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Item 2020 Year in Review: Pharmacologic Treatments for COVID-19(2021-04) Saunders, Jessica L.; Davis, Michael D.; Pediatrics, School of MedicineCOVID-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.Item A Case Series of Persistent SARS-CoV-2 Infection in Immunocompromised Pediatric Patients(Hindawi, 2023-05-16) Ahmed, Mohamed Y.; Taylor, Jane B.; Aneja, Rajesh K.; Wang, Qian; Williams, John V.; Pediatrics, School of MedicineDiagnosis and management of SARS-CoV-2 infection in immunocompromised patients are extremely challenging. These patients can have atypical clinical courses, and there is a paucity of data regarding clinical features, diagnostic findings, and the safety and efficacy of available therapeutic agents used to treat COVID-19 in these patients. In this case series, we report atypical COVID-19 presentations in 4 immunocompromised pediatric patients who were admitted with acute respiratory failure after an initial diagnosis of COVID-19 a few weeks earlier. All patients included in this cohort showed persistent worsening respiratory symptoms for several weeks before hospital presentation. While they manifested common COVID-19 sequelae, they also had rare COVID-19-related pathognomonic and radiographic features developed along their hospital course. Multiple therapeutic agents were used in their COVID-19 management, including corticosteroids, remdesivir, and monoclonal antibodies. All three patients who have received concurrent therapy with remdesivir, hydrocortisone, and monoclonal antibodies survived, and only one patient died as a direct complication of COVID-19 ARDS with secondary pulmonary mucormycosis. Our outcomes suggest the potential benefit of remdesivir use in combination with hydrocortisone and monoclonal antibodies in the management of severe COVID-19 ARDS in this group, as well as the importance of close surveillance and early administration of broad empirical antimicrobial and antifungal coverage if clinically indicated in this high-risk population.Item A Description of COVID-19-Directed Therapy in Children Admitted to US Intensive Care Units 2020(Oxford University Press, 2022) Schuster, Jennifer E.; Halasa, Natasha B.; Nakamura, Mari; Levy, Emily R.; Fitzgerald, Julie C.; Young, Cameron C.; Newhams, Margaret M.; Bourgeois, Florence; Staat, Mary A.; Hobbs, Charlotte V.; Dapul, Heda; Feldstein, Leora R.; Jackson, Ashley M.; Mack, Elizabeth H.; Walker, Tracie C.; Maddux, Aline B.; Spinella, Philip C.; Loftis, Laura L.; Kong, Michele; Rowan, Courtney M.; Bembea, Melania M.; McLaughlin, Gwenn E.; Hall, Mark W.; Babbitt, Christopher J.; Maamari, Mia; Zinter, Matt S.; Cvijanovich, Natalie Z.; Michelson, Kelly N.; Gertz, Shira J.; Carroll, Christopher L.; Thomas, Neal J.; Giuliano, John S., Jr.; Singh, Aalok R.; Hymes, Saul R.; Schwarz, Adam J.; McGuire, John K.; Nofziger, Ryan A.; Flori, Heidi R.; Clouser, Katharine N.; Wellnitz, Kari; Cullimore, Melissa L.; Hume, Janet R.; Patel, Manish; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineBackground: It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods: Between March 15, 2020 and December 27, 2020, children <18 years of age in the ICU/SDU with acute COVID-19 at 48 pediatric hospitals in the United States were identified. Demographics, laboratory values, and clinical course were compared in children who did and did not receive COVID-19-directed therapies. Trends in COVID-19-directed therapies over time were evaluated. Results: Of 424 children in the ICU/SDU, 235 (55%) received COVID-19-directed therapies. Children who received COVID-19-directed therapies were older than those who did not receive COVID-19-directed therapies (13.3 [5.6-16.2] vs 9.8 [0.65-15.9] years), more had underlying medical conditions (188 [80%] vs 104 [55%]; difference = 25% [95% CI: 16% to 34%]), more received respiratory support (206 [88%] vs 71 [38%]; difference = 50% [95% CI: 34% to 56%]), and more died (8 [3.4%] vs 0). Of the 235 children receiving COVID-19-directed therapies, 172 (73%) received systemic steroids and 150 (64%) received remdesivir, with rising remdesivir use over the study period (14% in March/April to 57% November/December). Conclusion: Despite the lack of pediatric data evaluating treatments for COVID-19 in critically ill children, more than half of children requiring intensive or high acuity care received COVID-19-directed therapies.Item Development and validation of a paper spray mass spectrometry method for the rapid quantitation of remdesivir and its active metabolite, GS-441524, in human plasma(Elsevier, 2022-08) Skaggs, Christine; Zimmerman, Hannah; Manicke, Nicholas; Kirkpatrick, Lindsey; Chemistry and Chemical Biology, School of ScienceIntroduction Remdesivir (GS-5734) is a nucleoside analog prodrug with antiviral activity against several single-stranded RNA viruses, including the novel severe respiratory distress syndrome virus 2 (SARS-CoV-2). It is currently the only FDA-approved antiviral agent for the treatment of individuals with COVID-19 caused by SARS-CoV-2. However, remdesivir pharmacokinetics/pharmacodynamics (PK/PD) and toxicity data in humans are extremely limited. It is imperative that precise analytical methods for the quantification of remdesivir and its active metabolite, GS-441524, are developed for use in further studies. We report, herein, the first validated anti-viral paper spray-mass spectrometry (PS-MS/MS) assay for the quantification of remdesivir and GS-441524 in human plasma. We seek to highlight the utility of PS-MS/MS technology and automation advancements for its potential future use in clinical research and the clinical laboratory setting. Methods Calibration curves for remdesivir and GS-441524 were created utilizing seven plasma-based calibrants of varying concentrations and two isotopic internal standards of set concentrations. Four plasma-based quality controls were prepared in a similar fashion to the calibrants and utilized for validation. No sample preparation was needed. Briefly, plasma samples were spotted on a paper substrate contained within pre-manufactured plastic cassette plates, and the spots were dried for 1 h. The samples were then analyzed directly for 1.2 min utilizing PS-MS/MS. All experiments were performed on a Thermo Scientific Altis triple quadrupole mass spectrometer utilizing automated technology. Results The calibration ranges were 20 – 5000 and 100 – 25000 ng/mL for remdesivir and GS-441524, respectively. The calibration curves for the two antiviral agents showed excellent linearity (average R2 = 0.99–1.00). The inter- and intra-day precision (%CV) across validation runs at four QC levels for both analytes was less than 11.2% and accuracy (%bias) was within ± 15%. Plasma calibrant stability was assessed and degradation for the 4 °C and room temperature samples were seen beginning at Day 7. The plasma calibrants were stable at −20 °C. No interference, matrix effects, or carryover was discovered during the validation process. Conclusions PS-MS/MS represents a useful methodology for rapidly quantifying remdesivir and GS-441524, which may be useful for clinical PK/PD, therapeutic drug monitoring (TDM), and toxicity assessment, particularly during the current COVID-19 pandemic and future viral outbreaks.Item The Effect of Remdesivir and Convalescent Plasma in Severe COVID-19 in Pregnancy(ClinMed International Library, 2021-05-31) Elantably, Ahmed; Elantably, Dina; Ashraf, Usman; Medicine, School of MedicineThere are limited data regarding treatment options for pregnant women with severe coronavirus disease 2019 (COVID-19). However, the use of convalescent plasma therapy and remdesivir in was reported to be successful in the management of a critically ill obstetric patient with novel coronavirus 2019 infectionItem Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2(MDPI, 2022-03-14) Gianlupi, Juliano Ferrari; Mapder, Tarunendu; Sego, T.J.; Sluka, James P.; Quinney, Sara K.; Craig, Morgan; Stratford, Robert E., Jr.; Glazier, James A.; Medicine, School of MedicineWe extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism.Item Remdesivir as a possible therapeutic option for the COVID-19(Elsevier, 2020) Al-Tawfiq, Jaffar A.; Al-Homoud, Ali H.; Memish, Ziad A.; Medicine, School of Medicine