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

Malone, Robert E.; Tisdall, Philip; Fremont-Smith, Philip; Liu, Yongfeng; Huang, Xi‐Ping; White, Kris M.; Miorin, Lisa; Moreno, Elena; Alon, Assaf; Delaforge, Elise; Hennecker, Christopher; Wang, Guanyu; Pottel, Joshua; Smith, Nora; Hall, Julie M.; Shapiro, Gideon; Mittermaier, Anthony; Kruse, Andrew C.; Garcı́a-Sastre, Adolfo; Roth, Bryan L.; Glasspool-Malone, Jill; Ricke, Darrell O.

doi:10.21203/rs.3.rs-30934/v3

Cited by 4 publications

(3 citation statements)

References 99 publications

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“…Famotidine, a specific histamine-type 2 receptor antagonist that suppresses gastric acid production, has been proposed as an attractive candidate for COVID-19 treatment, based on the potential role that the histamine pathway may play in immune modulation 1 and its long history of safe use 2 .…”

Section: Introductionmentioning

confidence: 99%

“…SARS-CoV-2 virus infection can induce histamine release via aberrant mast cell activation. The pathological histamine release has a potential to provoke the excessive synthesis of proinflammatory cytokines that may lead to acute respiratory distress syndrome observed in patients with severe COVID-19 1 . The finding of lower levels of inflammatory markers (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

Shoaibi

Fortin

Weinstein

et al. 2020

Preprint

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Background: Famotidine has been posited as a potential treatment for COVID-19. We compared the incidence of COVID-19 outcomes (i.e., death; and death or intensive services use) among hospitalized famotidine users vs. proton pump inhibitors (PPIs) users, hydroxychloroquine users or famotidine non-users separately. Methods: We constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. Study population were COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing one of the three drugs on the day of admission. The famotidine non-user group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient prior to or on the day of admission. Time-at-risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score (PS) model through large-scale regularized logistic regression. The outcome was modeled using a survival model. Results: We identified 2193 users of PPI, 5950 users of the hydroxychloroquine, 1816 users of famotidine and 26,820 non-famotidine users. After PS stratification, the hazard ratios for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18); vs PPIs: HR 1.14 (0.94-1.39); vs hydroxychloroquine:1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use. Conclusion: We found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared to those who did not or compared to PPI or hydroxychloroquine users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

Shoaibi

Fortin

Weinstein

et al. 2020

Preprint

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“…This shows that suppression of inflammation due to mast cells can be an effective treatment for the prevention of SARS-CoV-2 infection and various drugs are considered for this. It was observed that Famotidine can prevent the SARS-CoV-2 infection by targeting the activity of histamine receptor H 2 [ 52 ]. Mast cells stabilizers were also considered which can control the serum TNF levels [ 140 ].…”

Section: Immunopathogenesis Of Covid-19mentioning

confidence: 99%

COVID-19: Immunology, Immunopathogenesis and Potential Therapies

Bhardwaj

Sapra

Saini

et al. 2021

International Reviews of Immunology

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The Coronavirus Disease-2019 (COVID-19) imposed public health emergency and affected millions of people around the globe. As of January 2021, 100 million confirmed cases of COVID-19 along with more than 2 million deaths were reported worldwide. SARS-CoV-2 infection causes excessive production of pro-inflammatory cytokines thereby leading to the development of “Cytokine Storm Syndrome.” This condition results in uncontrollable inflammation that further imposes multiple-organ-failure eventually leading to death. SARS-CoV-2 induces unrestrained innate immune response and impairs adaptive immune responses thereby causing tissue damage. Thus, understanding the foremost features and evolution of innate and adaptive immunity to SARS-CoV-2 is crucial in anticipating COVID-19 outcomes and in developing effective strategies to control the viral spread. In the present review, we exhaustively discuss the sequential key immunological events that occur during SARS-CoV-2 infection and are involved in the immunopathogenesis of COVID-19. In addition to this, we also highlight various therapeutic options already in use such as immunosuppressive drugs, plasma therapy and intravenous immunoglobulins along with various novel potent therapeutic options that should be considered in managing COVID-19 infection such as traditional medicines and probiotics.

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Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

Yang

George

Thompson

et al. 2022

Mol Med

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Background Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. Methods The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Results Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. Conclusions These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

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

Cited by 4 publications

References 99 publications

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

COVID-19: Immunology, Immunopathogenesis and Potential Therapies

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

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