Research

21 pages, 4547 KiB

Open AccessArticle

Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2

by Francisco Faísca, Vanessa Correia, Željko Petrovski, Luís C. Branco, Helena Rebelo-de-Andrade and Miguel M. Santos

Pharmaceutics 2022, 14(4), 877; https://doi.org/10.3390/pharmaceutics14040877 - 17 Apr 2022

Cited by 5 | Viewed by 2639

Abstract

The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization [...] Read more.

The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization of seven HCQ room temperature ionic liquids (HCQ-ILs) obtained by direct protonation of the base with two equivalents of organic sulfonic, sulfuric and carboxylic acids of different polarities. Two non-toxic and hydrophilic HCQ-ILs, in particular, [HCQH₂][C₁SO₃]₂ and [HCQH₂][GlcCOO]₂, decreased the virus-induced cytopathic effect by two-fold in comparison with the original drug, [HCQH₂][SO₄]. Despite there being no significant differences in viral RNA production between the three compounds, progeny virus production was significantly affected (p < 0.05) by [HCQH₂][GlcCOO]₂. Overall, the data suggest that the in vitro antiviral activities of the HCQ-ILs are most likely the result of specific intra- and intermolecular interactions and not so much related with their hydrophilic or lipophilic character. This work paves the way for the development of future novel ionic formulations of hydroxychloroquine with enhanced physicochemical properties. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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18 pages, 966 KiB

Open AccessArticle

COVID-19 Drug Repurposing: A Network-Based Framework for Exploring Biomedical Literature and Clinical Trials for Possible Treatments

by Ahmed Abdeen Hamed, Tamer E. Fandy, Karolina L. Tkaczuk, Karin Verspoor and Byung Suk Lee

Pharmaceutics 2022, 14(3), 567; https://doi.org/10.3390/pharmaceutics14030567 - 04 Mar 2022

Cited by 6 | Viewed by 4120

Abstract

Background: With the Coronavirus becoming a new reality of our world, global efforts continue to seek answers to many questions regarding the spread, variants, vaccinations, and medications. Particularly, with the emergence of several strains (e.g., Delta, Omicron), vaccines will need further development to [...] Read more.

Background: With the Coronavirus becoming a new reality of our world, global efforts continue to seek answers to many questions regarding the spread, variants, vaccinations, and medications. Particularly, with the emergence of several strains (e.g., Delta, Omicron), vaccines will need further development to offer complete protection against the new variants. It is critical to identify antiviral treatments while the development of vaccines continues. In this regard, the repurposing of already FDA-approved drugs remains a major effort. In this paper, we investigate the hypothesis that a combination of FDA-approved drugs may be considered as a candidate for COVID-19 treatment if (1) there exists an evidence in the COVID-19 biomedical literature that suggests such a combination, and (2) there is match in the clinical trials space that validates this drug combination. Methods: We present a computational framework that is designed for detecting drug combinations, using the following components (a) a Text-mining module: to extract drug names from the abstract section of the biomedical publications and the intervention/treatment sections of clinical trial records. (b) a network model constructed from the drug names and their associations, (c) a clique similarity algorithm to identify candidate drug treatments. Result and Conclusions: Our framework has identified treatments in the form of two, three, or four drug combinations (e.g., hydroxychloroquine, doxycycline, and azithromycin). The identifications of the various treatment candidates provided sufficient evidence that supports the trustworthiness of our hypothesis. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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11 pages, 3275 KiB

Open AccessArticle

Anticoronaviral Activity of the Natural Phloroglucinols, Dryocrassin ABBA and Filixic Acid ABA from the Rhizome of Dryopteris crassirhizoma by Targeting the Main Protease of SARS-CoV-2

by Young-Hee Jin, Sangeun Jeon, Jihye Lee, Seungtaek Kim, Min Seong Jang, Chul Min Park, Jong Hwan Song, Hyoung Rae Kim and Sunoh Kwon

Pharmaceutics 2022, 14(2), 376; https://doi.org/10.3390/pharmaceutics14020376 - 08 Feb 2022

Cited by 5 | Viewed by 2029

Abstract

The rhizome of Dryopteris crassirhizoma Nakai. (Dryopteridaceae) has been used in traditional medicine in East Asia and has recently been reported to have anticancer, anti-inflammation, and antibacterial activity as well as antiviral activity. Natural phloroglucinols from D. crassirhizoma, dryocrassin ABBA and filixic [...] Read more.

The rhizome of Dryopteris crassirhizoma Nakai. (Dryopteridaceae) has been used in traditional medicine in East Asia and has recently been reported to have anticancer, anti-inflammation, and antibacterial activity as well as antiviral activity. Natural phloroglucinols from D. crassirhizoma, dryocrassin ABBA and filixic acid ABA were reported to inhibit influenza virus infection with an inhibitory activity on neuraminidase. In this study, we found that dryocrassin ABBA and filixic acid ABA have an inhibitory activity against the main protease of SARS-CoV-2. Therefore, dryocrassin ABBA and filixic acid ABA exhibited inhibitory activity against SARS-CoV-2 infection in Vero cells dose-dependently using the immunofluorescence-based antiviral assays. Moreover, these compounds inhibited SARS-CoV and MERS-CoV infection, suggesting their broad-spectrum anticoronaviral activity. In addition, a 5-day repeated-dose toxicity study of dryocrassin ABBA and filixic acid ABA suggested that an approximately lethal dose of these compounds in mice was >10 mg/kg. Pharmacokinetic studies of dryocrassin ABBA showed good microsomal stability, low hERG inhibition, and low CYP450 inhibition. In vivo pharmacokinetic properties of dryocrassin ABBA showed a long half-life (5.5–12.6 h) and high plasma exposure (AUC 19.3–65 μg·h/mL). Therefore, dryocrassin ABBA has therapeutic potential against emerging coronavirus infections, including COVID-19. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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24 pages, 7904 KiB

Open AccessArticle

Drug Repurposing for the Identification of Compounds with Anti-SARS-CoV-2 Capability via Multiple Targets

by Pei-Chen Yu, Chen-Hao Huang, Chih-Jung Kuo, Po-Huang Liang, Lily Hui-Ching Wang, Max Yu-Chen Pan, Sui-Yuan Chang, Tai-Ling Chao, Si-Man Ieong, Jun-Tung Fang, Hsuan-Cheng Huang and Hsueh-Fen Juan

Pharmaceutics 2022, 14(1), 176; https://doi.org/10.3390/pharmaceutics14010176 - 12 Jan 2022

Cited by 5 | Viewed by 3240

Abstract

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been rapidly spreading worldwide, causing hundreds of millions of infections. Despite the development of vaccines, insufficient protection remains a concern. Therefore, the screening of drugs for the treatment of coronavirus disease 2019 (COVID-19) [...] Read more.

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been rapidly spreading worldwide, causing hundreds of millions of infections. Despite the development of vaccines, insufficient protection remains a concern. Therefore, the screening of drugs for the treatment of coronavirus disease 2019 (COVID-19) is reasonable and necessary. This study utilized bioinformatics for the selection of compounds approved by the U.S. Food and Drug Administration with therapeutic potential in this setting. In addition, the inhibitory effect of these compounds on the enzyme activity of transmembrane protease serine 2 (TMPRSS2), papain-like protease (PL^pro), and 3C-like protease (3CL^pro) was evaluated. Furthermore, the capability of compounds to attach to the spike-receptor-binding domain (RBD) was considered an important factor in the present assessment. Finally, the antiviral potency of compounds was validated using a plaque reduction assay. Our funnel strategy revealed that tamoxifen possesses an anti-SARS-CoV-2 property owing to its inhibitory performance in multiple assays. The proposed time-saving and feasible strategy may accelerate drug screening for COVID-19 and other diseases. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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24 pages, 6845 KiB

Open AccessArticle

Investigating Structural Property Relationships to Enable Repurposing of Pharmaceuticals as Zinc Ionophores

by Oisín Kavanagh, Robert Elmes, Finbarr O’Sullivan, John Farragher, Shane Robinson and Gavin Walker

Pharmaceutics 2021, 13(12), 2032; https://doi.org/10.3390/pharmaceutics13122032 - 29 Nov 2021

Cited by 3 | Viewed by 2699

Abstract

The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer’s, and for antiviral purposes. [...] Read more.

The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer’s, and for antiviral purposes. Despite the growth of knowledge and increased interest in zinc, little is known about the structure and function of zinc ionophores. In this study we analyse the Cambridge Structural Database and solution complexation studies found in the literature to identify key functional groups which may confer zinc ionophorism. Pharmaceuticals, nutraceuticals and amino acids with these functionalities were selected to enable us to explore the translatability of ionophoric activity from in vitro assays to cellular systems. We find that although certain species may complex to zinc in the solid and solution states, and may carry ions across simple membrane systems, this does not necessarily translate into ionophoric activity. We propose that the CSD can help refine key functionalities but that ionophoric activity must be confirmed in cellular systems. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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17 pages, 3216 KiB

Open AccessArticle

Co-Spray Dried Nafamostat Mesylate with Lecithin and Mannitol as Respirable Microparticles for Targeted Pulmonary Delivery: Pharmacokinetics and Lung Distribution in Rats

by Ji-Hyun Kang, Young-Jin Kim, Min-Seok Yang, Dae Hwan Shin, Dong-Wook Kim, Il Yeong Park and Chun-Woong Park

Pharmaceutics 2021, 13(9), 1519; https://doi.org/10.3390/pharmaceutics13091519 - 19 Sep 2021

Cited by 10 | Viewed by 3155

Abstract

Coronavirus disease 2019 (COVID-19), caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. Nafamostat mesylate (NFM) suppresses transmembrane serine protease 2 and SARS-CoV-2 S protein-mediated fusion. In this study, pharmacokinetics and lung distribution [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. Nafamostat mesylate (NFM) suppresses transmembrane serine protease 2 and SARS-CoV-2 S protein-mediated fusion. In this study, pharmacokinetics and lung distribution of NFM, administered via intravenous and intratracheal routes, were determined using high performance liquid chromatography analysis of blood plasma, lung lumen using bronchoalveolar lavage fluid, and lung tissue. Intratracheal administration had higher drug delivery and longer residual time in the lung lumen and tissue, which are the main sites of action, than intravenous administration. We confirmed the effect of lecithin as a stabilizer through an ex vivo stability test. Lecithin acts as an inhibitor of carboxylesterase and delays NFM decomposition. We prepared inhalable microparticles with NFM, lecithin, and mannitol via the co-spray method. The formulation prepared using an NFM:lecithin:mannitol ratio of 1:1:100 had a small particle size and excellent aerodynamic performance. Spray dried microparticles containing NFM, lecithin, and mannitol (1:1:100) had the longest residual time in the lung tissue. In conclusion, NFM-inhalable microparticles were prepared and confirmed to be delivered into the respiratory tract, such as lung lumen and lung tissue, through in vitro and in vivo evaluations. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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Review

Jump to: Research, Other

29 pages, 9037 KiB

Open AccessReview

Advances in the Prophylaxis of Respiratory Infections by the Nasal and the Oromucosal Route: Relevance to the Fight with the SARS-CoV-2 Pandemic

by Nadezhda Ivanova, Yoana Sotirova, Georgi Gavrailov, Krastena Nikolova and Velichka Andonova

Pharmaceutics 2022, 14(3), 530; https://doi.org/10.3390/pharmaceutics14030530 - 27 Feb 2022

Cited by 5 | Viewed by 3665

Abstract

In this time of COVID-19 pandemic, the strategies for prevention of the infection are a primary concern. Looking more globally on the subject and acknowledging the high degree of misuse of protective face masks from the population, we focused this review on alternative [...] Read more.

In this time of COVID-19 pandemic, the strategies for prevention of the infection are a primary concern. Looking more globally on the subject and acknowledging the high degree of misuse of protective face masks from the population, we focused this review on alternative pharmaceutical developments eligible for self-defense against respiratory infections. In particular, the attention herein is directed to the nasal and oromucosal formulations intended to boost the local immunity, neutralize or mechanically “trap” the pathogens at the site of entry (nose or mouth). The current work presents a critical review of the contemporary methods of immune- and chemoprophylaxis and their suitability and applicability in topical mucosal dosage forms for SARS-CoV-2 prophylaxis. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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Other

Jump to: Research, Review

13 pages, 893 KiB

Open AccessSystematic Review

Convalescent Plasma Therapy, Therapeutic Formulations of Repurposed Drugs in 20th Century Epidemics against COVID-19: A Systematic Review

by Diego Fernández-Lázaro, Carlos Domínguez Ortega, Nerea Sánchez-Serrano, Fahd Beddar Chaib, David Jerves Donoso, Elena Jiménez-Callejo and Saray Rodríguez-García

Pharmaceutics 2022, 14(5), 1020; https://doi.org/10.3390/pharmaceutics14051020 - 09 May 2022

Cited by 9 | Viewed by 1457

Abstract

Coronavirus 2019 disease (COVID-19) represents one of the largest pandemics the world has faced, and it is producing a global health crisis. To date, the availability of drugs to treat COVID-19 infections remains limited to supportive care although therapeutic options are being explored. [...] Read more.

Coronavirus 2019 disease (COVID-19) represents one of the largest pandemics the world has faced, and it is producing a global health crisis. To date, the availability of drugs to treat COVID-19 infections remains limited to supportive care although therapeutic options are being explored. Some of them are old strategies for treating infectious diseases. convalescent plasma (CP) therapy has been used successfully in other viral outbreaks in the 20th century. In this study, we systematically evaluated the effect and safety of CP therapy on hospitalized COVID-19 patients. A structured search was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines using Medline (PubMed), SciELO, Cochrane Library Plus, Web of Science, and Scopus. The search included articles published up to January 2022 and was restricted to English- and Spanish-language publications. As such, investigators identified six randomized controlled trials that met the search criteria. The results determined that in hospitalized COVID-19 patients the administration of CP therapy with a volume between 200–500 mL and a single transfusion performed in 1–2 h, compared to the control group, decreased viral load, symptomatology, the period of infection, and mortality, without serious adverse effects. CP did influence clinical outcomes and may be a possible treatment option, although further studies will be necessary. Full article

(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)

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