Search

While vaccines were being developed, the SARS-CoV-2 pandemic triggered a race to find known drugs that could be quickly repurposed to treat patients. One such candidate was famotidine, which retrospective cohort studies had shown increased survival in hospitalized patients. Computational studies had suggested that famotidine may target early viral proteases; however, ultimately, famotidine was shown not to function as a viral inhibitor. In contrast, we have observed a change in the cellular levels of phospho-tyrosine in A549 lung epithelial cells following treatment with famotidine. This quick change in phosphorylation was due mainly to a dose-dependent increase in cellular production of H 2 O 2 . Notably, these changes in phospho-tyrosine levels were able to affect cell signaling; we detected an increased short- and long-term response to IFNα stimulation. Our results suggest that famotidine can increase the anti-viral state of non-infected cells thereby potentially increasing viral resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicholas K. Tonks reports financial support was provided by National Institute of Health grants CA53840 and DK124907, the CSHL Cancer Centre Support Grant CA45508, the Robertson Research Fund of CSHL, the Don Monti Memorial Research Foundation, theHansen Foundation, and theSimons Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD), a chronic neurodegenerative disease, presents a substantial global health challenge. This study explored the potential therapeutic role of famotidine, a histamine (H2) receptor antagonist, as a glycogen synthase kinase-3β (GSK-3β) inhibitor in the context of AD induced by aluminium chloride (AlCl 3 ) in a rat model. The intricate relationship between GSK-3β dysregulation and AD pathogenesis, particularly in amyloid-β (Aβ) production, formed the basis for investigating famotidine's efficacy. Molecular modelling revealed famotidine's efficient binding to GSK-3β, suggesting inhibitory potential. In behavioural assessments, famotidine-treated groups exhibited dose-dependent improvements in Morris Water Maze, Novel Object Recognition, and Y-Maze tests, comparable to the standard Rivastigmine tartrate group. Biochemical analyses showed that famotidine inhibits acetylcholinesterase, decreases lipid peroxidation, increases antioxidant activity, and mitigates oxidative stress. Moreover, famotidine significantly lowered the levels of GSK-3β, IL-6, and Aβ(1-42). The neuroprotective effects of famotidine were further supported by histopathological analysis. This comprehensive investigation underscores famotidine's potential as a GSK-3β inhibitor, providing insights into its therapeutic impact on AD induced by AlCl 3 . The study offers a promising avenue for repurposing famotidine due to its established safety profile and widespread availability, highlighting its potential in addressing the formidable challenge of AD., Competing Interests: Declaration of Competing Interest All authors does not have any conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Famotidine is a competitive histamine H-receptor antagonist that reduces the formation of stomach acid and is used to treat gastrointestinal disorders associated with acid reflux, gastroesophageal reflux disease, duodenal ulcer, gastric ulcer, and pathological hypersecretory disorders. This study is designed to investigate the possible neuroprotective effects of the ranolazine scopolamine-induced Alzheimer's disease-like feature in a mouse model., Methods: Mice were divided equally into five groups (ten mice per group), including control group and induction group. The mice in the induction group were administered scopolamine 1 mg/kg i.p., once daily for 7 days, to induce features similar to Alzheimer's disease. The mice in the remaining three treatment groups were given tested medications prophylactically for 14 days. After that the induction was carried out with scopolamine 1 mg/kg i.p., once daily, while the tested medication dosages were continued for an additional 7 days. These treatment groups included: the donepezil group (5 mg/kg/day), the famotidine group (40 mg/kg/day) and the combined group with donepezil (5 mg/kg/day) and famotidine (40 mg/kg/day); all were administrated i.p., once daily. Behavioral parameters were assessed, among others with the Y-maze test and novel object recognition test, and the inflammatory cytokines and oxidative stress parameters were assessed as well., Results: Famotidine exhibits significant improvements in behavior and memory, level of oxidative stress parame-ter, and inflammatory cytokines., Conclusions: Famotidine and its combination at prescribed doses in the current study improved learning and memory impairments in mice model of Alzheimer's disease probably via their antioxidant and anti-inflammatory properties confirmed by a significant increase in antioxidant mediator and a significant decrease in oxidative stress marker and inflammatory cytokines.

Background: Acid suppressant drugs (ASDs) are commonly used to decrease gastric acid production, but some evidence exists that ASDs exert immunomodulatory effects. Such an effect has not been investigated in dogs for which ASDs are routinely prescribed., Hypothesis: Compared to naïve subjects, dogs treated with ASDs will exhibit differences in leukocyte ratios after treatment., Animals: Fifty-one dogs with mast cell tumors (MCTs)., Materials and Methods: Dogs with MCT that were either AS naïve or treated with ASDs (i.e., histamine-2-receptor antagonists [H2RA] or proton pump inhibitors [PPI]) were included in this retrospective study. Subjects were categorized into 3 treatment groups (AS naïve, H2RA treated, and PPI treated), and leukocyte ratios (neutrophil:eosinophil, lymphocyte:monocyte, and neutrophil:lymphocyte [NLR]) were calculated before and after treatment. A mixed effects analysis of variance on ranks was used to assess differences in ratios between treatments, between pre- and post-treatment time points, and between pre- and post-time points for each treatment. Concurrent administration of antihistamines, corticosteroids, and chemotherapeutic drugs was assessed as a confounding factor., Results: Famotidine (n = 14/14) and omeprazole (n = 12/12) were the only H2RA and PPI used, respectively. Dogs receiving famotidine had a significant increase in median NLR from pre- to post-treatment (3.429; range, 1.417-15 to 5.631; range, 2.654-92; P < 0.01) compared to PPI treated or AS naïve dogs. No differences existed in chemotherapeutic drug or corticosteroid use between groups., Conclusions: A significant difference in NLR was identified in famotidine treated dogs compared with omeprazole treated or AS naïve dogs., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

This study aims to identify FDA-approved drugs that can target the kappa-opioid receptor (KOR) for the treatment of demyelinating diseases. Demyelinating diseases are characterized by myelin sheath destruction or formation that results in severe neurological dysfunction. Remission of this disease is largely dependent on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLGs) in demyelinating lesions. KOR is an important regulatory protein and drug target for the treatment of demyelinating diseases. However, no drug targeting KOR has been developed due to the long clinical trials for drug discovery. Here, a structure-based virtual screening was applied to identify drugs targeting KOR among 1843 drugs of FDA-approved drug libraries, and famotidine was screen out by its high affinity cooperation with KOR as well as the clinical safety. We discovered that famotidine directly promoted OPC maturation and remyelination using the complementary in vitro and in vivo models. Administration of famotidine was not only effectively enhanced CNS myelinogenesis, but also promoted remyelination. Mechanically speaking, famotidine promoted myelinogenesis or remyelination through KOR/STAT3 signaling pathway. In general, our study provided evidence of new clinical applicability of famotidine for the treatment of demyelinating diseases for which there is currently no effective therapy., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.

Taxifolin (dihydroquercetin) is a flavanonol isolated from various plants and has antioxidant effects. The aim of our study was to macroscopically and biochemically investigate the effects of taxifolin on aspirin-induced oxidative gastric damage in rats and to evaluate them by comparison with those of famotidine. Rats were divided into four drug administration groups: a healthy control group, an aspirin-only group (ASG), a taxifolin + aspirin group (TASG), and a famotidine + aspirin group (FASG). The results revealed that in light of the results that we obtained, 50 mg/kg taxifolin had anti-ulcer effects. At this dose, taxifolin was able to bring COX-1 activities to a level close to those seen in healthy rats with appropriate macroscopic, oxidant/antioxidant, and biochemical parameters. Based on these results, it can be said that taxifolin may be successfully used as a more potent alternative to famotidine, which is the currently accepted treatment for aspirin-induced ulcers.

Objective: Famotidine, an H 2 receptor antagonist (H 2 RA), is mainly prescribed to alleviate the early symptoms of gastritis. Our aim was to explore the possibilities of low-dose esomeprazole as a treatment of gastritis as well as the pharmacodynamic (PD) properties of esomeprazole and famotidine., Materials and Methods: A randomized, multiple-dose, 6-sequence, 3-period crossover study was conducted with a 7-day washout between periods. For each period, the subjects were administered one dose of esomeprazole 10 mg or famotidine 20 mg or esomeprazole 20 mg each day. To evaluate the PDs, the 24-hour gastric pH was recorded after single and multiple doses. The mean percentage of time during which the gastric pH was above 4 was evaluated for PD assessment. To confirm the pharmacokinetic (PK) characteristics of esomeprazole, blood was collected for up to 24 hours after multiple doses., Results: 26 subjects completed the study. Following the multiple doses of esomeprazole 10 mg, esomeprazole 20 mg, and famotidine 20 mg, the mean percentages of time during which the gastric pH was above 4 over the course of 24 hour were 35.77 ± 19.56%, 53.75 ± 20.55%, and 24.48 ± 17.36%, respectively. After multiple doses, the time of peak plasma concentration at steady state (t max,ss ) was 1.00 and 1.25 hours for 10 and 20 mg of esomeprazole, respectively. The geometric mean ratio and its 90% confidence interval of area under the plasma drug concentration-time curve in steady state (AUC T,ss ) and maximum concentration of drug in plasma in steady state (C max,ss ) for esomeprazole 10 mg compared to 20 mg were 0.3654 (0.3381 - 0.3948) and 0.5066 (0.4601 - 0.5579), respectively., Conclusion: The PD parameters of esomeprazole 10 mg were comparable to those of famotidine after multiple doses. These findings provide support for further evaluating the use of 10 mg of esomeprazole as a treatment option for gastritis.

Deglutition aid foods are used to help patients with dysphagia take oral medications. Yoghurt is occasionally used to help swallow medications; however, its influence on pharmacokinetics is poorly understood. Yoghurt made with Lactococcus cremoris subsp. cremoris FC has a characteristic viscous texture that facilitates bolus formation and deglutition due to its metabolite exopolysaccharide. We assessed yoghurt prepared with L. cremoris FC as a food deglutition aid. We performed a dissolution test using famotidine powder mixed with yoghurt and a food thickener. Famotidine dissolution rates without deglutition-assisting foods and with yoghurt or food thickener were 102.3 ± 1.7, 85.7 ± 4.6, and 46.4 ± 1.1% after 15 min, respectively. Next, we orally administered famotidine powder with water, yoghurt, and food thickener to rats and measured plasma famotidine levels. We observed no significant differences between all test groups. The T max of famotidine mixed with a food thickener was significantly lower than that with yoghurt. These results suggest that yoghurt with L. cremoris FC did not remarkably affect the dissolution and pharmacokinetic profiles of famotidine powder. Thus, the administration of famotidine with yoghurt might be a suitable alternative to powder administration as a deglutition aid for patients., (© 2023. The Author(s).)

Histamine-2 receptor antagonists such as famotidine and proton pump inhibitors such as esomeprazole are commonly used in canine MCT disease, but direct effects on dog MCs have not been evaluated. Omeprazole is a proton pump inhibitor which has been demonstrated to cause structural and functional changes to in vitro murine mast cells (MCs). It has not yet been determined if esomeprazole, the commercially available and commonly prescribed S-isomer of omeprazole, has similar effects. Our primary study objective was to evaluate and compare the effects of acid suppressants (esomeprazole and famotidine) on MC ultrastructure, viability, and function in vitro using both healthy and neoplastic MCs. Murine bone marrow derived mast cells (BMMC), human LAD2, and canine C2 and BR cells, were used for these studies, representing a single healthy (i.e., BMMCs) MC model and multiple neoplastic MC models (i.e., LAD2, C2, BR), respectively. The rat basophilic leukemic (RBL-2H3) and canine B cell lymphoma 17-71 cell lines served as granulocytic and agranulocytic control lines for experiments, respectively. The treatment effect of acid suppressants on MC ultrastructure was assessed via both light and transmission electron microscopy. Differences in MC viability was assessed between groups via MTS-based, colorimetric assays and flow cytometry. Degranulation was assessed by quantification of β-hexosaminidase (i.e., LAD2 and RBL-2H3). Esomeprazole-treated MCs of all lines exhibited dramatic time and concentration-dependent alterations in ultrastructure (i.e., increased vacuolization, compromise of cell membrane), increased apoptosis, and altered degranulation responses in comparison to famotidine and vehicle-treated cells. The canine B cell lymphoma cells consistently exhibited either no significant (i.e., cytotoxicity assays) or greatly diminished treatment responses (i.e., apoptosis) compared to MCs. Esomeprazole, but not famotidine, induces significant cytotoxicity, as well as alterations to cell structure and function to multiple lines of in vitro neoplastic MCs. Continued in vitro work investigating the specific mechanisms by which proton pump inhibitors induce these effects, as well as prospective, in vivo work comparing the treatment effects of acid suppressants on canine MCTs, are warranted., Competing Interests: Conflict of Interest None to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Famotidine (FMT) is a competitive histamine-2 (H2) receptor antagonist that inhibits gastric acid secretion for the treatment of Gastroesophageal reflux disease. To study the promoting effect and mechanism of terpenes, including l-menthol, borneol, and geraniol, as chemical enhancers, FMT was used as a model drug. Attenuated total reflectance-Fourier transform IR spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to explore the effects of terpenes on the skin. Hairless mouse skin was mounted on Franz-type diffusion cell, and skin permeation experiment of FMT hydrogel was carried out. The results suggested that the thermodynamic activity influenced the permeability of the drug, and the main mechanism of terpenes to enhance skin permeation of the drug was based on increasing the fluidity of the intercellular lipids. Moreover, it was revealed that l-menthol simultaneously relaxed the packing structure and lamellar structure, whereas geraniol had a great influence on the lamellar structure only. Collectively, all terpenes had a promoting effect on skin permeation of FMT, indicating their potential as chemical enhancers to change the microstructure of stratum corneum and improve the permeation of FMT through the skin, and it has great potential to be used in transdermal formulations of FMT.

This study aimed to evaluate the bitterness of famotidine (FAM) combined with each of three non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen (IBU), flurbiprofen (FLU), and naproxen (NAP), which have potential as fixed-dose combination (FDC) drugs. We evaluated the bitterness of FAM and each NSAID by taste sensor AN0 and C00, respectively. FAM showed high sensor output representing sensitivity to bitterness, whereas three NSAIDs did not show large sensor output, suggesting that the bitterness intensities of three NSAIDs were lower than that of FAM. The bitterness of FAM on sensor AN0 was suppressed in a concentration-dependent manner when mixed with IBU, FLU, or NAP. Among three NSAIDs, IBU most effectively inhibited bitterness on sensor output, and the gustatory sensation test confirmed that adding IBU to FAM reduced the bitterness of FAM in a concentration-dependent manner. MarvinSketch confirmed that the drugs were mostly present in an ionic solution when FAM was mixed with NSAIDs. The 1 H-NMR spectroscopy analysis also revealed the presence of electrostatic interactions between FAM and NSAIDs, suggesting that the electrostatic interaction between FAM and NSAIDs might inhibit the adsorption of FAM on the bitter taste sensor membrane, thereby masking the bitter taste.

The research was performed to study the mechanism whereby histamine affects the profile of plasma lipids. Six groups of ten male rats were received two injections with histamine or its H1- and H2-agonists and antagonists. Histamine caused a significant decrease in the concentrations of triglyceride, total cholesterol, and LDLc, while HDLc had no significant change. The rate of VLDL secretion was 263.6 ± 25.8 mg/h dL in control rats and was inhibited by about 68% in histamine injected rats. These changes have been mimicked by either histamine H1- or H2-agonists. The effects of H1- and H2-agonists were abolished in the presence of cetirizine and famotidine respectively. Histamine causes a significant decrease in serum triglyceride, total, and LDL-cholesterol by both H1 and H2-receptors. The decrease in serum lipids is due to the inhibitory effect of histamine or its agonists on VLDL secretion from the liver.

With the world threatened by a second surge in the number of Coronavirus cases, there is an urgent need for the development of effective treatment for the novel coronavirus (COVID-19). Recently, global attention has turned to preliminary reports on the promising anti-COVID-19 effect of histamine H2-receptor antagonists (H2RAs), most especially Famotidine. Therefore, this study was designed to exploit a possible molecular basis for the efficacy of H2RAs against coronavirus. Molecular docking was performed between four H2RAs, Cimetidine, Famotidine, Nizatidine, Ranitidine, and three non-structural proteins viz. NSP3, NSP7/8 complex, and NSP9. Thereafter, a 100 ns molecular dynamics simulation was carried out with the most outstanding ligands to determine the stability. Thereafter, Famotidine and Cimetidine were subjected to gene target prediction analysis using HitPickV2 and eXpression2Kinases server to determine the possible network of genes associated with their anti-COVID activities. Results obtained from molecular docking showed the superiority of Famotidine and Cimetidine compared to other H2RAs with a higher binding affinity to all selected targets. Molecular dynamic simulation and MMPBSA results revealed that Famotidine as well as Cimetidine bind to non-structural proteins more efficiently with high stability over 100 ns. Results obtained suggest that Famotidine and Cimetidine could be a viable option to treat COVID-19 with a mechanism of action that involves the inhibition of viral replication through the inhibition of non-structural proteins. Therefore, Famotidineand Cimetidine qualify for further study as a potential treatment for COVID-19.

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., (© 2022. The Author(s).)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cell pyroptosis has been characterized by cell swelling and pro-inflammatory factors release to aggravate inflammatory reaction., such as interlukin-1 beta (IL-1β) and interlukin18 (IL-18). However, the function of famotidine, an antagonist of histamine H2-receptor antagonists, in cell pyroptosis remained unknown., Methods: Real-time quantitative PCR (qPCR), western blotting (WB), LDH release assay and enzyme linked immunosorbent assay (Elisa) combined with inhibitor were performed to analyze the effect of famotidine on cell pyroptosis-related gene expression., Results: In this study, we found that famotidine (300 μm) treatment led to a phenomenon of cell pyroptosis as confirmed by LDH assay. Further results showed that famotidine triggered cell pyroptosis in gastric cancer cells by activation of NLPR3 inflammasomes including ASC, Caspase-1 and NLRP, leading to enhanced IL-18, not IL-1β, mature and secretion. What's more, the results also showed GSDME, not GSDMD, was increased in response to famotidine stimulation in BGC823 and AGS cells. Mechanically, phosphorylation of ERK1/2 was drastically enhanced in present with famotidine treatment, while inhibition of ERK1/2 activity by U0126 could reverse the promotion of famotidine in IL-18 secretion., Conclusion: These findings revealed a novel role of famotidine in cell pyroptosis in patients with gastric cancer, a comprehensive consideration is needed in treatment of gastric cancer., (© 2021. The Author(s).)

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., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The study aims at evaluating the effects of the combinatory famotidine/cimetidine diet on radiated mice's survival., Materials and Methods: Two hundred and seventy male mice were categorized into 11 groups, a number of which were comprised of subgroups too. The groups under analysis were posed to varying doses of gamma-radiation, including 6, 7, 8, and 9 Gy, followed by treatments using various drug doses 2, 4, and 8 mg/kg, with survival fractions as long as a month after irradiation being measured and recorded., Results: LD 50/30 was calculated as 7.47 Gy for the group with radiation only. Following mouse treatment with a concentration of 4 and 20 mg/kg for famotidine and cimetidine, respectively, the survival fraction for the mice grew significantly compared to LD 50/30 . The combinatory famotidine/cimetidine diet had a higher dose-reduction factor (DRF) than single doses of the drug in radioprotection. The DRF for combinatory famotidine/cimetidine, famotidine, and cimetidine diets was 08.09, 1.1, and 1.01, respectively., Conclusions: Results imply that the combined regimen of famotidine + cimetidine in radioprotection had no significant higher DRF than with regimens including each of them separately. In addition, we did not find a synergic effect of combined oral famotidine and cimetidine on irradiated mice., Competing Interests: None

Background: COVID-19 caused by SARS-CoV-2 was declared as a global pandemic by the WHO. Famotidine is a histamine-2 (H2) receptor antagonist which blocks the H2 receptors in the parietal cells, decreasing gastric acid secretion. Our review aims to study all the available scientific evidence on famotidine research outcomes systematically to introspect its clinical efficacy and probable mechanisms and clinical efficacy against SARS-CoV-2., Methodology: An electronic search of PubMed, Scopus and Google Scholar was performed using MeSH terms "SARS CoV-2" OR "COVID-19" AND"FAMOTIDINE". Relevant informationwas extracted from studies reporting the efficacy of famotidine in COVID-19., Results: We found a total of 32 studies, out of which only 14 were relevant and were included in our review.Molecular computational studies showed that famotidine selectively acts on viral replication proteases papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro). Additionally, it acts via inverse-agonism on the H2 receptors present in neutrophils and eosinophils which leads to inhibition of cytokine release. Clinical study findings have pointed toward significant improvements in COVID-19 patient-reported symptoms in non-hospitalized patients and reduction in intubation or death in critically ill patients associated with the usage of famotidine. However,in one of the studies,famotidine has failed to show any significant benefit in reducing mortality due to COVID-19., Conclusion: Famotidine has the potential to answer the ongoing global challenge owing to its selective action on viral replication. Additionally, clinical findings in COVID-19 patients support its efficacy to reduce clinical symptoms of COVID-19.We suggest that further optimally powered randomized clinical trials should be carried out to come up with definitive conclusions., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background & Aims: In upper airway cells, T helper 2 cytokines that signal through interleukin-4 (IL-4) receptor-α have been shown to stimulate eotaxin-3 secretion via a nongastric proton pump (ngH + ,K + ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH + ,K + ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL-4 receptor-α signaling., Methods: ngH + ,K + ATPase expression in EoE cells was evaluated by quantitative real-time polymerase chain reaction and Western blotting. IL-4-stimulated eotaxin-3 secretion was measured by enzyme-linked immunosorbent assay after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetoxymethyl ester (calcium chelator), 2-aminoethoxydiphenyl borate (inhibitor of endoplasmic reticulum calcium release), verapamil, and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of patients with EoE and controls., Results: EoE cells expressed ngH + ,K + ATPase messenger RNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetoxymethyl ester, 2-aminoethoxydiphenyl borate, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls., Conclusions: EoE cells express a nongastric proton pump that mediates T helper 2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block T helper 2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: In testicular torsion, testicular blood flow is impaired, resulting in ischemic changes. Torsion must be corrected urgently with surgical treatment. Detorsioning and restoration of blood supply to the testis cause reperfusion injury., Objective: In this experimental study, we aimed to investigate the effect of famotidine on ischemia-reperfusion injury in a rat model of testicular torsion., Study Design: The rats were randomly divided into three groups; Group I (control, no torsion) (n = 8), Group II (torsion + detorsion) (n = 8), Group III (torsion + detorsion + famotidine) (n = 8). Levels of oxidative stress markers, such as malondialdehyde (MDA) and nitric oxide (NO), and antioxidants, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), were measured for biochemical analysis. Testicular tissues were assessed by Johnsen Scoring for spermatogenic evaluation. Tissues were also examined with TUNEL staining to determine the extent of apoptosis., Results: Average MDA level was higher in Group II than Groups I and III. The difference was only significant between Group I and II (p = 0.03). Average NO level was significantly higher in Group II than Groups I and III (p = 0.03; p = 0.04; respectively). Conversely, average SOD level was lower in Group II than Groups I and III. The difference was only significant between Group II and III (p < 0.001). Average GSH-Px level was lower in Group II than Groups I and III, but the differences were not significant (p = 0.37; p = 0.35; respectively). The average Johnsen score in Group II was significantly lower than the scores in Groups I and III (p < 0.001; p < 0.001; respectively). The apoptotic index of Group II was significantly higher than those of Groups I and III (p < 0.001; p < 0.001; respectively)., Discussion: Famotidine prevented increases in oxidative stress markers and reductions of antioxidants during ischemia-reperfusion injury in our study. Spermatogenesis was less affected and DNA injury was reduced in rats treated with famotidine. The antioxidant characteristics of famotidine and its protective effects have been shown in our study., Conclusion: Famotidine may prevent oxidative tissue injury during ischemia-reperfusion., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

The lack of coronavirus-specific antiviral drugs has instigated multiple drug repurposing studies to redirect previously approved medicines for the treatment of SARS-CoV-2, the coronavirus behind the ongoing COVID-19 pandemic. A recent, large-scale, retrospective clinical study showed that famotidine, when administered at a high dose to hospitalized COVID-19 patients, reduced the rates of intubation and mortality. A separate, patient-reported study associated famotidine use with improvements in mild to moderate symptoms such as cough and shortness of breath. While a prospective, multi-center clinical study is ongoing, two parallel in silico studies have proposed one of the two SARS-CoV-2 proteases, 3CL pro or PL pro , as potential molecular targets of famotidine activity; however, this remains to be experimentally validated. In this report, we systematically analyzed the effect of famotidine on viral proteases and virus replication. Leveraging a series of biophysical and enzymatic assays, we show that famotidine neither binds with nor inhibits the functions of 3CL pro and PL pro . Similarly, no direct antiviral activity of famotidine was observed at concentrations of up to 200 µM, when tested against SARS-CoV-2 in two different cell lines, including a human cell line originating from lungs, a primary target of COVID-19. These results rule out famotidine as a direct-acting inhibitor of SARS-CoV-2 replication and warrant further investigation of its molecular mechanism of action in the context of COVID-19.

Background: Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin- based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in humans., Objectives: The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated., Methods: The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii., Results: Neither pentagastrin nor famotidine affected NQ absorption (AUC 0-t and C max ) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in humans did not show an effect of gastric pH. Compared to pure NQ (ED 90 , 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED 90 , 1.1 mg/kg). Correspondingly, the elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED 90 , 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity., Conclusions: Although the food was found to significantly impact NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with the acid-related disease is not expected to be clinically meaningful., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: This study aimed to demonstrate the role of serotonin 7 receptor (5-HT 7 ) and the effects of 5-HT 7 agonists and antagonists in an indomethacin-induced gastric ulcer., Material and Method: Male albino Wistar rats (n = 60) were used in the experiments. LP44 (5-HT 7 agonist) and SB269970 (5-HT 7 antagonist) were administered at 10 mg/kg as a pre-treatment. One hour after the drug treatments, 25 mg/kg of indomethacin (INDO) was administered to all groups except the healthy control group. Six hours after indomethacin administration, all the rats were euthanized., Results: We analyzed the iNOS, eNOS, and 5-HT 7 receptor mRNA levels in the stomach tissue of rats by real-time PCR. 5-HT 7 mRNA expression was increased in the INDO group compared to the healthy group. LP44 administration exerted a significant upregulatory effect on eNOS mRNA expression and downregulatory effects on iNOS and 5-HT 7 mRNA expression compared to the INDO group. However, antagonist (SB269970) administration did not result in such difference in gene expression, but even partially decreased the agonist's effect in combination. Famotidine and agonist exerted similar effects. Histopathological findings supported the beneficial effects of 5-HT 7 agonist on gastric tissue., Conclusion: The study suggested that activation of 5-HT 7 receptor showed a significant anti-ulcerogenic effect in the indomethacin-induced gastric ulcer model.

Background: Upper gastrointestinal (GI) ulceration and bleeding in critically ill dogs can cause severe anemia and increase morbidity. Acid suppressants using proton pump inhibitors or histamine-2 receptor blockers administered IV is commonly recommended., Hypothesis/objectives: To evaluate the efficacy of IV administered esomeprazole, pantoprazole, and famotidine constant rate infusion (CRI) on increasing the intragastric pH of dogs. We hypothesized that esomeprazole and famotidine CRI would provide superior acid suppression compared to pantoprazole and reach pH goals for the treatment of GI bleeding., Animals: Nine healthy research Beagles., Methods: Randomized, 3-way crossover. Dogs received pantoprazole or esomeprazole at 1 mg/kg IV q12h and famotidine with a loading dose of 1 mg/kg followed by 8 mg/kg IV CRI daily for 3 consecutive days. The intragastric pH was recorded at baseline and for 72 hours of treatment. The mean pH and the mean percentage time (MPT) the intragastric pH was ≥3 or ≥4 were compared among and within treatment groups., Results: Significant increases in mean pH (P < 0.0001), MPT ≥3 (P < 0.001), and MPT ≥4 (P = 0.0006) were noted over time with all 3 treatments. The time effect did not differ by treatment for mean pH, MPT ≥3, and MPT ≥4 (P = .29, .56, and .37, respectively); however, only esomeprazole and famotidine CRI achieved the goals established for the treatment of gastroduodenal ulceration in people., Conclusions and Clinical Importance: Famotidine CRI and esomeprazole might be superior acid suppressants compared to standard doses of pantoprazole for the first 72 hours of treatment., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Famotidine (FM) is considered among the first-line therapy for treatment of gastric ulcers; however, its poor aqueous solubility resulted in low bioavailability and limited therapeutic efficacy. Therefore, fast disintegrating tablet (FDT) incorporating FM solid dispersion was developed in a combined formulation approach for efficient treatment of ulcers. Within the investigated polymers, solid dispersions were prepared using the novel copolymer, Soluplus ® (SP) by kneading and freeze-drying techniques at various FM:SP ratios. FM solid dispersion prepared at 1:10 ratio using freeze drying (FM-SP10) manifested the highest saturation solubility, having smooth porous surface with the complete conversion of FM to the amorphous form. FDTs of FM-SP10 was produced by direct compression using three ready-to-use excipients; F-melt, Pearlitol Flash, and Fujicalin. All tablets showed adequate thickness, diameter, weight variation, drug content, and friability (<1%). Fujicalin-FDTs (FM-FDT-FU) exhibited the shortest disintegration time with almost complete dissolution of the drug (>95%) within 30 min. It also revealed remarkable antiulcerogenic effect on ethanol induced gastric ulcers in terms of ulcer and protection indices compared to the market product. Pretreated rats with FM-FDT-FU demonstrated normal gastric area with the absence of edema and leucocytes infiltration, supported by the histological examination. FM-FDT-FU administration protected the stomach from oxidative damage and severe inflammatory response via the significant increase of glutathione level and the decreased levels of nitric oxide, interleukin and cyclooxygenase. Thus, the present study provides a promising dosage form of FM characterized by superior antiulcerogenic potential with desired tableting properties.

Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 μM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 μM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 μM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P = .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P = .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.

Famotidine, an antiulcer drug belonging to the H 2 antagonists class of pharmacological agents, was recently shown to potently inhibit human (h) and bacterial carbonic anhydrases (CAs, EC 4.2.1.1). We investigated the inhibitory effects of famotidine against all classes of CAs from the pathogenic bacteria Vibrio cholerae, Burkholderia pseudomallei and Mycobacterium tuberculosis Rv3273 β-CA, as well as the CAs from the nonpathogenic bacteria/cyanobacteria Sulfurihydrogenibium yellowstonensis, S. azorense, Pseudoalteromonas haloplanktis, Colwellia psychrerythraea and Nostoc commune. The δ- and ζ-CAs from the diatom Thalassiosira weissflogii, the fungal enzymes from Cryptococcus neoformans, Candida glabrata and Malassezia globosa, as well as the protozoan enzymes from Trypanosoma cruzi and Plasmodium falciparum, were also investigated. Anopheles gambiae β-CA was also investigated. All these enzymes were effectively inhibited by famotidine, with affinities between the low nanomolar to the micromolar range. The best inhibition was observed against C. glabrata β-CA and TweCAζ, with K I s ranging between 13.6 and 22.1 nM.

Schizophrenia cannot be treated sufficiently with existing antipsychotic drugs. Taken into account that increased Glycogen Synthase Kinase 3 Beta (GSK-3β) activity is associated with schizophrenia pathophysiology and certain antipsychotics can be able to decrease GSK3β activity, inhibition of GSK-3β activity could be a novel approach for the treatment of schizophrenia. In the present study MK-801, a widely used chemical for the in vivo/in vitro modeling of schizophrenia was selected to evoke a detrimental effect on cellular survival via GSK3β and related proteins. A limited number of studies have reported the curative effects of famotidine, an antiulcer drug, in schizophrenic patients. To the best of our knowledge, no study investigated the molecular mechanism of the beneficial effect of famotidine in the patients. A recent study based on computerized drug modeling software (docking) indicated that famotidine might inhibit the GSK3β activity due to its chemical structure independent from histaminergic receptors. In this study, we aimed to investigate the effects of famotidine on the Akt/GSK-3β/β-catenin signaling pathway on SH-SY5Y neuroblastoma cells in the presence of MK-801. We investigated the effects of famotidine, olanzapine (an antipsychotic drug), and SB 415286 (specific GSK-3β inhibitor), on the basal cellular survival and MK-801 induced neuronal death beside of Akt/GSK-3β/β-catenin protein and gene expressions in SH-SY5Y cells. Cell viability, protein and gene expressions were determined by the real-time cell analysis (xCELLigence) system, western blotting and real-time polymerase chain reactions (Rt-PCR), respectively. Our findings suggested that MK-801 administration decreased cell survival probably via the increasing GSK-3β gene expression and activity in the SH-SY5Y cells. Pre-treatments with famotidine, olanzapine, and SB 415286 prevented MK-801 induced cell death via inhibitory effects on the MK-801 induced GSK-3β activity. Overall, the present results suggest that famotidine has a neuroprotective effect against MK-801 via modulation of the Akt/GSK-3β/β-catenin signaling pathway, an important mechanism in schizophrenia neurobiology., (Copyright © 2019. Published by Elsevier B.V.)

Background: Famotidine is sometimes administered as a continuous rate infusion (CRI) to treat gastrointestinal ulceration in critically ill dogs. However, clinical studies have not evaluated the efficacy of a famotidine CRI in dogs., Hypothesis/objectives: To evaluate the efficacy of famotidine at raising intragastric pH when it is administered as a CRI in dogs. We hypothesized that CRI treatment with famotidine would meet clinical goals for raising intragastric pH ≥3 and 4., Animals: Nine healthy Beagle dogs., Methods: Randomized 2-way crossover. All dogs received 1.0 mg/kg IV q12h famotidine or CRI famotidine at 1.0 mg/kg IV loading dose and 8.0 mg/kg/d for 3 consecutive days. Beginning on day 0 of treatment, intragastric pH monitoring was used to continuously record intragastric pH. Mean percentage times (MPTs) for which intragastric pH was ≥3 and ≥4 were compared between groups using analysis of variance., Results: There was a statistically significant difference (P < .05) in MPT ≥3 and ≥4 between the CRI and IV q12h groups on all treatment days. On days 1, 2, and 3, the MPTs ± SD for which pH was ≥3 were 92.1 ± 8.5, 96.3 ± 6.2, and 90.0 ± 15.7 for the CRI treatment group and 49.3 ± 27.3, 42.2 ± 19.6, and 45.8 ± 10.1, respectively, for the twice-daily group., Conclusions and Clinical Importance: These results suggest that a famotidine CRI, but not standard doses of famotidine, achieves the clinical goals established in people to promote healing of gastric tissue injury and offers an alternative to intravenous treatment with proton pump inhibitors in dogs., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Filgotinib is a potent, selective Janus kinase-1 inhibitor being developed to treat chronic inflammatory diseases. This phase 1 study in healthy subjects evaluated the relative bioavailability of filgotinib maleate tablets versus the reference tablet (filgotinib hydrochloride) and effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of filgotinib and its major metabolite. Noncompartmental pharmacokinetic parameters of filgotinib and its major metabolite were compared between the 2 tablets at 100- and 200-mg doses and with or without food or ARAs. Filgotinib maleate tablets resulted in equivalent plasma exposures (area under concentration-time curve to infinity [AUC ∞ ] and maximum concentration [C max ]) of filgotinib and its metabolite as the reference tablet (90%CIs of geometric least-squares mean ratios were within the prespecified no-effect boundary of 70% to 143%). Food intake had no effect on filgotinib AUC ∞ , but a high-fat meal reduced C max by 20%. Coadministration of filgotinib with omeprazole or famotidine had no effect on filgotinib AUC ∞ , but omeprazole decreased C max by 27%. Neither food nor ARAs affected metabolite exposure. Single-dose filgotinib 100 or 200 mg was well tolerated. This study supports evaluation of filgotinib maleate tablets, administered without regard to food or ARAs, in future clinical studies., (© 2019, The American College of Clinical Pharmacology.)

Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides their coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) extracellular signal-related kinase 1/2 (ERK1/2), but the cellular effects are not known. In the present study, we show in HASM cells that TAS2R agonists initially stimulate phosphorylated ERK1/2 (pERK1/2) but by 24 hours cause a marked (50-70%) downregulation of pERK1/2 without a change in total ERK1/2. It was hypothesized that TAS2R agonists suppress cell growth through this pERK1/2 downregulation. Agonist-dependent inhibition of cell proliferation was indeed found in HASM cells derived from normal and asthmatic human lungs, as well as in an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase). Various structurally diverse TAS2R agonists evoked a range of inhibition of HASM proliferation, the magnitude of which directly correlated with the downregulation of pERK1/2 ( R 2  = 0.86). Some TAS2R agonists were as effective as pharmacological inhibitors of Raf1 and MEK1/2 in suppressing growth. siRNA silencing of TAS2Rs (subtypes 10, 14, and 31) ablated the pERK1/2 and growth-inhibitory effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G protein G αi and by knocking down β-arrestin 1/2, indicating a dual pathway, although there may be additional mechanisms involved in this HASM TAS2R multidimensional signaling. Thus, TAS2R agonist structure can be manipulated to maintain the relaxation response and can be biased toward suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, in which an increase in smooth muscle mass contributes to airway obstruction.

Background: Famotidine is commonly administered to cats. Prolonged famotidine administration results in decreased efficacy in humans, dogs, and cows, but the long-term effects in cats are unknown., Objectives: To compare the effect of 2 oral administration frequencies of famotidine, twice daily (Group 1) and twice daily every second day (Group 2), on intragastric pH and serum gastrin concentrations in cats. We hypothesized a diminished effect on intragastric pH would be observed over time in Group 1 but not Group 2., Animals: Sixteen healthy cats., Methods: Randomized, 2-factor repeated measures crossover design. Cats received 0.5-1.24 mg/kg (median, 0.87 mg/kg) famotidine twice daily or twice daily every second day for 14 consecutive days. Intragastric pH monitoring was used to record intragastric pH on treatment days 1-3 and 11-13. Mean pH and mean percentage time (MPT) intragastric pH was ≥3 and 4 were compared between and within treatment groups by analysis of variance., Results: Significant treatment group by time interactions were observed for mean intragastric pH, MPT intragastric pH ≥3 and 4 (P = .009, P = .02, P = .005, respectively). Interaction post hoc tests identified significant decreases in mean intragastric pH (P = .001), MPT ≥3 (P = .001), and MPT ≥4 (P = .001) on day 13 compared to day 1 in Group 1 but not in Group 2., Conclusions and Clinical Importance: Oral famotidine administration results in a diminished effect on intragastric pH in healthy cats when given twice daily every day., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

The association of histamine with adverse cardiac remodeling in chronic pressure overload has not received much attention. A pilot study in spontaneously hypertensive rats (SHRs) indicated a reduction of left ventricular hypertrophy (LVH) with a histamine-2-receptor (H2R) antagonist (famotidine). This finding prompted a detailed investigation of temporal variation in myocardial histamine and H2R expression and the cardiovascular response to H2R antagonism compared with that of the conventional beta-blocker metoprolol. Reduction of LVH is known to reduce the risk of adverse cardiovascular events. The myocardial histamine content and H2R expression increased with age in SHRs but not in normotensive Wistar rats. The cardiovascular response to famotidine (30 mg kg -1 ) was compared with that of metoprolol (50 mg kg -1 ) in 6-month-old male SHRs treated for 60 days. The decrease in diastolic blood pressure and improvement in cardiac function induced by famotidine and metoprolol were comparable. Both treatments caused the regression of LVH as assessed from the hypertrophy index, histomorphometry, B type natriuretic peptide (BNP), pro-collagen 1, and hydroxyproline levels. Calcineurin-A expression (marker of pathological remodeling) decreased, and Peroxiredoxin-3 expression (mitochondrial antioxidant) increased in response to the treatments. The myocardial histamine levels decreased with the treatments. The age-dependent increase in myocardial histamine and H2R in the SHRs signifies their association with progressive cardiac remodeling. The regression of LVH and improvement in cardiac function by famotidine further demonstrates the role of histamine in cardiac remodeling. Hypertrophy of cultured cardiac cells upon exposure to histamine and the H2R agonist amthamine substantiates the role of histamine in cardiac remodeling. The cardiovascular response to famotidine is comparable to that of metoprolol, suggesting repurposing of H2R antagonists for the management of hypertensive heart disease.

Schizophrenia (SCZ) is one of the brain disorders which affects the thinking and behavioral skills of patients. This disorder comes along with an overproduction of kynurenic acid in the cerebrospinal fluid and the prefrontal cortex of SCZ patients. In this study, marine bacterial compounds were screened for their suitability as antagonists against human kynurenine aminotransferase (hKAT-1) which causes the synthesis of kynurenic acid downstream which ultimately causes the SCZ disorder according to the kynurenic hypothesis of SCZ. The marine actinobacterial compound bonactin shows more promising results than other tested marine compounds such as the histamine H2 blocker famotidine and indole-3-acetic acid (IAC) from docking and in silico toxicological studies carried out here. The obtained results of the Grid-based Ligand Docking with Energetics (Glide) scores of extra-precision (XP) Glide against the target protein hKAT-1 on IAC, famotidine, and bonactin were - 6.581, - 6.500 and - 7.730 kcal/mol where Glide energies were - 29.84, - 28.391, and - 47.565 kcal/mol, respectively. Bonactin is known as an antibacterial and antifungal compound being extracted from a marine Streptomyces sp. Comparing tested compounds against the drug target hKAT-1, bonactin alone showed the best Glide score and Glide energy on the target protein hKAT-1.

Background: Abomasal ulceration is recognized in neonatal and adult cattle, but research regarding treatment is limited. Histamine-2 receptor antagonists (H 2 RA), such as famotidine, are used clinically with little evidence-based research about efficacy in adult cattle., Hypothesis and Objectives: Intravenous famotidine administered at 0.4 mg/kg will increase the pH of abomasal outflow digesta compared to saline control in adult cattle. The objectives were to assess the effect of famotidine, administered as a single dose and as multiple doses, on abomasal outflow fluid pH in adult cattle. A third objective was to describe the pharmacokinetic parameters of IV famotidine in cattle., Animals: Four clinically healthy adult Angus-cross steers previously fitted with duodenal cannulae placed orad to the biliary and pancreatic ducts., Methods: Randomized, 2-way cross-over clinical trial. Steers received IV famotidine (0.4 mg/kg) as a single and 3-dose regimen (every 8 hours) versus saline control. Blood for analysis of serum famotidine concentration was collected intermittently for 12 hours, and abomasal outflow fluid pH was measured at intervals for a 24-hour period. After a 34-hour washout period, the opposite treatments were administered and the sampling repeated., Results: Abomasal outflow fluid pH was higher in steers treated with famotidine for up to 4 hours after a single dose but the effect decreased with subsequent doses. The median (range) elimination half-life was 3.33 (3.21-3.54) hours., Conclusions and Clinical Importance: Famotidine may be useful for treatment or prevention of abomasal ulceration in adult cattle, but the duration of effect may decrease with time., (Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Doxorubicin (DOX), an anthracycline-based antibiotic, is regularly used in the management of carcinomas, and haematological malignancies have been downplayed in chemotherapy because of its ability to induce dilated cardiomyopathy (DCM). Dexrazoxane is approved to combat the cardiotoxicity, but limited by its adverse effects. Redox imbalance and reactive oxygen species generation plays major role in DOX-induced cardiotoxicity. Histamine, known to mediate various cardiovascular effects, but nevertheless the role of histamine or its receptors in DOX-induced DCM is remained obscure. Hence, this study is aimed to examine the effect of Famotidine (FAM), a H2 receptor antagonist on DOX-induced DCM in Wistar rats. Myocardial antioxidant status, stress and apoptosis markers, myocardial morphology and function were evaluated as the end points. Treatment with FAM has alleviated DOX doxorubicin-induced cardiotoxicity by reducing oxidative and nitrosative stress evident from lipid peroxidation and total nitrate-to-nitrite ratio, and enhanced the activity of super oxide dismutase. Cardiac stress markers like LDH and Na + -K + ATPase activities as well as CK-MB and Cardiac troponin levels were reduced by FAM treatment. It also normalised the myocardial function as assessed by 2D echocardiography and myocardial index. Treatment imparted anti-apoptotic effect as evident from decrease in myocardial caspase 3 and 9 activity and cleaved PARP expression. Effect of FAM is found to be comparable to the standard ACE inhibitor Captopril (CAP). The results from this study collectively suggest H2 receptor antagonism as a novel therapeutic strategy to impart biochemical, structural and functional improvement indicating its cardio-protective activity.

This present study aimed to determine the optimal oral insulin delivery conditions that would maximize the utility of cell-penetrating peptides (CPPs) by using a noncovalent strategy. We first compared the effectiveness of two potential CPPs, penetratin and its analog PenetraMax, as absorption enhancers for insulin. The combined effect was evaluated under in vivo oral administration conditions. Both D-forms of CPPs were highly effective for increasing the oral absorption of insulin, and D-PenetraMax showed a more rapid onset of absorption enhancement effects compared with those of D-penetratin. However, synergistic absorption enhancement effects after combination treatment were not observed. Next, we tried a theoretical approach to establish optimized oral insulin delivery conditions. A surface plasmon resonance (SPR)-based analysis demonstrated that binding between insulin and penetratin (2 mM) might be saturated at 100-500 µM penetratin, while the bound concentration of penetratin could increase in accordance with an increased concentration of mixed insulin. To test this hypothesis, we investigated the effectiveness of different insulin doses in the gastric pH-neutralized mice. The results showed that the dissociation of noncovalent complexes of insulin and CPPs at the low gastric pH was prevented in these mice. Our findings clearly suggested that a noncovalent strategy with CPPs represents an effective approach for the L-form of CPP to increase the concentration of CPP-bound insulin to attain greater absorption of insulin, although this approach may not be appropriate for the D-form of CPP. Our findings will contribute to the development of oral dosage forms of insulin for noncovalent strategies involving CPP.

Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H 2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyse the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. The impact of PPIs on the plasma MTX concentration on 73 cycles of HD-MTX therapy was analysed retrospectively in 43 patients. Also investigated was the involvement of OAT3 in PPI-MTX drug interaction in an in vitro study using human OAT3 expressing HEK293 cells. In a retrospective study, patients who received a PPI had significantly higher MTX levels at 48 h (0.38 vs. 0.15 μmol l -1 , respectively, p = 0.000018) and 72 h (0.13 vs. 0.05 μmol l -1 , respectively, p = 0.0002) compared with patients who did not receive a PPI (but received famotidine). Moreover, in vitro experiments demonstrated that PPIs (esomeprazole, lansoprazole, omeprazole and rabeprazole) inhibited hOAT3-mediated uptake of MTX in a concentration-dependent manner (IC 50 values of 0.40-5.5 μ m), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3-mediated MTX uptake. These results demonstrated that co-administration of PPI, but not famotidine, could result in a pharmacokinetic interaction that increases the plasma MTX levels, at least in part, via hOAT3 inhibition., (Copyright © 2017 John Wiley & Sons, Ltd.)

Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively. In vitro assessment suggested that the presence of bile salt mixed micelles to mimic the fed state can significantly enhance the solubility of palbociclib. Subsequently, study 2 was conducted under fed conditions and demonstrated that coadministration of rabeprazole decreased palbociclib maximum observed plasma concentration by 41% but had limited impact on area under the concentration-time curve from 0 to infinity (13% decrease). This study also showed that the histamine-2 receptor antagonist famotidine and local antacid with staggered dosing had no impact on palbociclib exposure under fed conditions. Food intake effectively mitigated the impact of acid-reducing agents on palbociclib exposure. Palbociclib free base capsule should be taken with food, and acid-reducing agent use does not need to be avoided., (© 2017, The American College of Clinical Pharmacology.)

Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), C max , and C 24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89-1.17. Similarly, GMRs of elbasvir AUC(0,∞), C max , and C 24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO₄. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide) was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.

Background: Famotidine is an acid suppressant commonly administered to dogs. Prolonged famotidine use in people results in decreased efficacy, but the effect in dogs is unknown., Hypothesis/objectives: To compare the effect of repeated oral administration of famotidine or placebo on intragastric pH and serum gastrin in dogs. We hypothesized that famotidine would have a diminished effect on intragastric pH on day 13 compared to day 1., Animals: Six healthy adult colony Beagles., Methods: Randomized, 2-factor repeated-measures crossover design. All dogs received oral placebo or 1.0 mg/kg famotidine q12h for 14 consecutive days. Intragastric pH monitoring was used to continuously record intragastric pH on treatment days 1-2 and 12-13. Mean pH as well as mean percentage time (MPT) that intragastric pH was ≥3 or ≥4 were compared between and within groups by analysis of variance. Serum gastrin was measured on days 0, 3, and 12 for each treatment., Results: Continued administration of famotidine resulted in a significant decrease in mean pH, MPT ≥3, and MPT ≥4 (P < .0001) on day 12 and 13. This resulted in a mean decrease in pH by 1.63 on days 12 and 13 compared to days 1 and 2. Furthermore, a mean decrease of MPT ≥3 and MPT ≥4 by 33 and 45% was observed for the same time period, respectively., Conclusions and Clinical Importance: Continued administration of famotidine results in a diminished effect on intragastric pH in dogs. Caution is advised when recommending long-term, daily oral administration of famotidine to dogs., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background/aims: Acotiamide, a prokinetic drug, is used to treat functional dyspepsia (FD), especially postprandial distress syndrome (PDS). However, a treatment for FD patients with PDS and/or epigastric pain syndrome (EPS) has not been established. We investigated the efficacy of famotidine in combination with acotiamide for FD., Methods: Fifty blindly randomized FD patients received placebo with acotiamide, or famotidine with acotiamide, for 4 weeks. Treatment efficacy was assessed by overall treatment effects (OTE), total, PDS and EPS symptom scores, and impairment of quality of life (QOL)., Results: After OTE assessment, patients who felt affected by treatment comprised 40.9 and 57.9% of famotidine and placebo groups, respectively, after 4 weeks' treatment, with no significant difference between groups. A significant decrease was seen in total, PDS, and EPS symptom scores, and in QOL impairment, after 4 weeks' treatment compared with pretreatment scores for famotidine and placebo groups, but was not observed between groups. The proportion of patients showing a ≥50% decrease in EPS symptom scores was greater in the famotidine than that in the placebo group for every observation point, with the greatest difference observed after 2 weeks' treatment., Conclusion: The effectiveness of famotidine and acotiamide combination therapy in FD was similar to the effectiveness of acotiamide therapy alone., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Histamine is a key immunoregulatory mediator in immediate-type hypersensitivity reactions and chronic inflammatory responses, in particular histamine suppresses proinflammatory responses to bacterial ligands, through histamine receptor 2 (H2R). The aim of this study was to investigate the effects of histamine and H2R on bacteria-induced inflammatory responses in patients with IBD., Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Crohn's disease, patients with ulcerative colitis, and healthy controls. PBMC histamine receptor expression was evaluated by flow cytometry. Cytokine secretion following Toll-like receptor (TLR)-2, TLR-4, TLR-5, or TLR-9 stimulation in the presence or absence of histamine or famotidine (H2R antagonist) was quantified. Biopsy histamine receptor gene expression was evaluated using reverse transcription-polymerase chain reaction. The in vivo role of H2R was evaluated in the T-cell transfer murine colitis model., Results: The percentage of circulating H2R monocytes was significantly reduced in patients with IBD. Histamine effectively suppressed TLR-induced cytokine secretion from healthy volunteer PBMCs but not for PBMCs from patients with IBD. Famotidine reversed this suppressive effect. H1R, H2R, and H4R gene expression was increased in inflamed gastrointestinal mucosa compared with noninflamed mucosa from the same patient and expression levels correlated with proinflammatory cytokine gene expression. Mice receiving lymphocytes from H2R donors, or treated with famotidine, displayed more severe weight loss, higher disease scores and increased numbers of mucosal IFN-γ and IL-17 T cells., Conclusion: Patients with IBD display dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated with H2R signaling. Deliberate manipulation of H2R signaling may suppress excessive TLR responses to bacteria within the gut.

The gastric proton pump (H(+),K(+)-ATPase) consists of a catalytic α-subunit (αHK) and a glycosylated β-subunit (βHK). βHK glycosylation is essential for the apical trafficking and stability of αHK in gastric parietal cells. Here, we report the properties of sialic acids at the termini of the oligosaccharide chains of βHK. Sialylation of βHK was found in LLC-PK1 cells stably expressing αHK and βHK by staining of the cells with lectin-tagged fluorescent polymeric nanoparticles. This sialylation was also confirmed by biochemical studies using sialic acid-binding lectin beads and an anti-βHK antibody. The sialic acids of βHK are cleaved enzymatically by neuraminidase (sialidase) and nonenzymatically by an acidic solution (pH5). Interestingly, the enzymatic activity of H(+),K(+)-ATPase was significantly decreased by cleavage of the sialic acids of βHK. In contrast, βHK was not sialylated in the gastric tubulovesicles prepared from the stomach of fed hogs. The H(+),K(+)-ATPase activity in these tubulovesicles was not significantly altered by neuraminidase. Importantly, the sialylation of βHK was observed in the gastric samples prepared from the stomach of famotidine (a histamine H2 receptor antagonist)-treated rats, but not histamine (an acid secretagogue)-treated rats. The enzymatic activity of H(+),K(+)-ATPase in the samples of the famotidine-treated rats was significantly higher than in the histamine-treated rats. The effects of famotidine were weakened by neuraminidase. These results indicate that βHK is sialylated at neutral or weakly acidic pH, but not at acidic pH, suggesting that the sialic acids of βHK positively regulate the enzymatic activity of αHK., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers., Methods: Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1]., Results: Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005]., Conclusions: These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.

The aim of the current study was to investigate the interaction of the lipopolysaccharide (LPS) and histaminergic systems on appetite regulation in broilers. Effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptor antagonist), famotidine (histamine H2 receptor antagonist) and thioperamide (histamine H3 receptor antagonist) on LPS-induced hypophagia in broilers were studied. A total of 128 broilers were randomly allocated into 4 experiments (4 groups and 8 replications in each experiment). A cannula was surgically implanted into the lateral ventricle. In Experiment 1, broilers were ICV injected with LPS (20 ng) prior to α-FMH (250 nmol). In Experiment 2, chickens were ICV injected with LPS followed by chlorpheniramine (300 nmol). In Experiment 3, broilers were ICV injected with famotidine (82 nmol) after LPS (20 ng). In Experiment 4, ICV injection of LPS was followed by thioperamide (300 nmol). Then, cumulative food intake was recorded until 4 h post-injection. According to the results, LPS significantly decreased food intake. Chlorpheniramine significantly amplified food intake, and LPS-induced hypophagia was lessened by injection of chlorpheniramine. α-FMH, famotidine and thioperamide had no effect on LPS-induced hypophagia. These results suggest that there is an interaction between central LPS and the histaminergic system where LPS-induced hypophagia is mediated by H1 histamine receptors in 3 h food-deprived broilers.