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      Niclosamide–Clay Intercalate Coated with Nonionic Polymer for Enhanced Bioavailability toward COVID-19 Treatment

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          Abstract

          Niclosamide (NIC), a conventional anthelmintic agent, is emerging as a repurposed drug for COVID-19 treatment. However, the clinical efficacy is very limited due to its low oral bioavailability resulting from its poor aqueous solubility. In the present study, a new hybrid drug delivery system made of NIC, montmorillonite (MMT), and Tween 60 is proposed to overcome this obstacle. At first, NIC molecules were immobilized into the interlayer space of cationic clay, MMT, to form NIC–MMT hybrids, which could enhance the solubility of NIC, and then the polymer surfactant, Tween 60, was further coated on the external surface of NIC–MMT to improve the release rate and the solubility of NIC and eventually the bioavailability under gastrointestinal condition when orally administered. Finally, we have performed an in vivo pharmacokinetic study to compare the oral bioavailability of NIC for the Tween 60-coated NIC–MMT hybrid with Yomesan ®, which is a commercially available NIC. Exceptionally, the Tween 60-coated NIC–MMT hybrid showed higher systemic exposure of NIC than Yomesan ®. Therefore, the present NIC–MMT–Tween 60 hybrid can be a potent NIC drug formulation with enhanced solubility and bioavailability in vivo for treating Covid-19.

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          Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

          Summary Background No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. Methods We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Findings Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. Interpretation In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Funding Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
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            Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19

            LETTER The currently unfolding coronavirus pandemic threatens health systems and economies worldwide. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated disease coronavirus disease 2019 (COVID-19) has initially been limited to China. However, the virus has now been detected in more than 100 countries outside China, and major outbreaks are ongoing in the United States, Italy, and Spain. At present, our antiviral arsenal offers little protection against SARS-CoV-2, although recent progress has been reported (1), and novel antivirals are urgently needed to mitigate the COVID-19 health crisis. The SARS-CoV-2 spike protein (S) is inserted into the viral envelope and mediates viral entry into cells. For this, the S protein depends on the cellular enzyme transmembrane protease serine 2 (TMPRSS2), which cleaves and thereby activates the S protein (2). SARS-CoV (3 – 5) and other coronaviruses (6, 7) also use TMPRSS2 for S protein activation, and the protease is expressed in SARS-CoV target cells throughout the human respiratory tract (8). Moreover, TMPRSS2 is required for spread of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) in rodent models (9, 10) but is dispensable for development and homeostasis in mice (11). Thus, TMPRSS2 constitutes an attractive drug target. Recent work shows that camostat mesylate (NI-03), a serine protease inhibitor active against TMPRSS2 and employed for treatment of pancreatitis in Japan, inhibits SARS-CoV-2 infection of human lung cells (2). The suitability of camostat mesylate for treatment of COVID-19 is currently being evaluated in a clinical trial (12), but it is unclear whether compound concentrations can be attained in the lung that are sufficient to suppress viral spread. In the absence of this information, testing of other serine protease inhibitors for blockade of SARS-CoV-2 entry is an important task. For this, we tested gabexate mesylate (FOY) and nafamostat mesylate (Futhan) (13) along with camostat mesylate for inhibition of SARS-CoV-2 infection of lung cells. All compounds are approved for human use in Japan, and nafamostat mesylate inhibits TMPRSS2-dependent host cell entry of MERS-CoV (14). A comparison of the antiviral activities of the three compounds revealed that none interfered with cell viability or with host cell entry mediated by the glycoproteins of vesicular stomatitis virus or Machupo virus (Fig. 1A), which served as negative controls. Gabexate mesylate slightly inhibited SARS-CoV-2 S-driven host cell entry while camostat mesylate robustly suppressed entry (Fig. 1A). Notably, nafamostat mesylate, which is FDA approved for indications unrelated to coronavirus infection, inhibited SARS-CoV-2 S-mediated entry into host cells with roughly 15-fold-higher efficiency than camostat mesylate, with a 50% effective concentration [EC50] in the low-nanomolar range (Fig. 1A). Moreover, nafamostat mesylate blocked SARS-CoV-2 infection of human lung cells with markedly higher efficiency than camostat mesylate while both compounds were not active against vesicular stomatitis virus infection, as expected (Fig. 1B to D). In light of the global impact of COVID-19 on human health, the proven safety of nafamostat mesylate, and its increased antiviral activity compared to camostat mesylate, we argue that this compound should be evaluated in clinical trials as a COVID-19 treatment. FIG 1 Nafamostat mesylate inhibits SARS-CoV-2 infection of lung cells in the nanomolar range. The lung-derived human cell line Calu-3 was incubated with the indicated concentrations of the indicated serine protease inhibitors, and (A) either cell viability was measured or the cells were inoculated with vesicular stomatitis virus reporter particles pseudotyped with the indicated viral glycoproteins. The efficiency of viral entry was determined at 16 h postinoculation by measuring luciferase activity in cell lysates. The 50% effective dose values are indicated below the graphs. In parallel, cells exposed to serine protease inhibitors were infected with replication-competent vesicular stomatitis virus encoding green fluorescent protein (B) or infected with SARS-CoV-2 (C), and infection efficiency was quantified by focus formation assay and by measuring genome copies via quantitative RT-PCR, respectively. A scheme of how camostat and nafamostat mesylate block activation of SARS-2-S is shown in panel D. The average from three independent experiments is shown in panels A and C while the average from four independent experiments is presented in panel B. For panels A to C, statistical significance was tested by two-way analysis of variance with Dunnett’s posttest. In addition, statistical significance of differences between SARS-CoV-2 genome equivalents at identical concentrations of camostat or nafamostat mesylate was tested by one-way analysis of variance with Sidak’s posttest. Abbreviations: VSV-G, vesicular stomatitis virus glycoprotein, MACV-GPC, Machupo virus glycoprotein complex; MERS-S, Middle East respiratory syndrome coronavirus spike glycoprotein; SARS-S, severe acute respiratory syndrome coronavirus spike glycoprotein; SARS-2-S, severe acute respiratory syndrome coronavirus 2 spike glycoprotein.
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              The genetic sequence, origin, and diagnosis of SARS-CoV-2

              Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new infectious disease that first emerged in Hubei province, China, in December 2019, which was found to be associated with a large seafood and animal market in Wuhan. Airway epithelial cells from infected patients were used to isolate a novel coronavirus, named the SARS-CoV-2, on January 12, 2020, which is the seventh member of the coronavirus family to infect humans. Phylogenetic analysis of full-length genome sequences obtained from infected patients showed that SARS-CoV-2 is similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and uses the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), as SARS-CoV. The possible person-to-person disease rapidly spread to many provinces in China as well as other countries. Without a therapeutic vaccine or specific antiviral drugs, early detection and isolation become essential against novel Coronavirus. In this review, we introduced current diagnostic methods and criteria for the SARS-CoV-2 in China and discuss the advantages and limitations of the current diagnostic methods, including chest imaging and laboratory detection.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Polymers (Basel)
                Polymers (Basel)
                polymers
                Polymers
                MDPI
                2073-4360
                26 March 2021
                April 2021
                : 13
                : 7
                : 1044
                Affiliations
                [1 ]Department of Chemistry, College of Science and Technology, Dankook University, Cheonan 31116, Korea; 32182808@ 123456dankook.ac.kr
                [2 ]Intelligent Nanohybrid Materials Laboratory (INML), Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea; 12192032@ 123456dankook.ac.kr (H.P.); sanojrejinold@ 123456dankook.ac.kr (N.S.R.)
                [3 ]R&D Center, CnPharm Co., Ltd., Seoul 03759, Korea; geunwoo.jin@ 123456cnpharm.co.kr
                [4 ]College of Science and Technology, Dankook University, Cheonan 31116, Korea
                [5 ]Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
                [6 ]Department of Pre-Medical Course, College of Medicine, Dankook University, Cheonan 31116, Korea
                [7 ]Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5561-1103
                https://orcid.org/0000-0002-5424-8322
                Article
                polymers-13-01044
                10.3390/polym13071044
                8036780
                33810527
                6dd4f0f7-9c25-4cfc-b7df-4e93bc1cce68
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 February 2021
                : 23 March 2021
                Categories
                Article

                niclosamide,poorly-soluble drug,montmorillonite,tween 60,drug delivery,solubility enhancement,bioavailability

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