Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro

Schloer, Sebastian; Brunotte, Linda; Mecate-Zambrano, Angeles; Zheng, Shuyu; Tang, Jing; Ludwig, Stephan; Rescher, Ursula

doi:10.1101/2020.10.16.342410

Cited by 25 publications

(36 citation statements)

References 50 publications

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“…This drug screening revealed antiviral activity of itraconazole and its metabolite hydro-itraconazole [1], comparable with the in vitro antiviral activity of hydroxychloroquine. This activity was also confirmed by others [2] (both reports are at the time of writing available as preprints only).…”

Section: Introductionsupporting

confidence: 76%

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

et al. 2021

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Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to

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Section: Introductionsupporting

confidence: 76%

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

et al. 2021

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“…However, according to in vitro data, it is quite conceivable that the combination of remdesivir with a FIASMA will provide additional benefits. This has been shown for the combinations remdesivir−emetine [72] and remdesivir−fluoxetine [99]. (7) Plasma ceramides are elevated in sepsis patients and predict sepsis-associated mortality [100].…”

Section: The Asm/ceramide Model Of Sars-cov-2 Infection and Covid-19mentioning

confidence: 94%

The acid sphingomyelinase/ceramide system in COVID-19

2021

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Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of “old” drugs against COVID-19.

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“…The EC 50 values that were obtained are in line with recently reported values for itraconazole inhibition of SARS-CoV-2 replication in Calu-3 and VeroE6 cell lines (0.43 and 0.39 μM, respectively). 24 To obtain further evidence for the antiviral potency of the drugs, the Itraconazole has documented activity against several enteroviruses, including rhinovirus. 8,15 Further, at a dose of 5.7 mg/kg, itraconazole resulted in improved mortality and a lower viral load in mice that had been infected with human influenza (strain PR8M) compared with the control group.…”

Section: This Reduction Was Also Observed At Higher Concentrations As Inmentioning

confidence: 99%

In vitro activity of itraconazole against SARS‐CoV‐2

Damme

Meyer

Bojkova

et al. 2021

Journal of Medical Virology

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Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID‐19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID‐19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell‐based phenotypic assays, the in vitro antiviral activity of itraconazole and 17‐OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with SARS‐CoV‐2. Itraconazole demonstrated antiviral activity in human Caco‐2 cells (EC 50 = 2.3 µM; MTT assay). Similarly, its primary metabolite, 17‐OH itraconazole, showed inhibition of SARS‐CoV‐2 activity (EC 50 = 3.6 µM). Remdesivir inhibited viral replication with an EC 50 = 0.4 µM. Itraconazole and 17‐OH itraconazole resulted in a viral yield reduction in vitro of approximately 2‐log 10 and approximately 1‐log 10 , as measured in both Caco‐2 cells and VeroE6‐eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS‐441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3‐log 10 drop and >4‐log 10 drop in Caco‐2 cells and VeroE6‐eGFP cells, respectively. Itraconazole and 17‐OH itraconazole exert in vitro low micromolar activity against SARS‐CoV‐2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID‐19 patients in a clinical study (EudraCT Number: 2020‐001243‐15). This article is protected by copyright. All rights reserved.

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Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro

Cited by 25 publications

References 50 publications

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

The acid sphingomyelinase/ceramide system in COVID-19

In vitro activity of itraconazole against SARS‐CoV‐2

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