Browsing by Author "Davis, Michael D."

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    2020 Year in Review: Pharmacologic Treatments for COVID-19
    (2021-04) Saunders, Jessica L.; Davis, Michael D.; Pediatrics, School of Medicine
    COVID-19, caused by SARS-CoV-2 infection, has led to a pandemic of acute respiratory illness. Pharmacologic treatments for COVID-19 have included treatments targeting infection prevention, prevention of viral replication, reducing inflammation and managing symptoms of respiratory failure caused by the disease. This is a review of key pharmacologic treatments for COVID-19 based on peer-reviewed articles from 2020.
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    Local Effects of Two Intravenous Formulations of Pulmonary Vasodilators on Airway Epithelium
    (AARC, 2020-10) Kuch, Bradley A.; Linssen, Rosalie; Yoshikawa, Hiroki; Smallwood, Craig D.; Davis, Michael D.; Pediatrics, School of Medicine
    BACKGROUND: Intravenous formulations of epoprostenol are frequently delivered via nebulizer to treat pulmonary hypertension in acutely ill patients. Although their efficacy as pulmonary vasodilators has been shown to be comparable to inhaled nitric oxide, the local effects of these formulations within the airways have not been determined. We hypothesized that the alkaline diluents of these compounds would lead to increased airway epithelial cell death and ciliary cessation. METHODS: Human bronchial epithelial cells were exposed to epoprostenol in glycine and arginine diluents or control fluid. Ciliary beat frequency, lactate dehydrogenase, and total RNA levels were measured before and after exposure. Results were compared between exposure and control groups. RESULTS: Ciliary beat frequency ceased immediately after exposure to epoprostenol with both diluents. Lactate dehydrogenase levels increased by 200% after exposure to epoprostenol and glycine diluent (P = .002). Total RNA levels were undetectable after exposure to epoprostenol and arginine, indicating complete cell death and lysis (P = .015). Ciliary beat frequency ceased after 30 s of exposure to epoprostenol and glycine (P = .008). There was no difference between cells exposed to epoprostenol and those exposed only to diluent. CONCLUSIONS: Exposure to intravenous formulations of epoprostenol in glycine and arginine caused increased cell death and ciliary cessation in bronchial epithelial cells. These findings suggest that undesired local effects may occur when these compounds are delivered as inhaled aerosols to patients.
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    A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects
    (American Association for Respiratory Care (AARC), 2020-09-21) Davis, Michael D.; Clemente, Tatiana M.; Giddings, Olivia K.; Ross, Kristie; Cunningham, Rebekah S.; Smith, Laura; Simpson, Edward; Liu, Yunlong; Kloepfer, Kirsten; Ramsey, I. Scott; Zhao, Yi; Robinson, Christopher M.; Gilk, Stacey D.; Gaston, Benjamin; Pediatrics, School of Medicine
    Background: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense and worsens airway inflammation. Inhaled Optate is designed to safely to raise airway surface pH and is well-tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. Methods: Here, we grew primary normal human airway epithelial (NHAE) cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether it would prevent viral infection and replication. Cells were pre-treated with Optate or placebo prior to infection (MOI of 0.1) and viral replication was determined by plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. Results: Optate almost completely prevented viral replication at each time point between 24 and 120 hours, relative to placebo, both by plaque assay and by N protein expression (p < 0.001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs or oxygenation. Conclusions: Inhaled Optate may be well-suited for a clinical trial in patients with a pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regards to pH, isotonicity and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.
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    Using Predictive Scoring Systems for Asthma Exacerbations Could Help Safely Conserve Resources During the COVID-19 Pandemic
    (American Association for Respiratory Care (AARC), 2020-09-01) Davis, Michael D.; Pediatrics, School of Medicine
    Further studies evaluating the usefulness of mPIS for predicting outcomes in pediatric patients who are experiencing asthma exacerbations would also be beneficial during these times. These benefits could easily expand beyond the pediatric asthma population to all age groups and other patients with exacerbation-prone respiratory diseases, such as cystic fibrosis and COPD. These and other predictive tools could help us safely conserve respiratory health care resources and give the best care we can to our patients as we continue to adapt to the pandemic