COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

Robert W Malone, Philip Tisdall, Philip Fremont-Smith, Yongfeng Liu, Xi-Ping Huang, Kris M White, Lisa Miorin, Elena Moreno, Assaf Alon, Elise Delaforge, Christopher D Hennecker, Guanyu Wang, Joshua Pottel, Robert V Blair, Chad J Roy, Nora Smith, Julie M Hall, Kevin M Tomera, Gideon Shapiro, Anthony Mittermaier, Andrew C Kruse, Adolfo García-Sastre, Bryan L Roth, Jill Glasspool-Malone, Darrell O Ricke, Robert W Malone, Philip Tisdall, Philip Fremont-Smith, Yongfeng Liu, Xi-Ping Huang, Kris M White, Lisa Miorin, Elena Moreno, Assaf Alon, Elise Delaforge, Christopher D Hennecker, Guanyu Wang, Joshua Pottel, Robert V Blair, Chad J Roy, Nora Smith, Julie M Hall, Kevin M Tomera, Gideon Shapiro, Anthony Mittermaier, Andrew C Kruse, Adolfo García-Sastre, Bryan L Roth, Jill Glasspool-Malone, Darrell O Ricke

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.

Keywords: COVID-19; GPCR (G Protein Coupled Receptors); famotidine (PubChem CID: 3325); histamine (H2) receptor; hyperinflammation state; mast cell activating disorder.

Conflict of interest statement

RM, PT, and GS were employed by the companies RW Malone MD LLC, Medical School Companion LLC, and Pharmorx LLC, respectively. In all three cases, their contributions to the work described were voluntary and uncompensated. By joint agreement, no patent rights relating to these findings have been asserted by any of the authors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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.

Figures

FIGURE 1
FIGURE 1
Cleavage of ISG15 C-terminal 8 amino acids by SARS-CoV-2 PLpro purified from E. coli. ISG15 was incubated with SARS-CoV-2 PLpro (lanes 3–6). SARS-CoV-2 PLpro was present at 4 nM, ISG15 was present at 10 µM. For lane 4 to 6, famotidine was present at 100 µM, 10 µM and 1 µM respectively. Control was without enzyme (lane 2). Proteins were resolved by 15% SDS-PAGE and revealed by Coomassie blue staining. The molecular weights of the marker proteins are indicated on the left of the gel.
FIGURE 2
FIGURE 2
Famotidine does not directly inhibit SARS-CoV-2 infection. To assess the possibility that famotidine may inhibit SARS-CoV-2 infection by other routes, a Vero E6 cell-based assay was performed to compare median tissue culture infectious doses (TCID50/mL) of famotidine, remdesivir, and hydroxychloroquine. Vero E6 cells were cultured and infected as described in methods and scored for presence or absence of infection using the surrogate of an immunohistochemical stain for cell-associated SARS-CoV-2 NP protein as scored by imaging cytometer. Non-specific cytotoxicity (inverse of viability) was assessed using an MTT assay. As appropriate, infected supernatants were assayed for infectious viral titer using the TCID50 method. Results are displayed as % inhibition of the viral infection Vero E6 cells as a function of tested pharmaceutical, % infected cell viability, pharmaceutical agent concentration necessary to achieve 50% or 90% replication inhibition (IC50, IC90 respectively), and pharmaceutical agent concentration required to yield 10% or 50% reduction in cell viability (CC10, CC50).
FIGURE 3
FIGURE 3
Competition binding curves of Famotidine (blue circles), Cimetidine (red squares), and PB-28 (green triangle), a potent sigma receptor ligand as positive control. (A) [3H](+)-pentazocine competition curves in Expi293 membranes expressing sigma-1. (B) [3H]DTG competition curves in Expi293 membranes expressing sigma-2 (TMEM97).
FIGURE 4
FIGURE 4
Famotidine and cimetidine activity on histamine receptors. Experiments performed in duplicate. (A) Competitive binding dose-response curves for famotidine and cimetidine on four histamine receptors with reference compounds. (B) The partial agonist, famotidine, shows antagonist activity of H2 in the presence of potent endogenous agonist, histamine. (C) Inverse agonism of famotidine and cimetidine on H2, whereas histamine stimulated cAMP production by 20-fold of basal (N = 2). (D) Arrestin recruitment by famotidine (left) and cimetidine (right) upon interaction with histamine receptors.
FIGURE 5
FIGURE 5
Screen for activation of 318 receptors of the GPCR-ome. To test whether famotidine may act via other G-coupled protein receptors (GPCRs) in addition to its activity as an inverse agonist for the histamine H2 receptor, a screening assay method was applied to detect potential agonist activity of famotidine (10 microM final) when interacting with each of the 318 known human GPCRs. Prior surveys with other pharmaceuticals have defined the baseline for non-specific signal in this assay at 3x greater than the corresponding basal signal. GPCRs meeting the screening criteria of >3x baseline are listed. None of these screening signals were verified in follow up studies, yielding the conclusion that famotidine has no agonist activity for other human GPCRs.
FIGURE 6
FIGURE 6
Infiltration of mast cells into the pulmonary parenchyma of SARS-CoV-2 infected African Green monkeys (AGMs). 20× magnification. Toluidine blue stain. RA: right anterior; RM: right middle; RI: right intermediate; RL: right lower; LL: left lower.
FIGURE 7
FIGURE 7
ase Study JM: CXR and Timeline. Famotidine (60 mg PO tid) was started on Day 8 from start of symptoms. It was continued for 30 days. The anosmia and ageusia are still present at Day 50.
FIGURE 8
FIGURE 8
Lung alveolus cell interactions and gas exchange. Schematic diagram illustrating relevant cellular and tissue microanatomy of the pulmonary alveolus. Pulmonary edema results from loss of a regulation of fluid transfer that occurs at several levels in the alveolus, including disrupted capillary wall components, surfactant, Type I and II pneumocytes, as well as the pulmonary pericytes which are a histamine-responsive contractile cell which both synthesize the endothelial basement membrane and regulate blood flow in the precapillary arteriole, the capillary and the postcapillary venule via contraction and relaxation response to histamine and other signaling molecules.
FIGURE 9
FIGURE 9
Human single cell lung gene expression normalized to transcripts per million (TPM) from LunGENS web portal (Du et al., 2015). Single cell lung gene expression patterns from the Dropseq PND1 experiment for angiotensin-converting enzyme 2 (ACE2: black), transmembrane protease, serine 2 (TMPRSS2; orange), and histamine receptors H1 (blue), H2 (green), and H4 (yellow).
FIGURE 10
FIGURE 10
Lung pathology of early COVID-19. Early COVID-19 pulmonary histopathology, illustrating an atypical viral pathology pattern of interstitial and alveolar edema together with alveolar septae which retain normal architecture. Atypical for viral pneumonia, this resection from early in the course of COVID-19 disease lacks inflammation, and the accumulated fluid appears to be a transudate.
FIGURE 11
FIGURE 11
Micro-thrombosis in the pulmonary microvasculature in COVID-19 at autopsy (Magro et al., 2020). There is widening of the alveolar septae by extensive fibrinous occlusion of capillaries (open black arrows). There is alveolar space edema with red blood cell extravasation. Septae show a mild mononuclear infiltrate. Alveolar edema shows neutrophils in proportion to the blood.
FIGURE 12
FIGURE 12
The Natural History of COVID-19. Modified from Oudkerk et al. (2020).

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