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      Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections

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          Abstract

          The nose is the portal for SARS-CoV-2 infection, suggesting the nose as a target for topical antiviral therapies. Because detergents are virucidal, Johnson and Johnson’s Baby Shampoo (J&J) was tested as a topical virucidal agent in SARS-CoV-2 infected subjects. Twice daily irrigation of J&J in hypertonic saline, hypertonic saline alone, or no intervention were compared (n = 24/group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces. This study emphasizes the need to assess the pharmacokinetic characteristics of virucidal agents on airway surfaces to guide clinical trials.

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          Most cited references23

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          SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

          Summary The mode of acquisition and causes for the variable clinical spectrum of COVID-19 remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore SARS-CoV-2 pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest ACE2 expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) vs distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.
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            High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2

            Severe acute respiratory syndrome coronavirus 2 is the causative agent of the ongoing coronavirus disease pandemic. Initial estimates of the early dynamics of the outbreak in Wuhan, China, suggested a doubling time of the number of infected persons of 6–7 days and a basic reproductive number (R0) of 2.2–2.7. We collected extensive individual case reports across China and estimated key epidemiologic parameters, including the incubation period (4.2 days). We then designed 2 mathematical modeling approaches to infer the outbreak dynamics in Wuhan by using high-resolution domestic travel and infection data. Results show that the doubling time early in the epidemic in Wuhan was 2.3–3.3 days. Assuming a serial interval of 6–9 days, we calculated a median R0 value of 5.7 (95% CI 3.8–8.9). We further show that active surveillance, contact tracing, quarantine, and early strong social distancing efforts are needed to stop transmission of the virus.
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              SARS-CoV-2 D614G Variant Exhibits Efficient Replication ex vivo and Transmission in vivo

              The spike D614G substitution is prevalent in global SARS-CoV-2 strains, but its effects on viral pathogenesis and transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells, but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.
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                Author and article information

                Contributors
                Journal
                Res Sq
                ResearchSquare
                Research Square
                American Journal Experts
                14 May 2021
                : rs.3.rs-500168
                Affiliations
                University of North Carolina at Chapel Hill
                Vanderbilt University Medical Center
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                Vanderbilt University Medical Center
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                University of North Carolina at Chapel Hill
                Vanderbilt University Medical Center
                University of North Carolina at Chapel Hill
                Author notes

                Author Contributions

                CRE wrote the manuscript and performed mass spectrometric analysis. KSK, YM, TK, SHR performed cell culture experiments. CEE performed experiments with SARS-CoV-2, and RJP performed experiments with NL63 and RSV. SRD, MHF, BAS, HMB, BCW, VCG, KVW, QS, LCH, and DRB performed the clinical trial and analysis with input from AJK. ASC provided biostatistical support. RSB, JHT, and RCB provided overall oversight of the study.

                Article
                10.21203/rs.3.rs-500168
                10.21203/rs.3.rs-500168/v1
                8132247
                34013253
                bda88f8e-8bfe-4dcc-ae5f-c981a83240c7

                This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.

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                Article

                sars-cov-2,topical virucidal agent,irrigation
                sars-cov-2, topical virucidal agent, irrigation

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