AUTHOR=Malone Robert W. , Tisdall Philip , Fremont-Smith Philip , Liu Yongfeng , Huang Xi-Ping , White Kris M. , Miorin Lisa , Moreno Elena , Alon Assaf , Delaforge Elise , Hennecker Christopher D. , Wang Guanyu , Pottel Joshua , Blair Robert V. , Roy Chad J. , Smith Nora , Hall Julie M. , Tomera Kevin M , Shapiro Gideon , Mittermaier Anthony , Kruse Andrew C. , García-Sastre Adolfo , Roth Bryan L. , Glasspool-Malone Jill , Ricke Darrell O. TITLE=COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.633680 DOI=10.3389/fphar.2021.633680 ISSN=1663-9812 ABSTRACT=

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.