgio Tiecco and Francesco Castelli

Pharmaceuticals 2021, 14(12), 1272; https://doi.org/10.3390/ph14121272 - 6 Dec 2021

Cited by 25 | Viewed by 5982

Abstract

Monoclonal antibodies (mAbs) have been known since the 1970s. However, their therapeutic potential in the medical field has recently emerged, with the advancement of manufacturing techniques. Initially exploited mainly in the oncology field, mAbs have become increasingly relevant in Infectious Diseases. Numerous mAbs [...] Read more.

Monoclonal antibodies (mAbs) have been known since the 1970s. However, their therapeutic potential in the medical field has recently emerged, with the advancement of manufacturing techniques. Initially exploited mainly in the oncology field, mAbs have become increasingly relevant in Infectious Diseases. Numerous mAbs have been developed against SARS-CoV 2 and have proven their effectiveness, especially in the management of the mild-to-moderate disease. In this review, we describe the monoclonal antibodies currently authorized for the treatment of the coronavirus disease 19 (COVID-19) and offer an insight into the clinical trials that led to their approval. We discuss the mechanisms of action and methods of administration as well as the prophylactic and therapeutic labelled indications (both in outpatient and hospital settings). Furthermore, we address the critical issues regarding mAbs, focusing on their effectiveness against the variants of concern (VoC) and their role now that a large part of the population has been vaccinated. The purpose is to offer the clinician an up-to-date overview of a therapeutic tool that could prove decisive in treating patients at high risk of progression to severe disease. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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23 pages, 1324 KiB

Open AccessFeature PaperReview

Antirheumatic Drugs against COVID-19 from the Perspective of Rheumatologists

by Mai Kawazoe, Mari Kihara and Toshihiro Nanki

Pharmaceuticals 2021, 14(12), 1256; https://doi.org/10.3390/ph14121256 - 2 Dec 2021

Cited by 11 | Viewed by 5472

Abstract

Coronavirus disease 2019 (COVID-19) remains a global threat to humanity. Its pathogenesis and different phases of disease progression are being elucidated under the pandemic. Active viral replication activates various immune cells and produces large amounts of inflammatory cytokines, which leads to the cytokine [...] Read more.

Coronavirus disease 2019 (COVID-19) remains a global threat to humanity. Its pathogenesis and different phases of disease progression are being elucidated under the pandemic. Active viral replication activates various immune cells and produces large amounts of inflammatory cytokines, which leads to the cytokine storm, a major cause of patient death. Therefore, viral inhibition is expected to be the most effective early in the course of the disease, while immunosuppressive treatment may be useful in the later stages to prevent disease progression. Based on the pathophysiology of rheumatic diseases, various immunomodulatory and immunosuppressive drugs are used for the diseases. Due to their mechanism of action, the antirheumatic drugs, including hydroxychloroquine, chloroquine, colchicine, calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), glucocorticoids, cytokines inhibitors, such as anti-tumor necrosis factor-α (e.g., infliximab), anti-interleukin (IL)-6 (e.g., tocilizumab, sarilumab, and siltuximab), anti-IL-1 (e.g., anakinra and canakinumab) and Janus kinase inhibitors (e.g., baricitinib and tofacitinib), cytotoxic T lymphocyte-associated antigen 4 blockade agents (e.g., abatacept), and phosphodiesterase 4 inhibitors (e.g., apremilast), have been tried as a treatment for COVID-19. In this review, we discuss the mechanisms of action and clinical impact of these agents in the management of COVID-19. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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13 pages, 312 KiB

Open AccessReview

The Impact of SARS-CoV-2 Infection, and Application of Immunosuppressive Agents in Kidney Transplant Recipients Suffering from COVID-19

by Horng-Ta Tseng, Xiang-Chi Wu, Chun-Yao Huang, Chun-Ming Shih, Yi-Wen Lin and Feng-Yen Lin

Pharmaceuticals 2021, 14(10), 1054; https://doi.org/10.3390/ph14101054 - 17 Oct 2021

Cited by 4 | Viewed by 2472

Abstract

In December 2019, the COVID-19 pandemic began to ravage the world quickly, causing unprecedented losses in human life and the economy. A statistical study revealed that the proportion of solid organ transplant (SOT) recipients with severe symptoms and deaths after being infected by [...] Read more.

In December 2019, the COVID-19 pandemic began to ravage the world quickly, causing unprecedented losses in human life and the economy. A statistical study revealed that the proportion of solid organ transplant (SOT) recipients with severe symptoms and deaths after being infected by SARS-CoV-2 is considerably higher than that of non-SOT recipients, and the prognosis is relatively poor. In addition, the clinical manifestation of SOT recipients suffering from COVID-19 is different from that of general COVID-19 patients. Acute kidney injury (AKI) is a common complication in COVID-19 patients, and it is likely more common among SOT recipients infected with SARS-CoV-2. Clinical experts consider that SOT recipients have long-term treatment with immunosuppressants, and the comorbidities are driven by a high rate of severe symptoms and mortality. Orthotopic kidney allograft transplantation is an effective treatment for patients suffering from end-stage kidney disease/kidney failure through which they can easily extend their life. Indeed, kidney transplant recipients have suffered significant damage during this pandemic. To effectively reduce the severity of symptoms and mortality of kidney transplant recipients suffering from COVID-19, precise application of various drugs, particularly immunosuppressants, is necessary. Therefore, herein, we will collate the current clinical experience of treating COVID-19 infection in kidney transplant recipients and discuss the adjustment of patients using immunosuppressive agents in the face of COVID-19. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

16 pages, 750 KiB

Open AccessReview

Pharmacology and Adverse Events of Emergency-Use Authorized Medication in Moderate to Severe COVID-19

by Jen-Yu Hsu, Yan-Chiao Mao, Po-Yu Liu and Kuo-Lung Lai

Pharmaceuticals 2021, 14(10), 955; https://doi.org/10.3390/ph14100955 - 23 Sep 2021

Cited by 14 | Viewed by 2994

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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18 pages, 1700 KiB

Open AccessReview

Neuropsychiatric Disorders and COVID-19: What We Know So Far

by Fernanda Majolo, Guilherme Liberato da Silva, Lucas Vieira, Cetin Anli, Luís Fernando Saraiva Macedo Timmers, Stefan Laufer and Márcia Inês Goettert

Pharmaceuticals 2021, 14(9), 933; https://doi.org/10.3390/ph14090933 - 17 Sep 2021

Cited by 14 | Viewed by 4168

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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13 pages, 1611 KiB

Open AccessReview

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

by Giorgio Treglia, Marco Cuzzocrea, Luca Giovanella, Luigia Elzi and Barbara Muoio

Pharmaceuticals 2021, 14(8), 762; https://doi.org/10.3390/ph14080762 - 3 Aug 2021

Cited by 28 | Viewed by 6098

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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13 pages, 1481 KiB

Open AccessReview

Current Status of Baricitinib as a Repurposed Therapy for COVID-19

by Maha Saber-Ayad, Sarah Hammoudeh, Eman Abu-Gharbieh, Rifat Hamoudi, Hamadeh Tarazi, Taleb H. Al-Tel and Qutayba Hamid

Pharmaceuticals 2021, 14(7), 680; https://doi.org/10.3390/ph14070680 - 15 Jul 2021

Cited by 22 | Viewed by 6306

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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22 pages, 4263 KiB

Open AccessReview

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents

by Patrícia I. C. Godinho, Raquel G. Soengas and Vera L. M. Silva

Pharmaceuticals 2021, 14(6), 546; https://doi.org/10.3390/ph14060546 - 7 Jun 2021

Cited by 24 | Viewed by 4809

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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28 pages, 651 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Clinical Management of COVID-19: A Review of Pharmacological Treatment Options

by Ashli M. Heustess, Melissa A. Allard, Dorothea K. Thompson and Pius S. Fasinu

Pharmaceuticals 2021, 14(6), 520; https://doi.org/10.3390/ph14060520 - 28 May 2021

Cited by 23 | Viewed by 8248

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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19 pages, 1069 KiB

Open AccessReview

New Approaches and Repurposed Antiviral Drugs for the Treatment of the SARS-CoV-2 Infection

by Luana Vittoria Bauso, Chiara Imbesi, Gasparo Irene, Gabriella Calì and Alessandra Bitto

Pharmaceuticals 2021, 14(6), 503; https://doi.org/10.3390/ph14060503 - 25 May 2021

Cited by 8 | Viewed by 4299

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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16 pages, 1098 KiB

Open AccessReview

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

by Isabella Zanella, Daniela Zizioli, Francesco Castelli and Eugenia Quiros-Roldan

Pharmaceuticals 2021, 14(5), 454; https://doi.org/10.3390/ph14050454 - 11 May 2021

Cited by 34 | Viewed by 5627 | 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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21 pages, 1746 KiB

Open AccessEditor’s ChoiceReview

Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients

by Annalisa Noce, Maria Albanese, Giulia Marrone, Manuela Di Lauro, Anna Pietroboni Zaitseva, Daniela Palazzetti, Cristina Guerriero, Agostino Paolino, Giuseppa Pizzenti, Francesca Di Daniele, Annalisa Romani, Cartesio D’Agostini, Andrea Magrini, Nicola Biagio Mercuri and Nicola Di Daniele

Pharmaceuticals 2021, 14(4), 336; https://doi.org/10.3390/ph14040336 - 6 Apr 2021

Cited by 23 | Viewed by 9631

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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11 pages, 2339 KiB

Open AccessReview

Rapamycin: Drug Repurposing in SARS-CoV-2 Infection

by Jiri Patocka, Kamil Kuca, Patrik Oleksak, Eugenie Nepovimova, Martin Valis, Michal Novotny and Blanka Klimova

Pharmaceuticals 2021, 14(3), 217; https://doi.org/10.3390/ph14030217 - 5 Mar 2021

Cited by 35 | Viewed by 4458

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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14 pages, 1933 KiB

Open AccessReview

COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection

by Katarzyna Kotfis, Kacper Lechowicz, Sylwester Drożdżal, Paulina Niedźwiedzka-Rystwej, Tomasz K. Wojdacz, Ewelina Grywalska, Jowita Biernawska, Magda Wiśniewska and Miłosz Parczewski

Pharmaceuticals 2021, 14(1), 71; https://doi.org/10.3390/ph14010071 - 17 Jan 2021

Cited by 31 | Viewed by 11171

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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34 pages, 18804 KiB

Open AccessReview

Inhibition of SARS-CoV-2 Entry into Host Cells Using Small Molecules

by Kenana Al Adem, Aya Shanti, Cesare Stefanini and Sungmun Lee

Pharmaceuticals 2020, 13(12), 447; https://doi.org/10.3390/ph13120447 - 8 Dec 2020

Cited by 26 | Viewed by 6503

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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11 pages, 966 KiB

Open AccessReview

Role of 2-[¹⁸F]FDG as a Radiopharmaceutical for PET/CT in Patients with COVID-19: A Systematic Review

by Salvatore Annunziata, Roberto C. Delgado Bolton, Christel-Hermann Kamani, John O. Prior, Domenico Albano, Francesco Bertagna and Giorgio Treglia

Pharmaceuticals 2020, 13(11), 377; https://doi.org/10.3390/ph13110377 - 10 Nov 2020

Cited by 24 | Viewed by 3522

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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32 pages, 2554 KiB

Open AccessReview

Emerging Therapeutic Modalities against COVID-19

by Shipra Malik, Anisha Gupta, Xiaobo Zhong, Theodore P. Rasmussen, Jose E. Manautou and Raman Bahal

Pharmaceuticals 2020, 13(8), 188; https://doi.org/10.3390/ph13080188 - 8 Aug 2020

Cited by 20 | Viewed by 11198

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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17 pages, 1608 KiB

Open AccessReview

Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence?

by Mikhail Kiselevskiy, Irina Shubina, Irina Chikileva, Suria Sitdikova, Igor Samoylenko, Natalia Anisimova, Kirill Kirgizov, Amina Suleimanova, Tatyana Gorbunova and Svetlana Varfolomeeva

Pharmaceuticals 2020, 13(8), 166; https://doi.org/10.3390/ph13080166 - 26 Jul 2020

Cited by 16 | Viewed by 5849

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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29 pages, 2224 KiB

Open AccessReview

Substance Use Disorder in the COVID-19 Pandemic: A Systematic Review of Vulnerabilities and Complications

by Yufeng Wei and Rameen Shah

Pharmaceuticals 2020, 13(7), 155; https://doi.org/10.3390/ph13070155 - 18 Jul 2020

Cited by 86 | Viewed by 14712

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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29 pages, 1186 KiB

Open AccessReview

The Rationale for Potential Pharmacotherapy of COVID-19

by Maha Saber-Ayad, Mohamed A. Saleh and Eman Abu-Gharbieh

Pharmaceuticals 2020, 13(5), 96; https://doi.org/10.3390/ph13050096 - 14 May 2020

Cited by 40 | Viewed by 9152

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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1 pages, 165 KiB

Open AccessCorrection

Correction: Awad et al. Repurposing Potential of the Antiparasitic Agent Ivermectin for the Treatment and/or Prophylaxis of COVID-19. Pharmaceuticals 2022, 15, 1068

by Hoda Awad, Basmala Hassan, Sara Dweek, Yasmeen Aboelata, Mutasem Rawas-Qalaji and Iman Saad Ahmed

Pharmaceuticals 2024, 17(8), 1100; https://doi.org/10.3390/ph17081100 - 22 Aug 2024

Viewed by 435

Abstract

The following paragraph, “Coinciding but insignificant findings with regards to the time to negative PCR were established by Pott-Junior et al [...] Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

1 pages, 174 KiB

Open AccessCorrection

Correction: Palmeira et al. Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection. Pharmaceuticals 2020, 13, 132

by Andreia Palmeira, Emília Sousa, Aylin Köseler, Ramazan Sabirli, Tarık Gören, İbrahim Türkçüer, Özgür Kurt, Madalena M. Pinto and M. Helena Vasconcelos

Pharmaceuticals 2024, 17(4), 411; https://doi.org/10.3390/ph17040411 - 25 Mar 2024

Viewed by 834

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

31 pages, 558 KiB

Open AccessSystematic Review

Biologics in COVID-19 So Far: Systematic Review

by Milton Arias, Henry Oliveros, Sharon Lechtig and Rosa-Helena Bustos

Pharmaceuticals 2022, 15(7), 783; https://doi.org/10.3390/ph15070783 - 23 Jun 2022

Cited by 8 | Viewed by 2597

Abstract

This systematic review aimed to reevaluate the available evidence of the use of biologics as treatment candidates for the treatment of severe and advanced COVID-19 disease; what are the rationale for their use, which are the most studied, and what kind of efficacy [...] Read more.

This systematic review aimed to reevaluate the available evidence of the use of biologics as treatment candidates for the treatment of severe and advanced COVID-19 disease; what are the rationale for their use, which are the most studied, and what kind of efficacy measures are described? A search through Cochrane, Embase, Pubmed, Medline, medrxiv.org, and Google scholar was performed on the use of biologic interventions in COVID-19/SARS-CoV-2 infection, viral pneumonia, and sepsis, until 11 January 2022. Throughout the research, we identified 4821 records, of which 90 were selected for qualitative analysis. Amongst the results, we identified five popular targets of use: IL6 and IL1 inhibitors, interferons, mesenchymal stem cells treatment, and anti-spike antibodies. None of them offered conclusive evidence of their efficacy with consistency and statistical significance except for some studies with anti-spike antibodies; however, Il6 and IL1 inhibitors as well as interferons show encouraging data in terms of increased survival and favorable clinical course that require further studies with better methodology standardization. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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1 pages, 163 KiB

Open AccessCorrection

Correction: Zanella et al. Tenofovir, Another Inexpensive, Well Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection. Pharmaceuticals 2021, 14, 454

by Isabella Zanella, Daniela Zizioli, Francesco Castelli and Eugenia Quiros-Roldan

Pharmaceuticals 2021, 14(8), 827; https://doi.org/10.3390/ph14080827 - 23 Aug 2021

Cited by 3 | Viewed by 2258

Abstract

Text Correction [...] Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

15 pages, 370 KiB

Open AccessPerspective

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

by Gwenolé Loas and Pascal Le Corre

Pharmaceuticals 2021, 14(7), 691; https://doi.org/10.3390/ph14070691 - 18 Jul 2021

Cited by 12 | Viewed by 3859

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)

21 pages, 2194 KiB

Open AccessOpinion

COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?

by Jean Jacques Vanden Eynde

Pharmaceuticals 2021, 14(7), 664; https://doi.org/10.3390/ph14070664 - 11 Jul 2021

Cited by 4 | Viewed by 4777

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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15 pages, 1003 KiB

Open AccessPerspective

Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19

by Cara A. Timpani and Emma Rybalka

Pharmaceuticals 2021, 14(1), 15; https://doi.org/10.3390/ph14010015 - 26 Dec 2020

Cited by 28 | Viewed by 5684

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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17 pages, 371 KiB

Open AccessCommentary

Emetine Is Not Ipecac: Considerations for Its Use as Treatment for SARS-CoV2

by Martin D. Bleasel and Gregory M. Peterson

Pharmaceuticals 2020, 13(12), 428; https://doi.org/10.3390/ph13120428 - 27 Nov 2020

Cited by 13 | Viewed by 5392

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)

8 pages, 980 KiB

Open AccessOpinion

Can Nuclear Imaging of Activated Macrophages with Folic Acid-Based Radiotracers Serve as a Prognostic Means to Identify COVID-19 Patients at Risk?

by Cristina Müller, Roger Schibli and Britta Maurer

Pharmaceuticals 2020, 13(9), 238; https://doi.org/10.3390/ph13090238 - 9 Sep 2020

Cited by 9 | Viewed by 3829

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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Graphical abstract

14 pages, 601 KiB

Open AccessOpinion

Cancer Patients Have a Higher Risk Regarding COVID-19–and Vice Versa?

by Franz Geisslinger, Angelika M. Vollmar and Karin Bartel

Pharmaceuticals 2020, 13(7), 143; https://doi.org/10.3390/ph13070143 - 6 Jul 2020

Cited by 17 | Viewed by 5275

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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9 pages, 1321 KiB

Open AccessOpinion

COVID-19: An Update about the Discovery Clinical Trial

by Jean Jacques Vanden Eynde

Pharmaceuticals 2020, 13(5), 98; https://doi.org/10.3390/ph13050098 - 14 May 2020

Cited by 12 | Viewed by 5642

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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8 pages, 654 KiB

Open AccessOpinion

COVID-19: A Brief Overview of the Discovery Clinical Trial

by Jean Jacques Vanden Eynde

Pharmaceuticals 2020, 13(4), 65; https://doi.org/10.3390/ph13040065 - 10 Apr 2020

Cited by 29 | Viewed by 10804

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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9 pages, 259 KiB

Open AccessCommentary

Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses

by Martin D. Bleasel and Gregory M. Peterson

Pharmaceuticals 2020, 13(3), 51; https://doi.org/10.3390/ph13030051 - 21 Mar 2020

Cited by 61 | Viewed by 11602

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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