TY - JOUR
T1 - COVID-19
T2 - Famotidine, Histamine, Mast Cells, and Mechanisms
AU - Malone, Robert W.
AU - Tisdall, Philip
AU - Fremont-Smith, Philip
AU - Liu, Yongfeng
AU - Huang, Xi Ping
AU - White, Kris M.
AU - Miorin, Lisa
AU - Moreno, Elena
AU - Alon, Assaf
AU - Delaforge, Elise
AU - Hennecker, Christopher D.
AU - Wang, Guanyu
AU - Pottel, Joshua
AU - Blair, Robert V.
AU - Roy, Chad J.
AU - Smith, Nora
AU - Hall, Julie M.
AU - Tomera, Kevin M.
AU - Shapiro, Gideon
AU - Mittermaier, Anthony
AU - Kruse, Andrew C.
AU - García-Sastre, Adolfo
AU - Roth, Bryan L.
AU - Glasspool-Malone, Jill
AU - Ricke, Darrell O.
N1 - Funding Information:
The authors acknowledge the Department of Defense (DoD), Defense Threat Reduction Agency (DTRA), and the Joint Science and Technology Office (JSTO) of the Chemical and Biological Defense Program (CBDP) for funding under the Discovery of Medical countermeasures Against Novel Entities (DOMANE) initiative. This work has also benefitted from advice, guidance, information and comments provided by Drs. Revell Phillips, Howard Haimes, David Hone, and Roland Seifert. We appreciate the valuable input provided by Dr Frank Weichold of the Office of Regulatory Science and Innovation (ORSI), Office of the Chief Scientist (OCS), Office of the Commissioner (OC), FDA/HHS, and Dr. Lawrence Callahan of the Office of Health Informatics, Office of the Chief Scientist (OCS), Office of the Commissioner (OC), FDA/HHS. We also thank Dr Anton Yuryev from Elsevier for his assistance in literature mining and reconstruction of the histamine signaling model. D.R. gratefully acknowledges the support of the MIT SuperCloud team. In the interests of expediting COVID-19 related scientific communications, the initial version of this manuscript was made available via the Research Square preprint server 23 May 2020 as DOI 10.21203/rs.3.rs-30934/v1.
Funding Information:
This material is based upon work supported under Air Force Contract No. FA8702-15-D-0001. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the U.S. Air Force. Funding was also provided by grants from the Defense Advanced Research Projects Agency HR0011-19-2-0020 (to A. G-S.); by CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C) and by supplements to NIAID grant U19AI135972 and DoD grant W81XWH-20-1-0270 to A.G.-S.
Publisher Copyright:
© Copyright © 2021 Malone, Tisdall, Fremont-Smith, Liu, Huang, White, Miorin, Moreno, Alon, Delaforge, Hennecker, Wang, Pottel, Blair, Roy, Smith, Hall, Tomera, Shapiro, Mittermaier, Kruse, García-Sastre, Roth, Glasspool-Malone and Ricke.
PY - 2021/3/23
Y1 - 2021/3/23
N2 - 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.
AB - 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.
KW - COVID-19
KW - GPCR (G Protein Coupled Receptors)
KW - famotidine (PubChem CID: 3325)
KW - histamine (H2) receptor
KW - hyperinflammation state
KW - mast cell activating disorder
UR - http://www.scopus.com/inward/record.url?scp=85103787204&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.633680
DO - 10.3389/fphar.2021.633680
M3 - Article
AN - SCOPUS:85103787204
SN - 1663-9812
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 633680
ER -