Serial Viral Load Analysis by Ddpcr to Evaluate Fnc Efficacy and Safety in the Treatment of Moderate Cases of Covid-19 (preprint)

A highly pathogenic coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 causing coronavirus disease 2019 (COVID-19). Trials have been carried out to find drugs effective in fighting the disease, as COVID-19 is being considered a treatable disease only after we have antivirals. A clinical candidate originally developed for HIV treatment, AZVUDINE (FNC), is a promising drug in the treatment of COVID-19, being able to reduce the patient's viral load leading to cure. In this study, a randomized clinical trial was performed in moderate COVID-19 patients to evaluate the efficacy of FNC added to standard treatment, compared with placebo group added to standard treatment. RT-qPCR and ddPCR were applied to estimate the viral load in samples from patients, which was performed every 48 hours throughout the treatment. Also, the clinical improvement was evaluated as well as the liver and kidney function. Notably, FNC treatment in moderate COVID-19 patients may shorten the time of nucleic acid negativity conversion versus placebo group, accelerates the elimination of the virus, decreasing the viral load significantly, especially in the first days. Due to the lack of specific antiviral drug, the pandemic is not under the control and resurfaces in different waves of infection, which cause a large cumulative expense of medical resources. Fortunately, FNC could reduce treatment time of moderate COVID-19 patients and save a lot of medical resources, making it a strong candidate for the treatment of COVID-19. Trial registration number: NCT04668235 https://clinicaltrials.gov/ct2/show/NCT04668235?term=azvudine&cond=COVID-19&draw=2&rank=1 

Serial Viral Load Analysis by Ddpcr to Evaluate Fnc Efficacy and Safety in the Treatment of Mild Cases of Covid-19 (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has threatened the human population globally as the numbers of reinfection cases even after large-scale vaccination. Trials have been carried out to find drugs effective in fighting the disease, as COVID-19 is being considered a treatable disease only after we have antivirals. A clinical candidate originally developed for HIV treatment, AZVUDINE (FNC), is a promising drug in the treatment of COVID-19, being able to reduce the patient's viral load leading to cure. To predict the clinical outcome of COVID-19, we examined the course of viral load, every 48hs, by RT-PCR, and disease severity using a promising antiviral drug, AZVUDINE (FNC) with 281 participants. A randomized clinical trial was performed to evaluate the efficacy of FNC added to standard treatment, compared with placebo group added to standard treatment, for patients with mild COVID-19. RT-qPCR and ddPCR were applied to estimate the viral load in samples from patients, which was performed every 48 hours throughout the treatment. Also, the clinical improvement was evaluated as well as the liver and kidney function. Notably, the FNC treatment in the mild COVID-19 patients may shorten the time of the nucleic acid negative conversion (NANC) versus placebo group. In addition, the FNC was effective in reducing the viral load of these participants, in the first days (D3, D5, D7, D9). Therefore, the present clinical trial results showed that the FNC accelerate the elimination of the virus in and could reduce treatment time of mild patients and save a lot of medical resources, making it a strong candidate for the outpatient and home treatment of COVID-19. Trial registration number:NCT05033145 https://clinicaltrials.gov/ct2/show/NCT05033145

SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury (preprint)

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.