Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.

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.

Pharmaceutical Cocrystals of Famotidine: Structural and Biopharmaceutical Evaluation.

Famotidine (FMT) an anti-ulcer drug, recently being repurposed in COVID-19 treatment, suffers from poor aqueous solubility and restricted bioavailability (<40%). To conquer the limitations endured by this potent anti-ulcer agent, two novel 1:1 cocrystals of FMT, namely Famotidine-Sorbic Acid (FSOR) and Famotidine-Syringic Acid (FSY), were synthesized using the liquid-assisted grinding method and evaluated. Distinct DSC thermograms and PXRD patterns advocate the existence of a new crystalline form. The unique organization of the hydrogen-bonded network, in the prepared cocrystals, is inferred by variation in characteristic vibrational frequencies in FT-IR spectroscopic analysis and supported by crystal structure determination. FSOR cocrystallize in orthorhombic PNCB and FSY in triclinic P 1 crystal system. Further, a significant amplification in the solubility (9 to 5-fold) and dissolution (8 to 5-fold) of FMT in cocrystalline form, with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher) and relative bioavailability (approx. 200% to 135%). This is associated with the remarkable increment in their anti-ulcer and anti-oxidant potential. Thus, the study illustrates that cocrystallization as a worthy approach in the efficient delivery of neutral compounds suffering from inadequate solubility crisis.

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients.

BACKGROUND: Maintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19. METHODS: Using claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020. RESULTS: Up to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters. CONCLUSION: Maintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.

The association between famotidine and in-hospital mortality of patients with COVID-19.

Famotidine has been considered to be a potential treatment for COVID-19 but the current data is conflicting. This retrospective study was conducted by utilizing data of 9565 COVID-19 hospitalized patients. Patients treated with and without famotidine were matched by propensity score using a 1:1 matching scheme. A total of 1593 patients (16.7%) received famotidine. In-hospital mortality was similar in patients treated with and without famotidine in the propensity-matched cohorts (28.3% vs. 28.2%, p = 0.97), which remains similar irrespective of severity or concomitant treatment by steroids. Famotidine treatment was not associated with a lower risk of in-hospital mortality of COVID-19 patients.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

OBJECTIVE: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. DESIGN: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory). RESULTS: Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms. CONCLUSIONS: Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Immunomodulatory agents for COVID-19 treatment: possible mechanism of action and immunopathology features.

The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.

Therapeutic Status of Famotidine in COVID-19 Patients: A Review.

The novel coronavirus, SARS-coV-2, which emerged in Wuhan in November 2019, has increasingly spread worldwide. More than 272 million cases of infection have been identified. COVID-19 has affected 223 countries and territories across the world. The principal target of the SARS-CoV-2 infection is the lower respiratory tract. Series of moderate to non-specific severe clinical signs and symptoms appear two to fourteen days after exposure to SARS-CoV-2 in patients with COVID-19 disease, including cough, breath deficiency, and at least two of these symptoms: headache, fever, chills, repeated rigor, myalgia, oropharyngitis, anosmia, and ageusia. No therapeutic agents have been validated to have substantial efficacy in the clinical care of COVID-19 patients in large-scale trials, despite worsening infected rates of COVID-19. Early clinical evidence from many sources suggests that treatment with famotidine may decrease COVID-19-related morbidity and mortality. The mechanism by which famotidine could improve the outcomes of COVID-19 is currently unknown. A more recent postulated mechanism is that the effect of famotidine is mediated by histamine-2 receptor antagonism or inverse agonism, inferring that the SARS-CoV-2, resulting in COVID-19 infection, at least partially leads to the abnormal release of histamine and perhaps dysfunction of mast cells.

Effect of famotidine on hospitalized patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: Famotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with Coronavirus disease 2019 (COVID-19). The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19. METHODS: Five databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome (e.g. rate of death, intubation, or intensive care unit admissions) and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated. RESULTS: Four studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 (95% CI: 0.35, 1.16). Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death-HR 0.67 (95% CI: 0.26, 1.73) and OR 0.79 (95% CI: 0.19, 3.34). Heterogeneity ranged from 83.69% to 88.07%. CONCLUSION: Based on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further randomized controlled trials (RCTs) may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease.

Famotidine's Possible Cutaneous Rash in COVID-19 Patients: An Adverse Effect Case Series.

BACKGROUND: Various cutaneous manifestations have been observed in patients with COVID-19 infection. However, the side effects on skin of the medications used for COVID-19, such as famotidine, have not been studied. OBJECTIVE: This case series aims to present challenges in defining cutaneous manifestations of famotidine in the context of COVID-19. CASE PRESENTATION: We identified patients from Imam Khomeini hospital complex who were admitted to the ward due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), were taking famotidine and having cutaneous rash. Clinical data were obtained through observation and intervention. DISCUSSION: We found 4 SARS-CoV-2 patients with cutaneous manifestations. The mean (±SD) age of the patients was 57±2 years, 3 patients were men, and their COVID-19 symptoms appeared 10±3 days before admission. The most common symptoms were cough and shortness of breath. All the patients were admitted for hypoxemic respiratory failure. Patients received famotidine for gastrointestinal prophylaxis, and all 4 patients developed Acral macular mountainous skin lesions in the upper and lower extremities, then we discontinued famotidine and lesions were recovered completely in all patients. CONCLUSION: These cases prompted us to inform clinicians about cutaneous complications of famotidine in COVID-19 patients.

Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection.

Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19.