key: cord-315388-8sv00zqz
authors: Ghosh, Ritwik; Chatterjee, Subhankar; Dubey, Souvik; Lavie, Carl J.
title: Famotidine against SARS-CoV2: A hope or hype?
date: 2020-06-06
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.027
sha: 
doc_id: 315388
cord_uid: 8sv00zqz

nan

Title: Famotidine Against SARS-CoV2: A Hope or Hype?

To the Editor: 2019-coronavirus disease (COVID-19) is globe-trotting and thousands of researchers and stakeholders are spending repose-less days and sleepless nights in search of effective therapies. Currently, the entire research sphere is dealing with a pandemic triad: hypes, hypotheses and hopes. In the absence of a specific anti-viral or vaccine against the novel severe acute respiratory syndrome-corona virus (SARS-CoV2), "repurposing" of old time-tested medications are being tried. Famotidine is the most recent addition to this trend, creating a lot of hustle among the public and stirring criticism in the scientific arena [1] . A phase 3 trial titled "Multi-site Adaptive Trials Using Hydroxychloroquine for COVID-19" (MATCH)

[NCT04370262] has already been launched inconspicuously [1, 2] . This randomized, doubleblind clinical trial (n=1170) has been designed to compare clinical outcomes between two armsviz. one receiving hydroxychloroquine (HCQ) 200mg plus famotidine (360mg/day intravenous) and the other receiving HCQ plus placebo. Famotidine will be administered for a maximum of 14 days or to hospital discharge, whichever will come earlier [2] . In this briefing we will try to enlighten some facts regarding whether it is possible for famotidine to have a beneficial effect in COVID-19 truly or is it just hitting the castle in a Don Quixotic way.

Antithetical to the initial belief, SARS-CoV2 is a multi-systemic illness with an array of manifestations protean in disease progression, severity and outcome. The key pathogenesis revolves around the "cytokine storm" occurring due to disruption of delicate balance between pro-inflammatory and anti-inflammatory mediators and a depressed immune system [3] . The most climacteric role for resolution of viral infection will be imparted upon the complex interplay between innate and adaptive immune system in the host. While an irrefutable pathogenesis and an efficacious vaccine is still a dream, attenuation of perpetual hyperinflammation is the bull's eye at this moment.

It is not the maiden time that the scientists have decided to "repurpose" the drug famotidine, an age-old antacid, to combat a viral disease. The effects of histamine on different substrates of immune system and immunomodulatory effects of H 2 receptor antagonists (H 2 RA) are wellrecognized [4] . Through binding with H 2 R and modulating the effector pathways mediated by protein kinase A (PKA), famotidine potentially regulates innate and adaptive immune responses.

and proliferation, mast cell degranulation and dendritic cell (DC) response [5] . Innate immune system function is potentially boosted by stimulatory effects of H2RA on its effectors i.e. macrophages, neutrophils, monocytes, DCs, natural killer (NK) cells, NK-T cells and the adaptive system is filliped by activation of helper T cells (Th1, Th2, Th17), regulatory T cells, cytotoxic CD8+T cells [6] . It has been documented that famotidine completely demolishes H2R mediated negative effects on cytokine production, especially tumor necrosis factor (TNF)-α, interferon-γ) [7] , on lipopolysaccharide-induced TNF-α production, B7-1 expression on monocytes [8] and also curtails the inhibitory effects of histamine on production of Th-1 mediated cytokine release [9] . H 2 RA has been attempted in many other conditions, like cancer, viral infection, bone remodeling, burn management, and vaccine potency-enhancer, among other conditions, with mixed results [6] . Previously H2RA has been used with some success against human immunodeficiency virus [10, 11] , human papilloma virus [12] , herpes simplex virus [13] , Epstein-Burr virus [14] , chronic hepatitis B infection [15] . Ranitidine Bismuth citrate has been shown to inhibit the nucleoside triphosphate hydrolase and DNA unwinding activities of the SARS-CoV helicase and hinders its replication [16] .

Although the above mechanistic explanations sound reasonable, the real outcomes in clinical trials might be completely futile as evidenced previously [11] . The unpublished Chinese data which received publicity in the press claiming that the mortality rate for COVID-19 patients on famotidine was 14% compared to 27% for those not on the drug, reported not to be statistically significant [1] .However, before concluding anything from this, one needs to analyze actual complete data along with the confounders. Moreover, scientists' claims of famotidine having anti-protease like effects [1] have not stemmed from any strong published evidence, but rather on the evidence of the negative pharmacokinetic effects of famotidine on protease inhibitors [17] .

The dosage of famotidine being used in the MATCH trial is nearly 10 times greater than the usual dosage employed for severe forms of peptic ulcer diseases. Although famotidine is a timetested and safe drug, excessive inhibition of gastric acid secretion might precipitate pneumonia [18] . Cardiac failure and arrhythmias have also been reported with high doses of intravenous famotidine administration [19] .

Considering its relative cheapness, wide availability and prior experiences as an anti-viral agent, famotidine might usher some hope; however, we must wait for the trial results. Until then hoarding and therapeutic misadventure with this drug must be condemned. 

New York clinical trial quietly tests heartburn remedy against coronavirus

Multi-site Adaptive Trials Using Hydroxycholoroquine for COVID-19 (MATCH)

HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression

Comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients

Histamine receptor 2 modifies dendritic cell responses to microbial ligands

Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases

Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease

Cytokine responses of intraepithelial lymphocytes are regulated by histamine H(2) receptor

Histamine inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production in an intercellular adhesion molecule-1-and B7.1-dependent manner

The effect of histamine type 2 receptor antagonists on human immunodeficiency virus (HIV) replication: identification of a new class of antiviral agents

A placebocontrolled trial of ranitidine in patients with early human immunodeficiency virus infection

Treatment of viral warts with cimetidine: an open-label study

Cimetidine prevents recurrent erythema multiforme major resulting from herpes simplex virus infection

Cimetidine, ranitidine, and Epstein-Barr virus infection

Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8(+) T cell

Bismuth complexes inhibit the SARS coronavirus

Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients

Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis

Complete atrioventricular block and cardiac arrest following intravenous famotidine administration


