Famotidine Repurposing for Novel Corona Virus Disease of 2019: A Systematic Review.

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.

Effects of Cichorium Intybus L. Root Extract on Secretory Activity of the Stomach in Health and Ulcer Disease.

Gastroprotective effect of Cichorium intybus L. root extract is demonstrated on H. Shay's model of experimental ulcer in rats. The effect is attributed to the antisecretory activity of the plant and stimulation of defense barrier function of the gastric mucosa. The regulatory effect of the phytocomplex on seasonal characteristics of the gastric secretory and defense functions in dogs with Basov's fistula is detected.

Effect of famotidine and lansoprazole on serum phosphorus levels in hemodialysis patients on calcium carbonate therapy.

AIMS: Histamine H2 receptor antagonists (HRA) or proton pump inhibitors (PPI) are frequently administered to patients on hemodialysis, because their intestinal mucosa is fragile. Although three studies have indicated that concomitant HRA administration causes a decrease in the binding of phosphate by calcium carbonate, the HRA doses tested in these studies were 2-4 times higher than the recommended dose for hemodialysis patients. In addition, it remains unclear whether PPI therapy affects serum phosphate levels in hemodialysis patients taking calcium carbonate. Accordingly, the aim of this study was to evaluate the influence of lansoprazole and the recommended dose of famotidine on serum phosphate and calcium levels in hemodialysis patients. METHODS: The study included 115 hemodialysis patients who were taking calcium carbonate and who were also treated with either famotidine (10 mg/day) or lansoprazole (30 mg/day). Changes of the mean serum phosphate and calcium levels over 2 months before and after the start of famotidine or lansoprazole therapy were compared. The same parameters were also compared when famotidine was switched to lansoprazole. RESULTS: The mean serum phosphate level increased significantly after administration of either famotidine or lansoprazole (by 6.6 +/- 21.9% or 13.0 +/- 26.3%, p = 0.032 and p = 0.029, respectively). The mean serum calcium level was unchanged after administration of famotidine, but showed a significant decrease after administration of lansoprazole (by 3.44 +/- 7.73%, p = 0.013). Therefore, the calcium x phosphorus product was significantly increased by administration of famotidine, but not by administration of lansoprazole (6.68 +/- 23.37% and 8.73 +/- 27.41%, p = 0.046 and p = 0.251, respectively). When famotidine was switched to lansoprazole, the serum phosophate level did not change, but serum calcium decreased significantly by 3.8 +/- 13.0% (p = 0.0006). CONCLUSION: Not only administration of 20 mg/ day of famotidine as previously reported, but also 10 mg/day of this drug (the recommended dose for hemodialysis patients) caused a significant increase of serum phosphate in patients taking calcium carbonate. PPIs have been reported to show no effect on the serum phosphate level, but 30 mg/day of lansoprazole also caused a significant increase of serum phosphate in patients taking calcium carbonate.

Antiulcer and in vitro antioxidant activities of Jasminum grandiflorum L.

The study was aimed at evaluating the antiulcer and antioxidant activities of 70% ethanolic axtract of leaves of Jasminum grandiflorum L. (JGLE). The leaves of Jasminum grandiflorum L. (Family: Oleaceae) is used in folk medicine for treating ulcerative stomatitis, skin diseases, ulcers, wounds, corns - a hard or soft hyperkeratosis of the sole of the human foot secondary to friction and pressure (Stedman's Medical Dictionary, 28th ed. Lippincott Williams & Wilkins, Philadelphia. p. 443), etc., Antiulcerogenic activity of JGLE (100 and 200 mg/kg, b.w., orally) was evaluated employing aspirin + pylorus ligation (APL) and alcohol (AL) induced acute gastric ulcer models and ulcer-healing activity using acetic acid-induced (AC) chronic ulcer model in rats. Both the antisecretory and cytoprotection hypothesis were evaluated. The antioxidant activity of JGLE has been assayed by using in vitro methods like 2,2-diphenyl-1-picrylhydrazylhydrate (DPPH) assay, reductive ability, superoxide anion scavenging activity, nitric oxide scavenging activity and total phenolic content, in order to explain the role of antioxidant principles in the antiulcerogenic activity of the extract. There was a significant (P<0.01) dose-dependent decrease in the ulcerative lesion index produced by all the three models in rats as compared to the standard drug famotidine (20 mg/kg, b.w. orally). The reduction in gastric fluid volume, total acidity and an increase in the pH of the gastric fluid in APL rats proved the antisecretory activity of JGLE. Additionally, JGLE completely healed the ulcer within 20 days of treatment in AC model as evidenced by histopathological studies. Like antiulcer activity, the free radical scavenging activities of JGLE depends on concentration and increased with increasing amount of the extract. These results suggest that leaves of Jasminum grandiflorum possess potential antiulcer activity, which may be attributed to its antioxidant mechanism of action.

The role of histamine in dural vessel dilation.

The pain of migraine is often throbbing suggesting an important role for the cranial blood vessels and their innervation by the trigeminal nerve. It is proposed that clinically effective anti-migraine compounds, such as 5-HT(1B/1D) agonists, have actions that include inhibiting calcitonin gene-related peptide (CGRP) release from trigeminal nerves. Human studies suggest that histamine can induce migraine possibly by activating nitric oxide (NO) synthase to promote endogenous NO production. The present studies investigated the effect of histamine and its antagonists on the cranial blood vessels using intravital microscopy to assess directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. Histamine infusion caused immediate and reproducible dilation of meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by H(1)- (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as well as a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester; P<0.05). Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists, but was significantly inhibited by a H(1)-receptor antagonist at the high dose of 10 mg/kg. The present studies demonstrate that histamine is likely to activate NO synthase to promote NO production. There is also evidence that H(1)-receptors may be present on trigeminal neurones as the H(1)-receptor antagonist inhibited neurogenic vasodilation, albeit at a large dose.

Protective effect of famotidine, omeprazole, and melatonin against acetylsalicylic acid-induced gastric damage in rats.

It has been reported that both omeprazole and famotidine have a protective effect against gastric mucosal damage induced by acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs. Since active oxygen species and lipid peroxidation were reported to play a role in the pathogenesis induced by ASA, we aimed to study if omeprazole and famotidine have any antioxidant effect by comparing their protective effect with that of melatonin, an effective antioxidant and free radical scavenger. Mucosal damage was evaluated by macroscopic examination, histological analysis and by measurement of lipid peroxidation (LPO), glutathione (GSH), and myeloperoxidase (MPO) activity. Omeprazole (20 micromol/kg per os), famotidine (3 mg/kg per os), and melatonin (10 mg/kg intraperitoneally) significantly prevented gastric ulcerogenesis induced by ASA (200 mg/kg per os) and decreased the ulcer index. Gastric LPO and MPO activity that were increased significantly by ASA were decreased after treatment with omeprazole, famotidine, and melatonin. ASA treatment decreased significantly the gastric GSH levels, and pretreatment with omeprazole, famotidine, or melatonin increased it significantly. Famotidine and omeprazole decreased the gastric acidity, which was increased by ASA, whereas melatonin had no effect on this parameter. These findings suggest that active oxygene species and LPO have an important role in the pathogenesis of gastric mucosal damage induced by ASA and that both famotidine and omeprazole may be protective against this damage, although they were not as efficient as melatonin as an antioxidant. On the other hand, the antisecretory effect of omeprazole and famotidine may also be contributing to their antiulcer effect.

[Effect of histamine H2-receptor antagonists on the phosphorus-binding ability of phosphate binders in hemodialysis patients].

We examined the effects of histamine H2-receptor antagonists on the phosphorus binding ability of phosphate binders. Serum calcium, phosphorus, ALP, PTH and arterial blood pH and bicarbonate were measured during treatment with histamine H2-receptor antagonists accompanied by calcium carbonate in sixteen patients undergoing maintenance hemodialysis. Seven patients receiving histamine H2-receptor antagonists without calcium carbonate were selected as controls. In the sixteen patients receiving calcium carbonate, serum calcium, ALP, PTH and arterial blood pH and bicarbonate were not significantly altered during treatment with histamine H2-receptor antagonists, but serum phosphorus levels increased significantly after four (5.6 +/- 1.1 mg/dl) and eight weeks (5.9 +/- 0.8 mg/dl) of treatment as compared with that before treatment (4.8 +/- 1.2 mg/dl). Furthermore, serum phosphorus levels decreased significantly eight weeks after the discontinuation of treatment with histamine H2-receptor antagonists. In the seven control patients there were no statistical differences in serum calcium and phosphorus levels measured before and after treatment with histamine H2-receptor antagonists. In seven other patients receiving histamine H2-receptor antagonists with calcium carbonate, calcium carbonate was replaced with calcium lactate as the phosphate binder after four weeks of treatment with histamine H2-receptor antagonists. With the 4-week administration of histamine H2-receptor antagonists accompanied by calcium carbonate, the serum phosphorus level increased, similarly to that of the first study (from 6.3 +/- 0.9 to 7.1 +/- 0.5 mg/dl). However, with the substitution of calcium lactate, the serum phosphorus level decreased significantly (6.3 +/- 0.2 and 6.0 +/- 0.9 mg/dl after four and eight weeks, respectively, despite continued administration of histamine H2-receptor antagonists). These results suggest that histamine H2-receptor antagonists significantly affect the phosphorus binding ability of calcium carbonate, but not of calcium lactate. Although the exact mechanism remains obscure, one possible explanation may be related to the rise in pH of the gastric juice. Careful observation of changes in the serum phosphorus level is required in hemodialysis patients receiving calcium carbonate and histamine H2-receptor antagonists. Calcium lactate may be useful as a phosphate binder in such hemodialysis patients.

The liver regenerative response elicited by antisecretory agents in partially hepatectomized rats: a comparison between omeprazole and famotidine.

Liver regeneration after omeprazole (OMP) or famotidine (FAM) administration was examined in 66% hepatectomized rats. The regeneration was evaluated by the liver weight as a percentage of body weight (LRR) and the proportion of hepatocytes in mitosis per 1,000 counts (MI). Administration of OMP 0.4 mg/kg per day for 3 or 7 days suppressed LRR and MI 3 and 7 days after hepatectomy. However, the administration of FAM 0.8 mg/kg per day for 3 or 7 days did not change either LRR or MI. Increased gastrin levels in the blood were seen only after OMP administration. The food intake was unchanged by OMP or FAM, but FAM increased water intake. The liver functional score, glutamic pyruvic transaminase and alkaline phosphatase in the blood all increased with OMP, but FAM had no apparent effect on the hepatic or renal function. These observations suggest that a large dosage of OMP suppresses liver regeneration, while FAM appears to have no meaningful effect on regeneration.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats.

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H1-receptor in rats.

Effects of FK506, an immunosuppressive agent, on genesis of water-immersion stress-induced gastric lesions in rats.

We examined the effects of FK506, an immunosuppressive agent, on the genesis of water immersion stress-induced gastric lesions in rats. Using high-performance liquid chromatography, four kinds of prostaglandins, ie, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and prostaglandin D2, were detected, and no leukotrienes were detected in gastric mucosa in rats without stress. After 6 hr of stress, gastric lesions developed with decreases in all prostaglandin contents, and the emergence of peptide leukotrienes was observed. Intramuscular administration of FK506 (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) reduced lesion index dose-dependently. Administration of FK506 at doses over 0.25 mg/kg decreased all prostaglandin contents, but did not affect the increase in leukotriene contents. Pretreatment with famotidine or omeprazole reduced lesion index, and the protective effects were equivalent to those of 1.0 mg/kg of FK506, although FK506 did not affect gastric secretion during water-immersion stress. Water-immersion stress did not change the activities of xanthine oxidase in either stomach or serum. Polyoxyethylene-modified superoxide dismutase did not prevent gastric lesions. Water-immersion stress significantly increased myeloperoxidase activity in gastric mucosa, and FK506 reduced the increase in myeloperoxidase activity induced by stress. From our results, other factors besides gastric acid secretion and tissue eicosanoid contents, such as chemoattractant factor, might also be involved in the genesis of water-immersion stress-induced gastric lesions in rats.