ArticleMolecular medicine (Cambridge, Mass.)2022
Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.
Article in Molecular medicine (Cambridge, Mass.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Vagus nerve as the hub in peripheral immune-inflammatory response: implications for related therapeutic drugs.Molecular biology reports · 2026Review
- Development of a hybrid tablet-integrated superporous hydrogel for gastro-retentive delivery of famotidine.PloS one · 2026Article
- Pathogenic Crosstalk Between the Peripheral and Central Nervous System in Rheumatic Diseases: Emerging Evidence and Clinical Implications.International journal of molecular sciences · 2025Review
- Neuro-immune interactions in coronary microvascular disease: mechanisms and therapeutic prospect.Frontiers in immunology · 2025Review
- Therapeutic Potential Effect of Glycogen Synthase Kinase 3 Beta (GSK-3β) Inhibitors in Parkinson Disease: Exploring an Overlooked Avenue.Molecular neurobiology · 2024Review
- Combination of H1 and H2 Histamine Receptor Antagonists: Current Knowledge and Perspectives of a Classic Treatment Strategy.Life (Basel, Switzerland) · 2024Review
- Overlapping conditions in Long COVID at a multisite academic center.Frontiers in neurology · 2024Article
- Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.International journal of molecular sciences · 2023Article
- Histamine-2 Receptor Antagonists and Proton Pump Inhibitors Are Associated With Reduced Risk of SARS-CoV-2 Infection Without Comorbidities Including Diabetes, Hypertension, and Dyslipidemia: A Propensity Score-Matched Nationwide Cohort Study.Journal of Korean medical science · 2023Article
- Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.Naunyn-Schmiedeberg's archives of pharmacology · 2023Review
- SARS-CoV-2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck.ACS chemical neuroscience · 2023Article
- Bidirectional crosstalk between the peripheral nervous system and lymphoid tissues/organs.Frontiers in immunology · 2023Review
- Lots of long COVID treatment leads, but few are proven.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics.Bioengineering (Basel, Switzerland) · 2022Article
Corrections and comments
- Update of
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundSevere 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.
methodsThe 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.
resultsFamotidine 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.
conclusionsThese 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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.