gastrins and ebrotidine

Gastric mucosa is exposed to various aggressive factors such as stress, ulcerogenic drugs including acetyl-salicylic acid(ASA)-like agents, ethanol, bacteria, particularly Helicobacter pylori (Hp), and various endogenous irritants such as acid-pepsin secretion and bile salts. The maintenance of the mucosal barrier depends upon the activation of the pre-epithelial (mucus-alkali secretion), epithelial (surface-active phospholipids and rapid mucosal restitution) and post-epithelial (mucosal microcirculation, sensory nerves and mast cells) components of mucosal defense. Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]- 4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamid e, CAS 100981-43-9, FI-3542) is the first of a new generation of H2-receptor antagonists with both antisecretory and cytoprotective activities. Its inhibitory action is similar to that of ranitidine and approximately tenfold greater than cimetidine, and is accompanied by a small and transient increase in plasma gastrin levels. In contrast to ranitidine and other H2-receptor antagonists, ebrotidine exerts a unique cytoprotection against injury by various ulcerogens such as ethanol, ammonia, lipopolysaccharides (LPS), stress and ASA or acidified taurocholate. The mechanism of this protection by ebrotidine is not clear, but it has been shown to stimulate mucus secretion, to increase the quality of adherent mucus gel and to increase gastric mucosal blood flow (GBF), possibly due to enhanced mucosal formation of prostaglandin E2 (PGE2) and nitric oxide (NO). The cytoprotective effects of ebrotidine were observed in rats and confirmed also in humans with gastric lesions induced by ethanol or ASA. Ebrotidine also exerts anti-Helicobacter pylori (Hp) effects by interfering with surface receptors of epithelial cells and inhibiting urease, protease and lipase activity, and by counteracting the noxious effects of Hp-related substances such as ammonia and lipopoly-saccharides (LPS).

Topics: Adult; Animals; Benzenesulfonates; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Humans; Male; Peptic Ulcer; Ranitidine; Rats; Rats, Wistar; Thiazoles

To compare the efficacy and safety of ebrotidine and ranitidine administered once daily in equimolar doses of 800 and 300 mg, respectively.. A total of 298 duodenal ulcer patients were studied.. A multicentre, parallel, randomized clinical trial.. Of the 298 patients studied, 150 were randomly assigned to ebrotidine and 148 to ranitidine treatment. Digestive endoscopy was performed at enrolment and at weeks 4, 6 and 8 unless the ulcer had healed before. Endoscopic findings were the main parameter for the assessment of treatment efficacy. Plasma gastrin and pancreatic polypeptide concentrations were also measured before and after termination of the therapy.. Ebrotidine achieved a duodenal ulcer healing rate comparable to that of ranitidine, and no statistically significant difference was found between the two drugs. The drugs were equally effective in improving ulcerous dyspeptic symptoms and in relieving gastric pain. Both tobacco and ethanol consumption influenced ulcer healing adversely, but healing in smokers was more pronounced in patients treated with ebrotidine, possibly because of its cytoprotective activity.. Ebrotidine 800 mg is as effective and safe as ranitidine 300 mg in healing duodenal ulcer, but ebrotidine appears to be superior in promoting the healing of duodenal ulceration in smokers.

Topics: Adult; Anti-Ulcer Agents; Benzenesulfonates; Double-Blind Method; Duodenal Ulcer; Female; Gastrins; Humans; Male; Pancreatic Polypeptide; Ranitidine; Thiazoles

This study was designed to assess the gastroprotective and secretory effects of ebrotidine, a novel H2-receptor antagonist, in humans. Two groups (A and B) of male subjects with normal gastric mucosa were used. Group A (six subjects) was treated for 3 days with either ebrotidine or placebo in a randomized, crossover study, and on the 4th day 100 ml of 50% ethanol was sprayed on the mucosa via an endoscope. Pretreatment with ebrotidine significantly reduced the endoscopic score of mucosal damage and deep hemorrhagic lesions caused by ethanol as compared with those in placebo-treated subjects. In group B (six subjects) the 24-h pH-metry was assessed with an intraluminal pH electrode placed in the gastric corpus and connected to portable recording apparatus. A single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant inhibition of acid secretion for about 6 h on administration. We conclude that ebrotidine is highly effective as a gastroprotective agent, and as an H2-receptor antagonist shows a potent inhibitory effect on gastric acid secretion in humans.

Topics: Adult; Benzenesulfonates; Duodenal Ulcer; Ethanol; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastroscopy; Histamine H2 Antagonists; Humans; Male; Thiazoles

The antagonism of histamine H2-receptors by ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) was assessed on isolated guinea-pig right atrium. The dose-response curves obtained by histamine on the positive chronotropic effect in guinea-pig atrium were displaced to the right in parallel depending on the concentration of ebrotidine and ranitidine without change in the maximum response with pA2 values of 7.12 and 7.26, respectively. The slope of the regression line of log (DR-1) against log ebrotidine concentration was not significantly different from unity: 0.96 (95% confidence limits: 0.89-1.03). These results indicate that ebrotidine is a competitive H2-receptor antagonist. Following intravenous administration to rats, ebrotidine inhibited histamine- and pentagastrin-stimulated acid secretion in a dose-dependent manner, ED50 being 0.21 and 0.44 mg/kg, respectively. After oral administration to fasting rats 3 h before their sacrifice, ebrotidine decreased the total acid contents of the stomach in a dose-dependent manner, ED50 being 7.5 mg/kg. After a single dose of 100 mg/kg in fasting rats, ebrotidine increased significantly serum gastrin levels within 2 and 5 h after administration, but 8 h after administration serum gastrin levels returned to normal values. In contrast, ranitidine at a single oral dose of 100 mg/kg increased serum gastrin levels more markedly within 2 and 5 h after administration, while after 8 h, this increase still persisted although without significant differences with respect to control, and after 24 h levels returned to normal values. Both ebrotidine and ranitidine were administered orally at a dose of 100 mg/kg for 26 days showing significant increments in plasma gastrin levels 5 h after administration. Such increments were not so marked after ebrotidine and normal values were attained at 24 h after administration. The results obtained after repeated oral administration for 15 days of ebrotidine and ranitidine at the doses of 15 and 50 mg/kg demonstrated that ebrotidine did not increase significantly serum gastrin levels with respect to control 2 h after administration, and no dose-related effect was observed. In contrast, ranitidine increased serum gastrin levels significantly and in a dose-dependent manner with respect to control group. ED50 values of ebrotidine obtained in the experiments on the prevention of NSAID-induce

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzenesulfonates; Diclofenac; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastrins; Guinea Pigs; Heart Atria; Heart Rate; Histamine; Histamine H2 Antagonists; In Vitro Techniques; Indomethacin; Ketoprofen; Male; Naproxen; Pentagastrin; Ranitidine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Thiazoles

Four groups of male rats were orally administered for 60 days with daily doses of ebrotidine (N-[(E)-[[2-[[[2-[(diaminoethylene) amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo- benzenesulfonamide, CAS 100981-43-9, FI-3542) (500 mg/kg), ranitidine (500 mg/kg), cimetidine (500 mg/kg) and omeprazole (43.5 mg/kg). A fifth group received no treatment and was used as control. The curve of gastrinemia was obtained on days 1, 15 and 60 of administration. On each of these days gastrinemia was assessed at 0, 1, 5, 8, and 24 h on day 1, and 1, 5, 8, 10 and 24 h on days 15 and 60. The purpose of this study was to compare the plasma gastrin level profile in association with the administration of test drugs on days 1, 15 and 60 of treatment. The results showed a significant difference in the duration of hypergastrinemia of H2-receptor antagonists as compared to proton pump blockers. Although peak plasma gastrin levels were attained for all products between 5 and 8 h after day 1 of administration, H2-receptor antagonists, unlike omeprazole, achieved recovery of gastrin baseline levels within 24 h. On days 15 and 60 of ebrotidine, treatment, plasma gastrin levels returned to normal range at 5 and 8 h after administration, respectively. After ranitidine and cimetidine, hypergastrinemia was still present at this time, but normal levels were attained before 24 h. With omeprazole plasma gastrin levels did not return to normal range within 24 h after each administration, and a cumulative effect occurred during treatment. The omeprazole treated group showed the highest and more sustained plasma gastrin levels. It was concluded that ebrotidine was the antisecretory agent with the lowest hypergastrinemic effect during long-term treatment. With ebrotidine daily baseline gastrin levels were more rapidly recovered after each administration.

Topics: Animals; Benzenesulfonates; Cimetidine; Gastrins; Histamine H2 Antagonists; Male; Omeprazole; Ranitidine; Rats; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms; Thiazoles

Ebrotidine is a novel H2-receptor antagonist that exhibits both gastroprotective and ulcer-healing properties. Gastroprotection afforded by ebrotidine against ethanol damage was observed only after intragastric, but not parenteral administration, and it was accompanied by an increase in the mucosal blood flow. Ranitidine given at the same dose (100 mg/kg i.g. or s.c.) did not show any protective activity. When administered twice daily at various doses (1-100 mg/kg) for 10 days, ebrotidine reduced dose dependently the area of chronic gastric ulcers, and it was accompanied by significantly higher contents of epidermal growth factor (EGF) in the ulcer bed than in the intact mucosa. Administration of ranitidine resulted in a similar rate of ulcer healing and in a similar accumulation of EGF in the ulcer area to that observed after ebrotidine, but the increments in plasma gastrin levels in rats treated with ranitidine were observed at lower doses than in tests with ebrotidine. Concurrent administration of indomethacin delayed ulcer healing and reduced the accumulation of EGF in the ulcer area, but did not affect the ulcer healing by ebrotidine or ranitidine. We conclude that ebrotidine but not ranitidine shows gastroprotective activity, but it enhances the healing of chronic ulcerations in a similar manner to ranitidine.

Topics: Acetates; Acetic Acid; Animals; Benzenesulfonates; Epidermal Growth Factor; Ethanol; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Male; Ranitidine; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach Ulcer; Thiazoles