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Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic demands a swift response to find therapeutic tools that effectively reduce morbidity and mortality. Despite initial fears, evidence from retrospective observational studies supports the inhibition of the renin-angiotensin system as an emerging pathway to delay or moderate angiotensin II-driven lung inflammation. This has triggered several prospective clinical trials. In this commentary we provide an overview and analysis of current ongoing clinical trials aimed at evaluating the therapeutic efficacy of angiotensin receptor blocker (ARB) use in COVID-19. The relevance of the results of these trials will have to be interpreted depending on the stage and severity of the disease and in light of the start time of their prescription related to the time of diagnosis of COVID-19 as well as the administered doses. [ABSTRACT FROM AUTHOR]