Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics

Quinn, Tom; Gaughan, Erin; Bruce, Annya; Antonelli, Jean; O’Connor, Richard A.; Li, Feng; McNamara, Sarah; Koch, Oliver; Mackintosh, Claire; Dockrell, David H.; Walsh, Timothy; Blyth, Kevin G.; Church, Colin; Schwarze, Jürgen; Boz, Cecilia; Valančiūtė, Asta; Burgess, Matthew; Emanuel, Philip; Mills, Bethany; Rinaldi, Giulia; Hardisty, Gareth; Mills, Ross; Findlay, Emily Gwyer; Jabbal, Sunny; Duncan, Andrew; Plant, Sinéad; Marshall, Adam; Young, Irene; Russell, Kay; Scholefield, Emma; Nimmo, A. F.; Nazarov, Islom B.; Churchill, Grant C.; McCullagh, James; Ebrahimi, Kourosh Honarmand; Ferrett, Colin; Templeton, Kate; Rannard, Steve; Owen, Andrew; Moore, Anne; Finlayson, Keith; Shankar-Hari, Manu; Norrie, John; Parker, Richard; Akram, Ahsan; Anthony, Daniel C.; Dear, James W.; Hirani, Nik; Dhaliwal, Kevin

doi:10.1016/j.ebiom.2022.103856

Cited by 43 publications

(33 citation statements)

References 29 publications

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“…Several of the drugs predicted in this study, including azelastine have been shown to have activity against coronaviruses in vitro ( Zhang et al, 2005 ; Kim et al, 2019 ; Fan et al, 2020 ; Gordon et al, 2020 ; Jeon et al, 2020 ; Riva et al, 2020 ; Dittmar et al, 2021 ; Yang et al, 2021 ). Furthermore, several of the predicted drugs from our study were or are still being investigated for efficacy in clinical studies ( Chiu et al, 2021 ; Gunst et al, 2021 ; Kuno et al, 2021 ; Zhuravel et al, 2021 ; Quinn et al, 2022 ).…”

Section: Discussionmentioning

confidence: 94%

The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue

et al. 2022

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Background and purpose: The COVID-19 pandemic continues to pose challenges, especially with the emergence of new SARS-CoV-2 variants that are associated with higher infectivity and/or compromised protection afforded by the current vaccines. There is a high demand for additional preventive and therapeutic strategies effective against this changing virus. Repurposing of approved or clinically tested drugs can provide an immediate solution.Experimental Approach: We applied a novel computational approach to search among approved and commercially available drugs. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 cells, Vero cells stably overexpressing the human TMPRSS2 and ACE2 proteins as well as on reconstituted human nasal tissue using the predominant variant circulating in Europe in summer 2020, B.1.177 (D614G variant), and its emerging variants of concern; B.1.1.7 (alpha), B.1.351 (beta) and B.1.617.2 (delta) variants. The effect of azelastine on viral replication was assessed by quantification of viral genomes by droplet digital PCR or qPCR.Key results: The computational approach identified major drug families, such as anti-infective, anti-inflammatory, anti-hypertensive, antihistamine, and neuroactive drugs. Based on its attractive safety profile and availability in nasal formulation, azelastine, a histamine 1 receptor-blocker was selected for experimental testing. Azelastine reduced the virus-induced cytopathic effect and SARS-CoV-2 copy numbers both in preventive and treatment settings upon infection of Vero cells with an EC50 of 2.2–6.5 µM. Comparable potency was observed with the alpha, beta and delta variants. Furthermore, five-fold dilution (containing 0.02% azelastine) of the commercially available nasal spray formulation was highly potent in inhibiting viral propagation in reconstituted human nasal tissue.Conclusion and Implications: Azelastine, an antihistamine available as nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization by SARS-CoV-2. A Phase 2 efficacy indicator study with azelastine-containing nasal spray that was designed based on the findings reported here has been concluded recently, confirming accelerated viral clearance in SARS-CoV-2 positive subjects.

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Section: Discussionmentioning

confidence: 94%

The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue

et al. 2022

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“…Importantly, Nafamostat has a short half-life time due to rapid hydrolysis by blood and liver esterases [ 25 , 26 , 27 ]. Therefore, it remains unclear whether Nafamostat concentrations suitable to block −1PRF can be attained in patients receiving Nafamostat via continuous infusion, the approved route of Nafamostat administration [ 28 , 29 ], or upon topical application, a recently pursued approach to COVID-19 therapy [ 30 ]. Nevertheless, although Nafamostat-mediated inhibition of −1PRF did not translate into reduced SARS-CoV-2 replication in our study, interference with SARS-CoV-2 −1PRF by more potent compounds could still represent a promising antiviral strategy.…”

mentioning

confidence: 99%

Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

Jäger

Hoffmann

Pöhlmann

et al. 2022

Viruses

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“…Although a quicker clinical improvement in a subgroup of high-risk COVID-19 patients requiring oxygen treatment was reported, it requires further verification [ 104 ], along with studies as to whether CM or NM caused no or only mild adverse events [ 102 , 104 ]. No evidence of anti-inflammatory, anticoagulant, or antiviral activity was found after applying intravenous NM therapy in hospitalized COVID-19 patients and there were adverse events in the experimental study of Quinn et al [ 105 ]. The combination of NM and favipiravir is being examined in a clinical trial in Japan (jRCTs031200026).…”

Section: Cell Membrane and Golgi Apparatusmentioning

confidence: 99%

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

Gorący

Rosik

Szostak

et al. 2022

Viruses

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Since the end of 2019, the whole world has been struggling with the life-threatening pandemic amongst all age groups and geographic areas caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The Coronavirus Disease 2019 (COVID-19) pandemic, which has led to more than 468 million cases and over 6 million deaths reported worldwide (as of 20 March 2022), is one of the greatest threats to human health in history. Meanwhile, the lack of specific and irresistible treatment modalities provoked concentrated efforts in scientists around the world. Various mechanisms of cell entry and cellular dysfunction were initially proclaimed. Especially, mitochondria and cell membrane are crucial for the course of infection. The SARS-CoV-2 invasion depends on angiotensin converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cluster of differentiation 147 (CD147), expressed on host cells. Moreover, in this narrative review, we aim to discuss other cell organelles targeted by SARS-CoV-2. Lastly, we briefly summarize the studies on various drugs.

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Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics

Cited by 43 publications

References 29 publications

The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue

The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue

Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

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