Combination therapy with fluoxetine and the nucleoside analogue GS-441524 shows synergistic antiviral effects against various SARS-CoV-2 variants in vitro

Complete original article: Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro81 /

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

Abstract

The ongoing SARS-CoV-2 pandemic requires effective and safe antiviral treatment strategies. Drug repurposing is a fast and inexpensive approach to developing new treatment options. The direct antiviral agent remdesivir was found to have antiviral activity against SARS-CoV-2. While remdesivir has only a very short half-life and bioactivation, which depends on prodrug activating enzymes, its plasma metabolite GS-441524 can be activated by various kinases, including adenosine kinase (ADK), which is moderately expressed in all tissues. The pharmacokinetics of GS-441524 suggest that it is a suitable antiviral drug that can be administered to patients with COVID-19. In this work, we analyzed the antiviral properties of combination therapy with the metabolite remdesivir GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. Combination therapy with GS-441524 and fluoxetine was well tolerated and showed synergistic antiviral effects against the three circulating SARS-CoV-2 variants in vitro in commonly used drug interaction reference models. Thus, combination treatment with GS-441524 virus-targeted and host-targeted fluoxetine could offer a suitable therapeutic option for the treatment of SARS-CoV-2 infections.

Translator's note: Fluoxetine is produced under various trade names, of which Prozac is probably the best known.

… You can read the rest in complete article in english. Read "Combination therapy with fluoxetine and nucleoside analogue GS-441524 shows synergistic antiviral effects against different variants of SARS-CoV-2 in vitro"

The preclinical inhibitor GS441524 in combination with GC376 effectively suppressed SARS-CoV-2 proliferation in the respiratory tract of mice.

You can find the whole article on the server biorxiv.org;
13.11.2020.

Abstract

The unprecedented coronavirus disease pandemic of 2019 (COVID-19) caused by the second severe acute respiratory syndrome virus (SARS-CoV-2) poses a serious threat to public health worldwide. There is an urgent need to develop effective therapies against SARS-CoV-2. We evaluated the antiviral activity of the original remdesivirus nucleotide analog, GS441524, which targets the enzyme RNA-dependent RNA polymerase, and the protease inhibitor GC376, which targets the protease SARS-CoV 2 in infected mice. Our results showed that GS441524 effectively blocked SARS-CoV-2 proliferation (multiplication) in the upper and lower airways with combined intranasal (in) and intramuscular (im) therapy. The efficacy of the high dose of GC376 (im or in and im) was weaker than GS441524. However, it is noteworthy that the combined administration of GS441524 together with GC376 at low doses could effectively protect mice from SARS-CoV-2 infection during in or in and their treatment. We further found that the pharmacokinetic properties of GS441524 were superior to GC376, and the combined application of GC376 and GS441524 had a synergistic effect. Our findings will be used to further evaluate the combined application of GC376 and GS441524 in future clinical trials. Read "The preclinical inhibitor GS441524 in combination with GC376 effectively suppressed SARS-CoV-2 proliferation in the respiratory tract of mice."

Candidate gene markers associated with fecal secretion of feline enteric coronavirus (FECV)

Complete original article on portal of the US National Center for Biotechnology Information; 17.11.2020

Abstract

Feline coronavirus (FCoV) can cause a fatal disease - feline infectious peritonitis. Cats that permanently shed this virus are the most important sources of infection. The role of the host in faecal excretion of FCoV is unknown. The aim of this study was to identify gene markers and test their association with FCoV secretion patterns. Fecal samples were taken from 57 cats of 12 breeds at baseline and then at 2, 4 and 12 months. Variations from persistent and / or high intensity excretion to no excretion were observed. Thirteen immune-related genes were selected as functional and positional / functional candidates. Positional candidates were selected in the candidate area detected by GWAS analysis. Tens to hundreds of single nucleotide polymorphisms (SNPs) per gene have been identified by next generation sequencing. Associations with different phenotypes were evaluated by chi-square tests and Fisher's exact tests. SNP of one functional and one position candidate (NCR1 and SLX4IP ) and haplotypes of four genes ( SNX5 , NCR2 , SLX4IP , NCR1 ) were associated with FCoV excretion at cor<0.01. Highly significant associations have been observed in extreme phenotypes (persistent / high-intensity secretors and non-excretors), suggesting that there are two major phenotypes associated with different genotypes - highly susceptible cats that persistently excrete high levels of viral particles, and coronavirus-resistant cats. do not exclude.

Keywords: feline enteric coronavirus, faecal excretion patterns, polymerase chain reaction, genetic susceptibility, candidate immune-related genes, association study Read "Candidate gene markers associated with fecal secretion of feline enteric coronavirus (FECV)"

Clinical efficacy of itraconazole and prednisolone combination therapy in the treatment of feline infectious peritonitis

Satoshi KameshimaYuya Kimura Tomoyoshi Doki Tomomi Takano Chun-Ho Park Naoyuki Itoh

Original article in National Library of Medicine, 27.8.2020

Abstract

A 3-month-old Scottish Fold cat with pleural fluid and a low albumin to globulin ratio (A / G ratio) was brought to our small animal hospital. Because feline coronavirus type I (FCoV) RNA was detected in pleural fluid, the cat was pre-diagnosed with an fusion form of feline infectious peritonitis (FIP). After administration of itraconazole and prednisolone, the A / G ratio increased and the pleural fluid almost disappeared. Fecal FCoV levels have temporarily decreased. However, the cat began to show neurological symptoms, and we eventually had to proceed to euthanasia due to the persistent epileptic condition after 38 days of treatment. In conclusion, itraconazole has been shown to be beneficial in the treatment of cats with FIP. However, further investigation of the possible role of itraconazole in the treatment of FIP is needed.

Keywords: feline infectious peritonitis; itraconazole; neurological manifestation; pleural fluid; feline coronavirus type I.

Note: On the Slovak or Czech market, itraconazole contains, for example, drugs called Conisor, Sporanox, Procanazole. They are usually used to treat fungal infections, e.g. nails.

You can get an idea of dosing in cats in A clinical study on the use of itraconazole in the treatment of FCoV. Read "Clinical efficacy of combination therapy with itraconazole and prednisolone for the treatment of feline infectious peritonitis"

Mutian®X oral form has stopped fecal coronavirus excretion in naturally infected cats

Original complete article: Oral Mutian®X stopped faecal feline coronavirus shedding by naturally infected cats (June 2020)
Abstract translation: 17.1.2021

Diane D Addie, Sheryl Curran, Flora Bellini, Ben Crowe, Emily Sheehan, Lesya Ukrainchuk, Nicola Decaro

Abstract

Feline coronavirus (FCoV) is common in domestic cats living in groups. About 10% infected cats can potentially develop a fatal disease, feline infectious peritonitis (FIP). The virus is transmitted by the faecal-oral route. Mutian® Xraphconn (Mutian X) is a product for the treatment of FIP, but it is also used to stop coronavirus secretion, although there are no clear guidelines for its use. The aim of this study was to determine the minimum dose and duration of treatment required to reliably eliminate the virus in the faeces of asymptomatic, virus-secreting cats. In five households with several cats, Mutian X tablets received 29 cats naturally infected with FCoV, and actively shedding the virus in the feces. Virus shedding was monitored by a quantitative reverse transcription polymerase chain reaction (RT-qPCR) controlled on fecal inhibitors to ensure susceptibility. Mutian X administered orally eliminated the virus in 29 cats; although four cats required re-therapy to stop virus shedding. A dose of 4 mg / kg every 24 hours for four days was found to be the optimal treatment protocol: 2 mg / kg cleared only 80% cats. Therapeutic use of a sensitive RT-qPCR assay was necessary to ensure that virus was eliminated, as failure of even one cat could result in re-infection of other cats. Pre-treatment virus shedding records provided retrospective control: significantly more cats stopped shedding virus after Mutian X than recovered from infection during the control period (p <0.00001). This is the first report of successful elimination of FCoV excretion by the faecal route in chronically infected cats.

Keywords: Antivirals; Faecal shedding of the virus; Feline coronavirus (FCoV); Feline Infectious Peritonitis (FIP); Itraconazole; Mutian X tablets

Copyright © 2020 Authors. Published by Elsevier Ltd. All rights reserved.

Translator's note: To achieve the same effect, any drug containing GS441524. Read "Oral Mutian®X has stopped fecal coronavirus excretion in naturally infected cats"

Detection of Ascitic Feline Coronavirus RNA from Cats with Clinically Suspected Feline Infectious Peritonitis

Original article published on the portal National Center for Biotechnology Information
13.10.2013

Abstract

Ascitic feline coronavirus (FCoV) RNA was examined in 854 cats suspected of having feline infectious peritonitis (FIP) by RT-PCR. Positivity was significantly higher in purebreds (62.2%) than in hybrids (34.8%) (P <0.0001). Among purebred breeds, the positives of the Norwegian Forest Cat (92.3%) and the Scottish Fold cat (77.6%) were significantly higher than the average of purebred breeds (P = 0.0274 and 0.0251, respectively). Positivity was significantly higher in males (51.5%) than in cats (35.7%) (P <0.0001), whereas the prevalence of anti-FCoV antibodies generally showed no gender difference, suggesting that FIP in males infected with FCoV is more common, so males are more likely to break FIP. Genotyping was performed on 377 gene positive samples. Type I (83.3%) was detected much more frequently than type II (10.6%) (P <0.0001), similar to previous serological and genetic surveys.


See for more information original article. Among other things, it is mentioned that the incidence of FIP shows seasonal changes, and most often occurs in the autumn and winter months, while in summer the incidence is significantly lower. Read "Detection of feline coronavirus RNA from effusions in cats suspected of having FIP"

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