piperidines and Stomach-Ulcer

Topics: Anti-Ulcer Agents; Cisapride; Drug Resistance; Helicobacter Infections; Histamine H2 Antagonists; Humans; Piperidines; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Recurrence; Stomach Ulcer; Sucralfate

Disorders of gastric emptying are observed in many clinical situations. Their symptoms are diverse and correlate poorly with the objective abnormalities of gastric emptying. The underlying mechanism consists of abnormalities of basal electrical rhythm, fundic compliance, post-prandial antral motricity and, above all, antro-pyloro-duodenal co-ordination, associated to varying degrees. Among possible causes 3 clinical situations predominate: diabetes mellitus, functional gastrointestinal disorders (idiopathic dyspepsia) and sequelae of gastric surgery where retention of solids and accelerated evacuation of liquids may coexist in the same patient. Treatment of gastric incontinence rests, almost exclusively, on dietary measures, but several drugs, such as metoclopramide, domperidone and cisapride, are available to treat gastric stasis. Other compounds, notably motilin agonists (erythromycin and its derivatives) are currently being evaluated and will reinforce this therapeutic armentarium in a not too distant future.

Topics: Cisapride; Diabetes Complications; Domperidone; Dyspepsia; Gastric Emptying; Gastroesophageal Reflux; Humans; Metoclopramide; Piperidines; Postoperative Complications; Serotonin Antagonists; Stomach Diseases; Stomach Ulcer

Pharmacodynamic studies revealed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion. When administered orally as a capsule containing a granule formulation, the drug displayed modified-release properties, which led to a sustained suppression of gastric acid secretion. Clinical trials revealed that roxatidine acetate, 75 mg twice daily and 150 mg at night, was highly effective in healing duodenal and gastric ulcers and in reducing ulcer pain, over 4, 6, and 8 weeks of therapy. A steady reduction in diameter was observed in those ulcers not completely healed during therapy. The single bedtime dose regimen, while producing the same degree of healing as the divided daily dose during controlled clinical trials, may be of greater value in therapeutic use owing to improved patient compliance. In all efficacy criteria (cure, reduction in ulcer size, and pain relief) there was no significant difference between roxatidine acetate in a total daily dose of 150 mg, ranitidine in a total daily dose of 300 mg, and cimetidine in a total daily dose of 800 mg. Prevention of gastric and duodenal ulcer relapse was achieved by roxatidine acetate, 75 mg at night for 6 months, in about 70% of patients, as determined in open, pilot studies--a rate comparable to those reported for cimetidine and ranitidine. Roxatidine acetate shares with ranitidine an improved safety profile when compared with cimetidine. Human pharmacology studies and short-term and long-term clinical trials have all shown that roxatidine acetate is an exceptionally well tolerated compound, without the antiandrogenic activity and interference with hepatic drug metabolism which have characterized cimetidine treatment. A reason for the improved safety profile of roxatidine acetate may be its greater potency than cimetidine (six times less potent) and ranitidine (half as potent), so that lower doses of roxatidine acetate, representing a lower chemical load, are therapeutically effective. The novel structure of roxatidine acetate probably also underlies the improved safety of the compound.

Topics: Cimetidine; Clinical Trials as Topic; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; Stomach Ulcer

Topics: Aluminum; Antacids; Anti-Ulcer Agents; Benzimidazoles; Carbenoxolone; Domperidone; Gefarnate; Glycyrrhiza; Histamine H2 Antagonists; Humans; Metoclopramide; Microscopy, Electron, Scanning; Morpholines; Parasympatholytics; Piperidines; Plants, Medicinal; Proglumide; Stomach Ulcer; Sucralfate; Trimipramine

Proton pump inhibitors have been reported to be more useful than histamine-2 receptor antagonists for the prevention of bleeding after endoscopic submucosal dissection (ESD) for superficial gastric neoplasia. The aim of this study was to assess the effects of the proton pump inhibitor lansoprazole and the histamine-2 receptor antagonist roxatidine for the prevention of bleeding and the promotion of ulcer healing after ESD and to compare the cost-effectiveness of these two drugs.. The study subjects were 129 patients who underwent ESD for superficial gastric neoplasia. The patients were randomly assigned to the lansoprazole group (L group) or the roxatidine group (R group). Either drug was administered intravenously from the morning of the ESD day to the day after the ESD, followed by oral treatment for an additional 8 weeks. A second-look endoscopy was performed on the day after the ESD, and a repeat endoscopy was performed at 8 weeks after the ESD. The incidence of bleeding and the ulcer-healing rate at 8 weeks after the ESD were analyzed, as well as the total cost of treatment with these antisecretory agents.. Three patients in each group were excluded from the analysis, leaving 62 patients in L group and 61 in R group. Two of the 62 patients (3.2%) in L group and three of the 61 patients (4.9%) in R group showed bleeding after ESD ; there was no significant difference between the two groups (P = 0.68). The ulcer-healing rate was 93.5% (58/62) in L group and 93.4% (57/61) in R group (P = 1). The total cost of treatment with the antisecretory agent from the day of the ESD to day 56 after the ESD was Yen 13,212 for lansoprazole and Yen 5,841 for roxatidine.. Roxatidine appears to have high cost-effectiveness in the prevention of bleeding and in the promotion of ulcer healing after ESD for superficial gastric neoplasia.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Aged; Aged, 80 and over; Anti-Ulcer Agents; Cost-Benefit Analysis; Dissection; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Lansoprazole; Male; Middle Aged; Pilot Projects; Piperidines; Postoperative Complications; Prospective Studies; Stomach Neoplasms; Stomach Ulcer; Treatment Outcome

Improving the quality of ulcer healing (QOUH) is one of the valid methods of prevention of relapse of gastric ulcers. We investigated the effect of lafutidine on the QOUH of gastric ulcer compared with famotidine in a randomized, multi-centre controlled trial. Consecutive 80 patients with a gastric ulcer were randomly assigned to receive twice daily either lafutidine (10 mg) or famotidine (20 mg) for 12 weeks. Esophagogastroduodenoscopy was performed to examine the ulcer healing rate and rate of flat type ulcer scars using dye-contrast. The gastric ulcer healing rate was 92.1% in the lafutidine group (35/38) and 94.7% in the famotidine group (36/38). The rate of flat-type ulcer scars was significantly higher in the lafutidine group (68.4%, 26/38) than in the famotidine group (42.1%, 16/38) (P = 0.021). In conclusion, the present study demonstrated that lafutidine, as compared to famotidine, yields a significantly superior QOUH in patients with gastric ulcers in the clinical setting.

Topics: Acetamides; Adult; Aged; Anti-Ulcer Agents; Drug Administration Schedule; Famotidine; Female; Gastroscopy; Humans; Male; Middle Aged; Piperidines; Pyridines; Stomach Ulcer; Treatment Outcome; Wound Healing

This study reports preliminary results of a controlled, multicenter trial on the quality of ulcer healing induced by lansoprazole (LPZ) or roxatidine (R) in gastric ulcer (GU) or duodenal ulcer (DU) patients. Group A received LPZ 30 mg q.d. and group B received R 75 mg b.i.d. All drugs were given for 8 weeks in GU and for 6 weeks in DU. Endoscopy and gastric biopsy were performed to detect Helicobacter pylori before and on completion of treatment. The healing rates of groups A and B were 100 and 69.2%, respectively, in GU and 100 and 70.0%, respectively, in DU. This difference (p < 0.01) was significant between the two groups in GU. There was no significant difference between the two groups in the S2 stage shift rate in GU and DU. The H. pylori clearance rates of groups A and B were 33.3 and 20.0%, respectively, in GU and 62.5 and 33.3%, respectively, in DU. The differences in treatment response (healing rates and S2 shift rates) between the LPZ group and the R group may be related to the differences in suppression of acid secretion and in bactericidal effects on H. pylori.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Duodenal Ulcer; Female; Helicobacter pylori; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Peptic Ulcer; Piperidines; Proton Pump Inhibitors; Stomach Ulcer

Stimulation of gastric motility has been supposed to accelerate the healing of gastric ulcer. The combination of the prokinetic drug cisapride and the H2 blocker ranitidine was tested in the treatment of uncomplicated gastric ulcer.. Cisapride, 20 mg twice daily (Cis), and ranitidine, 150 mg twice daily (Ran), were given as monotherapies and in the combination 20 mg cisapride and 150 mg ranitidine daily (Cis + Ran) for a maximum of 8 weeks. The study was multicentre, randomized, and double-blind.. A total of 197 patients were included. Healing rates in the per-protocol analysis after 4 and 8 weeks' treatment were 61%/84%, 52%/69%, and 61%/92% for the Cis + Ran (n = 56), Cis (n = 58), and Ran (n = 59) treatment groups. No statistically significant difference in healing rates was seen when comparing Cis + Ran with the monotherapies. Symptom relief at the end of treatment was significantly better in the Ran group than in the Cis + Ran group with regard to epigastric pain (p = 0.01) and vomiting (p = 0.05). Patients' global evaluation of treatment was in favour of Ran in comparison with Cis + Ran treatment (p = 0.04).. Combination of cisapride and ranitidine in the treatment of gastric ulcer did not enhance the healing rate or improve symptom relief in patients treated for uncomplicated gastric ulcer when compared with the monotherapies.

Topics: Anti-Ulcer Agents; Cisapride; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines; Ranitidine; Stomach Ulcer; Time Factors

For prophylaxis of gastroduodenal lesions induced by non-steroidal antirheumatic drugs (NSAID) acid-lowering as well as mucosa protective substances are used. Direct comparison of both therapeutic regimens are lacking. In randomized parallel studies the gastroduodenal tolerability of 100 mg diclofenac daily in slow-release form was evaluated in the presence and absence of 150 mg roxatidine (CAS 78273-80-0) daily as well as in the presence of 75 mg bid roxatidine or 200 micrograms bid misoprostol (CAS 59122-46-2). The drugs were taken over a period of 14 days. Endoscopic controls were performed at entry, as well as after 14 days of treatment. A quantitative damaging score was used. Study A: Both treatment groups (n = 20) had at entry comparable mucosal damages: placebo/diclofenac: 0.9 +/- 0.1 (+/- SEM), roxatidine/diclofenac: 0.9 +/- 0.1; after 14 days of treatment the score increased in the diclofenac/placebo group to 7.6 +/- 1.9 and, in the corresponding diclofenac/roxatidine group, only to 2.1 +/- 0.9. The difference between the two treatment groups after 14 days was significant (p < 0.05). Study B: Both treatment groups (n = 24) had comparable mucosal damages at entry: diclofenac/roxatidine: 0.9 +/- 0.1, diclofenac/misoprostol: 0.8 +/- 0.1. Following 14 days treatment with 100 mg diclofenac daily the damaging score in both group rose to comparable levels: roxatidine group 2.1 +/- 0.7 and misoprostol group 2.0 +/- 0.4 (n.s.). The data suggest that for prophylaxis of NSAID-induced gastroduodenal lesions substances with different mechanism of action can be used. The findings underline the complex way by which NSAID can damage the mucosa of the upper gastrointestinal tract.

Topics: Adult; Anti-Ulcer Agents; Delayed-Action Preparations; Diclofenac; Gastric Acid; Gastroscopy; Histamine H2 Antagonists; Humans; Misoprostol; Piperidines; Stomach Ulcer

Among the factors involved in the pathogenesis of gastric ulcer, the reduced clearing capacity of the stomach seems to play an important role. On this basis, cisapride, which improves gastrointestinal motility, enhances gastric emptying, and prevents duodenogastric reflux, may be effective in the treatment of the gastric ulcer. We randomly allocated 60 consecutive patients, with uncomplicated antral gastric ulcer (diameter 5-25 mm), into three groups of treatment: cisapride 20 mg b.i.d. (C), ranitidine 150 mg b.i.d. (R), cisapride 20 mg b.i.d. + ranitidine 150 mg b.i.d. (C+R). Endoscopic examination with biopsy specimens was performed on admission, after 4 weeks and (if ulcer not healed) after 8 weeks of therapy. Three patients were lost to follow-up (two in C and one in C+R), and three were withdrawn, due to malignant ulcer (one case in R) or to side effects (one case of diarrhea in C, one case of headache in C+R). Healing rates at 4 weeks were 41.1% in C, 52.6% in R, and 50.0% in C+R; at 8 weeks they were 88.2% in C, 89.4% in R, and 94.4% in C+R. Though the lack of a placebo arm makes final considerations difficult, the results were similar in all three groups, with no evident differences. In conclusion, therapy with cisapride appears as effective as H2-blocker alone or combined treatments in healing benign gastric ulcer.

Topics: Adult; Aged; Anti-Ulcer Agents; Cisapride; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines; Ranitidine; Stomach Ulcer; Time Factors

A double-blind, randomized, parallel-group multicenter study was conducted in 120 patients with gastric ulcer to compare cisapride, 10 mg t.i.d., and ranitidine, 150 mg b.i.d., administered over 8 weeks. No significant differences between the results of the two treatments were found in terms of ulcer healing or symptomatic relief. Endoscopy showed that the incidence of medium-sized or large ulcers was reduced from 85% at the start to 11% and 4%, respectively, after 4 and 8 weeks in the ranitidine group, and from 98% to 15% and 4%, respectively, in the cisapride group. By week 8, the ulcer was healed in 89% of the ranitidine patients, and in 86% of the cisapride patients. Moderate to severe diurnal epigastric pain--the predominant symptom--was reported by about 80% of the patients in week 8, and by less than 15% from week 4 on. The response to nocturnal epigastric pain, epigastric pressure, sensation of fullness and other symptoms was similar. Except for gastrointestinal symptoms in the cisapride patients--nearly always indicative of enhanced bowel contractions--the occurrence of adverse effects was similar in the two groups. The improvement in gastrointestinal motility under cisapride, would appear to be as effective as suppression of acid secretion in the treatment of gastric ulcer disease.

Topics: Adult; Aged; Cisapride; Double-Blind Method; Female; Gastrointestinal Motility; Gastroscopy; Humans; Male; Middle Aged; Piperidines; Ranitidine; Stomach Ulcer; Treatment Outcome

Topics: Cisapride; Clinical Trials as Topic; Constipation; Dyspepsia; Gastroesophageal Reflux; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Intestinal Pseudo-Obstruction; Piperidines; Serotonin Antagonists; Stomach Ulcer

Topics: Adult; Aged; Cisapride; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Ranitidine; Serotonin Antagonists; Stomach Ulcer; Time Factors

Roxatidine acetate is a novel H2-receptor antagonist with a chemical structure different to the earlier drugs of this type. It is a potent inhibitor of histamine-mediated gastric acid secretion and in animal models is 4 to 6 times as potent as cimetidine. In a multicentre double-blind clinical trial of over 700 patients with gastric or duodenal ulcers roxatidine acetate 75 mg twice daily and cimetidine 200mg four times daily produced endoscopically confirmed and subjective and objective healing rates in excess of 90% for both types of ulcer, with no significant difference between the treatments. Roxatidine acetate's efficacy in stomal ulcer (marginal ulcer) and reflux oesophagitis has been confirmed in non-comparative studies of up to 8 weeks' duration. The overall incidence of adverse reactions in 1623 patients treated with roxatidine acetate 75 mg twice daily was 1.7%, with skin rashes and constipation the most frequently reported side effects.

Topics: Adult; Cimetidine; Duodenal Ulcer; Female; Gastrins; Histamine H2 Antagonists; Humans; Japan; Male; Middle Aged; Pepsinogens; Peptic Ulcer; Piperidines; Prolactin; Stomach Ulcer; Time Factors

A randomised multicentre double-blind study was conducted to compare the efficacy and safety of roxatidine acetate 75 mg twice daily and ranitidine 150 mg twice daily in 295 patients with endoscopically confirmed gastric ulcers. Substantial reductions in ulcer diameters and healing rates of 85.6 and 88.2% for roxatidine acetate and ranitidine, respectively, were obtained after 8 weeks of treatment. There was no difference in healing rates between smokers and non-smokers in either group. The relief of day and night-time epigastric pain was comparable for both treatment groups, as was antacid tablet consumption, with the majority of patients pain-free at the end of the study. The incidence of side effects was low, with 3 patients treated with roxatidine acetate, compared with 4 ranitidine-treated patients, reporting adverse reactions. There were no clinically significant changes in laboratory values. The present study suggests that 8 weeks of treatment with roxatidine acetate 75 mg twice a day produces effective and safe acute management of gastric ulcers which is comparable to that seen with ranitidine.

Topics: Adolescent; Adult; Aged; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain; Piperidines; Ranitidine; Stomach Ulcer

In 363 outpatients with endoscopically confirmed gastric ulcers the efficacy and safety of roxatidine acetate 150 mg at night was compared to 75 mg twice daily. After 8 weeks' treatment substantial reductions in gastric ulcer diameter were obtained in addition to healing rates of 83.7 and 86% for the twice daily and night-time dosing, respectively. Daily reductions in day and night-time epigastric pain were obtained with no significant differences between treatment groups for pain scores or antacid tablet consumption. Furthermore, cigarette smoking did not influence the healing rates produced by either treatment schedule. 26 patients reported 32 adverse reactions and 5 patients discontinued treatment because of side effects, although only 1 of these was a severe reaction. The present data suggest that a single night-time dose of roxatidine acetate 150 mg is as safe and effective as the twice daily dose regimen for the management of acute gastric ulceration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Random Allocation; Stomach Ulcer; Time Factors

Pharmacodynamic studies revealed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion. When administered orally as a capsule containing a granule formulation, the drug displayed modified-release properties, which led to a sustained suppression of gastric acid secretion. Clinical trials revealed that roxatidine acetate, 75 mg twice daily and 150 mg at night, was highly effective in healing duodenal and gastric ulcers and in reducing ulcer pain, over 4, 6, and 8 weeks of therapy. A steady reduction in diameter was observed in those ulcers not completely healed during therapy. The single bedtime dose regimen, while producing the same degree of healing as the divided daily dose during controlled clinical trials, may be of greater value in therapeutic use owing to improved patient compliance. In all efficacy criteria (cure, reduction in ulcer size, and pain relief) there was no significant difference between roxatidine acetate in a total daily dose of 150 mg, ranitidine in a total daily dose of 300 mg, and cimetidine in a total daily dose of 800 mg. Prevention of gastric and duodenal ulcer relapse was achieved by roxatidine acetate, 75 mg at night for 6 months, in about 70% of patients, as determined in open, pilot studies--a rate comparable to those reported for cimetidine and ranitidine. Roxatidine acetate shares with ranitidine an improved safety profile when compared with cimetidine. Human pharmacology studies and short-term and long-term clinical trials have all shown that roxatidine acetate is an exceptionally well tolerated compound, without the antiandrogenic activity and interference with hepatic drug metabolism which have characterized cimetidine treatment. A reason for the improved safety profile of roxatidine acetate may be its greater potency than cimetidine (six times less potent) and ranitidine (half as potent), so that lower doses of roxatidine acetate, representing a lower chemical load, are therapeutically effective. The novel structure of roxatidine acetate probably also underlies the improved safety of the compound.

Topics: Cimetidine; Clinical Trials as Topic; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; Stomach Ulcer

The influence of Domperidone and Metoclopramide on the Serum Gastrin Level and Gastric Acid Secretion was investigated in a crossed, randomized double blind study in 12 male subjects aged 29 years on the average and presenting a healthy stomach. Neither after Domperidone nor after Metoclopramide could a significant change in Gastrin Level and Acid Secretion be observed. Since both Domperidone and Metoclopramide exert a motility promoting but not secretagogue effect on the upper gastrointestinal tract, both drugs are suitable for the treatment of disordered motility and evacuation related to ulcer disease, as well as for the treatment of postoperative gastroatonia.

Topics: Adult; Antiemetics; Benzimidazoles; Domperidone; Gastric Acid; Gastrins; Gastrointestinal Motility; Humans; Male; Metoclopramide; Piperidines; Postoperative Complications; Stomach Ulcer

The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.

Topics: Animals; Edema; Ethanol; Gastric Mucosa; Glutathione; Leucine; Male; Malondialdehyde; Mice; Oxidative Stress; Piperidines; Quinolines; Ruthenium Red; Stomach Ulcer; Sulfonamides; Superoxide Dismutase; TRPV Cation Channels; Up-Regulation

Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism.. We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue.. AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity.. Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

Topics: Administration, Oral; Animals; Catalase; Diclofenac; Disease Models, Animal; Ethanol; Male; Mice; Omeprazole; Oxidative Stress; Peroxidase; Piperidines; Receptors, Adiponectin; Stomach Ulcer; Superoxide Dismutase; Treatment Outcome

Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the C

Topics: Administration, Oral; Animals; Biological Availability; Biomarkers; Case-Control Studies; Disease Models, Animal; Male; Metabolomics; Piperidines; Rats; Stomach Ulcer; Tandem Mass Spectrometry; Tissue Distribution; Treatment Outcome

Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1-18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities. All the active compounds inhibited the formation of gastric ulcers and increased the formation of gastric mucin secretion. Compound 15 was found to be the most potent compound of the series as anti-ulcer agent. Additional experimental studies on lead compound 15 will result in a new class of orally active molecule for anti-ulcer activity.

Topics: Animals; Anti-Ulcer Agents; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Models, Molecular; Molecular Structure; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Stomach Ulcer; Structure-Activity Relationship

This research was conducted to evaluate the hypothesis that gastric ulcers caused by the NSAID diclofenac sodium (DCF) can be prevented by the soluble epoxide hydrolase inhibitor TPPU.. Mice were administered a single dose of 10, 30 or 100mg/kg of DCF. Once an ulcerative dose of DCF was chosen, mice were pretreated with TPPU for 7days at 0.1mg/kg to evaluate anti-ulcer effects of the sEH inhibitor on anatomy, histopathology, pH, inflammatory markers and epithelial apoptosis of stomachs.. Diclofenac caused ulceration of the stomach at a dose of 100mg/kg and a time post dose of 6h. Ulcers generated under these conditions were associated with a significant increase in the levels of TNF-α and IL-6 in serum and increased apoptosis compared to control mice. Pretreatment with TPPU resulted in a decrease of ulceration in mice treated with DCF with a significant decrease in the level of apoptosis, TNF-α and IL-6 in the serum in comparison to diclofenac-treated mice. TPPU did not affect the pH of the stomach, whereas omeprazole elevated the pH of the stomach as expected. A similar anti-ulcer effect was observed in sEH gene knockout mice treated with DCF.. The sEH inhibitor TPPU decreases the NSAID-induced stomach ulcers.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Apoptosis; Diclofenac; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoxide Hydrolases; Gene Deletion; Hydrogen-Ion Concentration; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Omeprazole; Phenylurea Compounds; Piperidines; Stomach Ulcer; Time Factors; Tumor Necrosis Factor-alpha

The aim of this study was to evaluate the pharmacokinetics (PK) of single and multiple doses of oral lafutidine tablets and the effect of food on the PK properties in healthy Chinese subjects. The tolerability and the effect of gender on the PK properties were also evaluated to acquire more PK information.. Three PK studies were conducted in 12 healthy Chinese subjects (6 male, 6 female). Study 1 was a single-dose, three-period, three-dose level (10, 20, and 40 mg), three-sequence cross-over study under fasting conditions. Study 2 was a repeat-dose study (10 mg twice daily over 6 days; all 12 subjects). Study 3 was a two-period, two-sequence cross-over single-dose (10 mg) food interaction study. All randomizations (study 1, study 3) were done to ascertain 1:1 gender ratio per sequence. A validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to determine plasma lafutidine concentrations. PK parameters were calculated by the non-compartmental method.. The area under the time-concentration curve (AUC) and maximum plasma concentration (C. The PK of lafutidine showed dose proportionality. There was no significant accumulation of lafutidine tablets with multiple dosing. Food did not affect the degree of lafutidine absorption, but it did reduce the rate of absorption. Further study is needed regarding the effect of gender on lafutidine. Lafutidine was well tolerated within the dose range 10-40 mg, and no serious adverse events were observed.

Topics: Acetamides; Administration, Oral; Adult; Anti-Ulcer Agents; Area Under Curve; Asian People; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Monitoring; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Piperidines; Pyridines; Stomach Ulcer; Tablets; Tandem Mass Spectrometry

In this study, lafutidine (LAF) was used as a model compound to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA) through various techniques, including STD-NMR, WaterLOGSY-NMR, (1)H NMR relaxation times, tr-NOESY, molecule docking calculation, FT-IR spectroscopy, and CD spectroscopy. The analyses of STD-NMR, which derived relative STD (%) intensities, and WaterLOGSY-NMR, determined that LAF bound to HSA. In particular, the pyridyl group of LAF was in close contact with HSA binding pocket, whereas furyl group had a secondary binding. Competitive STD-NMR and WaterLOGSY-NMR experiments, with warifarin and ibuprofen as site-selective probes, indicated that LAF preferentially bound to site II in the hydrophobic subdomains IIIA of HSA. The bound conformation of LAF at the HSA binding site was further elucidated by transferred NOE effect (tr-NOESY) experiment. Relaxation experiments provided quantitative information about the relationship between the affinity and structure of LAF. The molecule docking simulations conducted with AutoDock and the restraints derived from STD results led to three-dimensional models that were consistent with the NMR spectroscopic data. The presence of hydrophobic forces and hydrogen interactions was also determined. Additionally, FT-IR and CD spectroscopies showed that LAF induced secondary structure changes of HSA.

Topics: Acetamides; Binding Sites; Circular Dichroism; Humans; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Domains; Protein Structure, Secondary; Protons; Pyridines; Serum Albumin; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Stomach Ulcer; Warfarin

The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knockout mice. The compounds were administered intracerebroventricularly. It was found, that 1. Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191pmol); the effect of angiotensin II (191pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2nmol). 2. Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3. The gastroprotective effect of angiotensin II (191pmol) was reduced by atropine (1mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus-mediated mechanism.

Topics: Angiotensin II; Animals; Atropine; CHO Cells; Cricetulus; Ethanol; Gastric Mucosa; Gene Expression Regulation; Injections, Intraventricular; Lactones; Lipoprotein Lipase; Male; Mice; Mice, Knockout; Orlistat; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Cannabinoid, CB1; Signal Transduction; Stomach; Stomach Ulcer; Vagotomy; Vagus Nerve

The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 (≥16 mg/kg) for 6 days displayed decreased CB1 receptor density and function in the brain, as assessed in [(3)H]SR141716A binding and CP55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, respectively. In contrast, normal CB1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB1 receptor tachyphylaxis/tolerance or cannabinoid dependence.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Arachidonic Acids; Benzodioxoles; Brain Chemistry; Cyclohexanols; Diclofenac; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Endocannabinoids; Glycerides; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Stomach Ulcer; Substance Withdrawal Syndrome; Substance-Related Disorders

Cannabis is widely used for treating a number of gastrointestinal ailments, but its use is associated with several adverse effects, particularly when the route of administration is via smoking. In the present study, we tested the effects (in rats) of a simple extract of medicinal cannabis (called "MFF") for its ability to promote resolution of colitis, to prevent gastric damage induced by naproxen, and to reduce gastric distention-induced visceral pain. Intracolonic, but not oral administration of MFF dose-dependently reduced the severity of hapten-induced colitis, an effect not reduced by pretreatment with antagonists of CB1 or CB2 receptors. Significant improvement of symptoms (diarrhea, weight loss) and healing of ulcerated tissue was evident with MFF treatment at doses that did not produce detectable urinary levels of 9-Δ-tetrahydrocannabinol (THC). MFF increased colonic hydrogen sulfide synthesis in healthy rats, but not in rats with colitis, and had no effect on colonic prostaglandin E2 synthesis. Orally, but not systemically administered MFF dose-dependently reduced the severity of naproxen-induced gastric damage, and a CB1 antagonist reversed this effect. MFF prevented gastric distention-induced visceral pain via a CB2-dependent mechanism. These results demonstrate that a simple extract of medicinal cannabis can significantly enhance resolution of inflammation and injury, as well as prevent injury, in the gastrointestinal tract. Interestingly, different cannabinoid receptors were involved in some of the effects. MFF may serve as the basis for a simple preparation of cannabis that would produce beneficial effects in the GI tract with reduced systemic toxicity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cannabis; Colitis; Gastrointestinal Tract; Hydrogen Sulfide; Indoles; Male; Naproxen; Piperidines; Plant Extracts; Protective Agents; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Stomach Ulcer; Visceral Pain

The present study was designed to evaluate the anti-ulcerogenic properties of an alkaloid chromane, rohitukine from Dysoxylum binectariferum. Anti-ulcer potential of rohitukine was assessed in cold restrained, pyloric ligated and ethanol induced ulcers in rats. In addition, rohitukine was tested in vitro for H(+) K(+)-ATPase inhibitory activity in gastric microsomes. Moreover, we studied the role of rohitukine on the cytosolic concentration of Ca(2+) in parietal cell-enriched cell suspension in order to ascertain its mechanism of action. Cytoprotective activity was evaluated through PGE(2) level. Rohitukine significantly attenuated the ulcers in cold restraint ulcer (CRU) model in a dose-related manner. Moreover, it significantly lowered the free acidity and pepsin activity in pyloric ligated rats while improved the depleted level of mucin. Furthermore, rohitukine significantly reversed the cold restrained-induced increase in gastrin level. Our in vitro study revealed that rohitukine moderately inhibited the microsomal H(+) K(+)-ATPase activity with respect to positive control omeprazole. Furthermore, rohitukine potently antagonized the gastrin-elicited increase in cytosolic Ca(2+) level in parietal cell-enriched suspension. In ethanol-induced gastric lesions in rats, rohitukine significantly inhibited the formation of erosions and increased PGE(2) content showing more potency than reference drug sucralfate. Our results thus suggest that rohitukine possess significant anti-ulcer and anti-gastrinic activity in rats. It is likely that gastro-protective influences of rohitukine are dependent partly on its acid-lowering potential and partly on cytoprotective property. The acid-reducing effect of rohitukine might be attributed to its lowering effect on gastrin production and/or antagonism of gastrin-evoked functional responses of parietal cells. Thus, rohitukine represent a useful agent in the treatment of peptic ulcer disease.

Topics: Animals; Anti-Ulcer Agents; Antineoplastic Agents; Calcium; Chromones; Cold Temperature; Disease Models, Animal; Ethanol; Gastrins; H(+)-K(+)-Exchanging ATPase; Ligation; Meliaceae; Microsomes; Piperidines; Plant Bark; Proton Pump Inhibitors; Pylorus; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Physiological

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Acetamides; Anti-Ulcer Agents; Central Nervous System Diseases; Clopidogrel; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Pyridines; Rabeprazole; Stomach Ulcer; Ticlopidine

It has been proposed that free radicals, reactive oxygen species (ROS) and reactive nitrogen species play a critical role in gastric mucosal damage. It is well known that the exposure of gastric mucosa to damaging factors such as stress and nonsteroidal anti-inflammatory drugs produces acute ulcers that are mainly mediated by ROS. The aim of the present study was to investigate the gastroprotective properties of bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC), a novel nonpeptidyl low-molecular-weight radical scavenger, in two different models of gastric ulcer in rats caused by ROS. IAC was orally administered at the doses of 50 and 100 mg/kg before gastric ulceration induced by indomethacin and water immersion and restraint stress. The number and severity of gastric lesions, following macroscopic inspection of the mucosa, were evaluated and expressed as an ulcer score. Oral administration of IAC dosed at 50 and 100 mg/kg was able to significantly prevent gastric ulceration induced by indomethacin and by stress. The gastroprotective effect of IAC on gastric mucosa could be attributed to its intrinsic antioxidant activity, suggesting it as a novel antiulcer agent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Disease Models, Animal; Free Radical Scavengers; Indomethacin; Male; Piperidines; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Psychological

We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Chromones; Gastric Acid; Gastric Mucosa; Indomethacin; Ischemia; Leukotriene Antagonists; Leukotrienes; Male; Mice; Mice, Inbred C57BL; Peroxidase; Piperidines; Receptors, Leukotriene; Reperfusion Injury; RNA, Messenger; Stomach Ulcer

We investigated the ability of a novel low-molecular-weight free-radical scavenger, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), to protect the gastric mucosa from indometacin-induced ulceration.. The pharmacological effects of IAC, administered orally or by intraperitoneal injection, on the gastric mucosa were assessed in a rat model of gastric ulceration induced by indometacin. The effect of IAC on the level of prostaglandin PGE2 in the gastric mucosa was also investigated.. IAC, which has no ulcerative activity per se, had a preventive and protective activity against indometacin-induced gastric ulceration. This effect could be only partially attributed to a modulatory effect of IAC on PGE2 levels; it is more likely to be due to the antioxidant activity of the compound.. Taking into account the properties of IAC and the mechanisms underlying gastric inflammation elicited by non-steroidal anti-inflammatory drugs, IAC may represent a novel anti-ulcer agent.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antioxidants; Dinoprostone; Disease Models, Animal; Esters; Free Radical Scavengers; Gastric Mucosa; Indomethacin; Injections, Intraperitoneal; Male; Piperidines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats.. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration.. The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected.. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Topics: Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CXCL1; Dinoprostone; Gastric Mucosa; Indomethacin; Inflammation; Interleukin-1beta; Male; Peroxidase; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Stomach Ulcer; Triazines; Triazoles; Tumor Necrosis Factor-alpha

Nociceptin (N/OFQ) and nocistatin (NST) are two endogenous neuropeptides derived from the same precursor protein, preproN/OFQ. The aim of the present work was to study the effect of NST on the ethanol-induced mucosal damage compared with that of N/OFQ following intracerebroventricular (i.c.v.) administration in the rat and to analyze the mechanism of the gastroprotective action. It was found that both NST and N/OFQ reduced the mucosal lesions in the same dose range (0.2-1 nmol i.c.v.), but in higher doses (2-5 nmol i.c.v.) the gastroprotective effect of both peptides was highly diminished. The gastroprotective effect of N/OFQ (1 nmol), but not that of NST (1 nmol), was reduced by the selective nociceptin receptor antagonist J-113397 (69 nmol i.c.v.). Similarly, decrease of the gastroprotective effect was observed after the combination of NST (1 nmol) with N/OFQ (0.6 or 1 nmol). However, addition of the gastroprotective effects was observed, when lower dose (0.2 nmol) of NST was given prior to N/OFQ (0.6 nmol). The gastroprotective effect of both N/OFQ and NST was antagonized by naloxone (27 nmol), beta-funaltrexamine (20 nmol), naltrindole (5 nmol) and norbinaltorphimine (14 nmol), the mu-, delta- and kappa-opioid receptor antagonists, respectively, given i.c.v. The mucosal protection was significantly decreased after bilateral cervical vagotomy. The present findings suggest that NST similar to N/OFQ, may also induce gastric mucosal protective action initiated centrally in a vagal-dependent mechanism. Opioid component is likely to be involved in the gastroprotective effect of both NST and N/OFQ.

Topics: Animals; Benzimidazoles; Ethanol; Gastric Mucosa; Injections, Intraventricular; Narcotic Antagonists; Nociceptin; Opioid Peptides; Piperidines; Rats; Rats, Wistar; Receptors, Opioid; Stomach Ulcer; Vagotomy

Sensory neuron activation reduces water-immersion restraint stress (WIR)-induced gastric mucosal injury by inhibiting neutrophil activation through increase in endothelial production of prostacyclin. This study was designed to examine whether lafutidine, which is an H(2)-receptor antagonist and activates sensory neurons, inhibits neutrophil activation, thereby reducing WIR-induced gastric mucosal injury. Lafutidine enhanced WIR-induced increases in gastric tissue levels of calcitonin gene-related peptide (CGRP) and 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, whereas famotidine, another H(2)-receptor antagonist, did not. Such lafutidine-induced increases in gastric tissue levels of 6-keto-PGF(1alpha) were reversed by pretreatment with capsazepine, an inhibitor of sensory neuron activation, CGRP(8-37), a CGRP antagonist, and indomethacin. Lafutidine inhibited acid-induced exacerbation of gastric mucosal injury in animals subjected to WIR by inhibiting neutrophil activation, whereas famotidine did not. Lafutidine synergistically increased CGRP release from isolated rat dorsal root ganglion neurons in the presence of anandamide, but famotidine did not. These observations suggest that lafutidine might reduce WIR-induced gastric mucosal injury not only by inhibiting acid secretion but also by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetamides; Animals; Anti-Ulcer Agents; Arachidonic Acids; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Cyclooxygenase Inhibitors; Disease Models, Animal; Endocannabinoids; Famotidine; Ganglia, Spinal; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Neurons, Afferent; Neutrophil Activation; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Pyridines; Rats; Rats, Wistar; Restraint, Physical; Stomach Ulcer; Stress, Psychological

We examined the prophylactic effect of lafutidine, a histamine H2 receptor antagonist, on the morphological and functional derangement of the rat stomach after the administration of 5-fluorouracil (5-FU) in the absence or presence of taurocholate Na (TC). Rats were given 5-FU p. o. once daily for 5 days. After 18 hr fasting, the animals were given omeprazole to inhibit acid secretion. Under urethane anesthesia, the stomach was mounted on an ex-vivo chamber, perfused with 100 mM HCl, and both the transmucosal potential difference (PD) and gastric mucosal blood flow (GMBF) were simultaneously measured before and after exposure of the mucosa to 20 mM TC for 30 min. The 5-FU treatment lowered the basal PD with a decrease in the mucosal height and caused few haemorrhagic lesions in the stomach when perfused with 100 mM HCl for 2 hr. The 5-FU treatment had no influence on the reduced PD response caused by TC, but significantly impaired the increase in GMBF after exposure to TC, resulting a marked aggravation of gastric lesions. Lafutidine, given together with 5-FU for 5 days, significantly antagonized the deleterious effect of 5-FU on the basal PD and the GMBF response to TC, and prevented the aggravation of gastric lesions. These effects of lafutidine were not mimicked by cimetidine and disappeared due to the chemical ablation of capsaicin-sensitive afferent neurons. We conclude that 1) 5-FU treatment caused the morphological and functional derangement of the stomach and increased the mucosal vulnerability against acid, and 2) lafutidine prevents such changes caused by 5-FU treatment, probably mediated through capsaicin-sensitive afferent neurons.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Cimetidine; Dinoprostone; Drug Interactions; Fluorouracil; Gastric Mucosa; Hydrochloric Acid; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Stomach; Stomach Ulcer; Taurocholic Acid

Recent studies have shown that stimulation of cannabinoid 1 (CB1) receptor reduces the area of ischemic myocardial necrosis and affects activity of the digestive tract. The aim of the present study was to check whether the administration of CB1 receptor agonist or antagonist affects the stress-induced gastric ulceration and development of edematous pancreatitis.. Experiments were performed on rats. Gastric lesions were induced by water immersion and restrain stress (WRS). Acute pancreatitis was induced by cerulein. Prior to WRS or before and during cerulein administration, a natural endogenous ligand for CB1 receptor, anandamide was administered intraperitoneally at the dose of 0.8, 1.5 or 3.0 micromol/kg. A synthetic CB1 receptor antagonist, AM 251 (ALEXIS(R) Biochemicals) was administrated at the dose of 4 micromol/kg i.p. alone or in combination with anandamide at the dose of 1.5 micromol/kg.. Administration of anandamide reduced gastric lesions and this effect was associated with am increase in gastric mucosal blood flow and mucosal DNA synthesis; whereas serum level of pro-inflammatory interleukin-1 beta was reduced. Treatment with AM 251 aggravated gastric damage and reversed protective effect of anandamide administration. Opposite effect was observed in the pancreas. Administration of anandamide increased dose-dependently the severity of pancreatitis. In histological examination, we observed an increase in pancreatic edema and inflammatory infiltration. Also, treatment with anandamide augmented the pancreatitis-induced increase in serum level of lipase, amylase, poly-C ribonuclease, and pro-inflammatory interleukin-1 beta; whereas pancreatic DNA synthesis was reduced. Treatment with AM 251 reduced histological and biochemical signs of pancreatic damage and reversed deleterious effect of anandamide in cerulein-induced acute pancreatitis.. Activation of CB1 receptors evokes opposite effects in the stomach and pancreas: in the stomach, exhibits protective effect against stress-induced gastric mucosal lesions; whereas in the pancreas, increases the severity of cerulein-induced pancreatitis.

Topics: Acute Disease; Animals; Arachidonic Acids; Cannabinoids; Ceruletide; DNA; Endocannabinoids; Gastric Mucosa; Interleukin-1beta; Male; Pancreas; Pancreatitis; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Restraint, Physical; Stomach Ulcer; Stress, Physiological

It is assumed that an overproduction of gastric acid is the most important factor in the development of peptic ulcer. However, it has been also demonstrated that gastric defense mechanisms, which prevent mucosal injury, are enhanced by the same factors that increase acid secretion. The aim of this study was to examine the role of capsaicin-sensitive sensory nerves and histamine H1, H2, and H3 receptors in histamine-induced gastroprotection against stress ulcers. Studies were performed on rats with intact or ablated sensory nerves. Ablation of sensory nerves was induced by neurotoxic doses of capsaicin. Gastric ulcers were induced by water immersion and restrain stress. Before exposure to stress, rats were pretreated with saline (control), histamine (10 micromol/kg), histamine H1 receptor antagonist pyrilamine (100 micromol/kg), histamine H2 receptor antagonist ranitidine (100 micromol/kg), histamine H3 receptor antagonist thioperamide (100 micromol/kg), or a combination of histamine with these histamine receptor antagonists.. Histamine alone reduced ulcer area evoked by stress and this effect was accompanied by an increase in gastric mucosal blood flow and mucosal DNA synthesis, as well as a decrease in serum pro-inflammatory interleukin-1beta concentration. Treatment with combination of pyrilamine plus histamine caused an increase in gastric ulcer area and serum interleukin-1beta above the value observed in animals treated with saline, and this effect was accompanied by a decrease in gastric mucosal DNA synthesis. Ranitidine, in combination with histamine, reduced the ulcer area and serum interleukin-1beta to a minimal value, whereas gastric mucosal blood flow and DNA synthesis reached a maximal value. Pretreatment with thioperamide before histamine administration abolished the histamine-evoked reduction in gastric ulcer area. Ablation of sensory nerves increased the ulcer area in animals treated with saline or histamine, or histamine in combination with pyrilamine or ranitidine. In animals with sensory nerves ablation combined with administration of thioperamide plus histamine, the ulcer area was similar to that in saline-treated animals with intact sensory nerves. We conclude that: (1) histamine exhibits protective effect against stress-induced gastric ulcer and that this gastroprotection is related to stimulation of histamine H1 and H3 receptors; (2) blockade of histamine H2 receptors exhibited beneficial effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors.

Topics: Animals; Capsaicin; DNA; Gastric Mucosa; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Immersion; Interleukin-1; Male; Neurons, Afferent; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Regional Blood Flow; Restraint, Physical; Stomach Ulcer; Stress, Physiological

Although functions of the neurokinin-1 receptor have been well explored in neurogenic inflammation and immunoinflammatory responses, little is known about neurokinin-1 receptors during gastric wound healing. The aim of this study was to assess whether neurokinin-1 receptors play a role in gastric wound healing.. In vitro neurokinin-1 receptor autoradiography and immunohistochemistry were performed to identify, locate, and quantify neurokinin-1 receptors during wound healing in rodents with cryoulcers in the gastric corpus and antrum. Moreover, to assess the functionality of these receptors, the effect of the neurokinin-1 receptor antagonist NKP608 on gastric wound healing was quantified in vivo in wild-type and cyclooxygenase-2(-/-) mice.. Regenerative glands of the mucosal ulcer margin of rat cryoulcers of the gastric corpus showed strong expression of neurokinin-1 receptors in binding studies between days 3 and 22, with little expression on days 29-84. In addition, strong immunoreactivity for neurokinin-1 receptors was detected on the cell membrane of these regenerative glands. Expression of neurokinin-1 receptors in regenerative glands was confirmed in the rat antrum and the mouse gastric corpus. Moreover, in vivo functional tests during gastric ulcer healing showed that cell proliferation in the regenerative epithelia of the ulcer margin was significantly decreased by NKP608 compared with placebo; furthermore, gastric ulcer healing was significantly delayed by NKP608 both in wild-type and cyclooxygenase-2(-/-) mice.. This report shows the time-limited overexpression of neurokinin-1 receptors in the mucosal repair tissue of the corpus and antrum. Our in vitro and in vivo data suggest that neurokinin-1 receptors are involved in gastric wound healing.

Topics: Animals; Autoradiography; Cell Division; Cell Membrane; Cyclooxygenase 2; Female; Freezing; Gastric Mucosa; Immunohistochemistry; Isoenzymes; Mice; Mice, Knockout; Neurokinin-1 Receptor Antagonists; Piperidines; Prostaglandin-Endoperoxide Synthases; Quinolines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Regeneration; Stomach Ulcer; Time Factors; Tissue Distribution; Wound Healing

Effects of vanilloid-receptor agonists and antagonists on HCl-induced gastric lesions in rats were investigated to elucidate the role of vanilloid receptor type 1 (VR1) in gastric mucosal defense mechanisms.. Gastric lesions in rats were evaluated after intragastric administration of 0.6 N HCl. The localization of VR1 in the stomach was investigated immunohistochemically.. Intragastric administration of capsaicin inhibited the formation of gastric lesions in a dose-dependent manner (0.1-2.5 mg/kg). The functional VR1 antagonists ruthenium red and capsazepine markedly aggravated HCl-induced gastric lesions in rats. The gastroprotective effect of capsaicin was attenuated by ruthenium red or capsazepine. It is reported that resiniferatoxin, [6]-gingerol and lafutidine are compounds that activate VR1 and/or capsaicin-sensitive afferent neurons. These compounds significantly inhibited the formation of HCl-induced gastric lesions, and their gastroprotective effects were inhibited by treatment with ruthenium red. The immunohistochemical studies revealed that nerve fibers expressing VR1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers, especially the circular muscle layer.. The results of this study suggest that VR1 plays a protective role in the gastric defensive mechanism in rats.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Catechols; Diterpenes; Famotidine; Fatty Alcohols; Gastric Mucosa; Hydrochloric Acid; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Drug; Stomach Ulcer

Lafutidine is a novel histamine H(2)-receptor antagonist with a potent and long-lasting anti-acid secretory effect that has also been found to have a potent gastroprotective effect. We investigated the effect of lafutidine on gastric mucosal injury induced in rats with the use of water-immersion restraint stress (WRS) by examining serum calcitonin gene-related peptide (CGRP) concentrations, which we measured with the use of an enzyme immunometric assay. WRS-induced mucosal erosive injury in the stomach was reduced significantly by both lafutidine and famotidine pretreatment (from 7.79 +/- 2.02 mm(2) to 3.09 +/- 0.74 mm(2) and 4.05 +/- 1.18 mm(2), respectively). A single administration of lafutidine or famotidine did not change the serum CGRP concentration from the control value when these drugs were administered without WRS. Lafutidine pretreatment before WRS caused a significant increase in serum CGRP concentration compared with famotidine (lafutidine, 86.64 +/- 9.52 pg/mL; famotidine, 47.55 +/- 4.35 pg/mL; control, 58.43 +/- 6.07 pg/mL). Our results suggest that lafutidine augments CGRP release from the rat stomach when administered before the induction of WRS.

Topics: Acetamides; Animals; Calcitonin Gene-Related Peptide; Famotidine; Histamine H2 Antagonists; Immersion; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Physiological; Water

It is well known that capsaicin-sensitive nerve signaling acts as a protective factor against various ulcerogens. However, the contribution of topical capsaicin-sensitive nerves within the stomach to rapid restitution has not been fully investigated. The present study was therefore conducted focusing on recovery from gastric mucosal damage induced by ethanol in vivo.. Male Sprague-Dawley rats were fasted and anesthetized. 51Cr-EDTA was administered intravenously and gastric mucosal integrity was continuously monitored by measuring the blood to lumen 51Cr-EDTA clearance. Capsaicin or vehicle was irrigated before, together with or after the perfusion of 20% ethanol, followed by perfusion with saline. In another experiment, ruthenium red, a capsaicin-sensitive cation antagonist, was given before the ethanol-capsaicin perfusion. Furthermore, this study was verified using lafutidine, a histamine H2-receptor antagonist, which has a gastric mucosal protective action through the capsaicin-sensitive afferent nerves.. When capsaicin was administered before ethanol treatment, mucosal damage was significantly reduced and recovery was significantly rapid compared to the control. When capsaicin (160 micro M) and ethanol were administered simultaneously, the mucosal damage was exacerbated but recovery was nevertheless more rapid than the control group. With a lower dose of capsaicin (80 micro M), mucosal damage was not exacerbated and recovery was enhanced. When capsaicin or lafutidine was administered after the induction of ethanol injury no change was detected regarding the damage. However, recovery was significantly accelerated. Ruthenium red reversed the action of post-treatment with capsaicin on restitution.. These results indicate that luminal administration of capsaicin exerts protection against and accelerates restitution from gastric damage in the very early phase after ethanol injury. This action is probably due to activation of topical capsaicin-sensitive afferent nerves in the rat.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capillary Permeability; Capsaicin; Edetic Acid; Ethanol; Gastric Mucosa; Male; Neurons, Afferent; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Ruthenium Red; Stomach Ulcer

The effect of cannabinoid drugs (i.p.) on cold/restraint stress-induced gastric ulcers was studied in rats. The cannabinoid receptor agonist (WIN 55,212-2, 0.1-1 mg/kg), but not the less active isomer WIN 55,212-3 (1 mg/kg), reduced gastric ulceration. The protective effect of WIN 55,212-2 (1 mg/kg) was counteracted by the cannabinoid CB1 receptor antagonist SR141716A, but not by the cannabinoid CB2 receptor antagonist SR144528. These results indicate that the antiulcer effect of the cannabinoid receptor agonist WIN 55,212-2 is mediated by cannabinoid CB1 receptors.

Topics: Animals; Benzoxazines; Camphanes; Male; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Stomach Ulcer; Stress, Physiological

Defunctionalization of capsaicin-sensitive afferent nerves by pretreatment with a neurotoxic dose of capsaicin aggravates gastric ulcers in rats. In the present study, we investigated the roles of vanilloid receptors in gastric antral ulcers, using vanilloid receptor agonists and antagonists. Gastric antral ulcers were induced by a combination of diethyldithiocarbamate and 1 N HCl in refed rats. The administration of ruthenium red (1.5 mg/kg, s.c., twice daily) aggravated gastric antral ulcers (ulcer index: control, 33.7+/-13.7 mm(2); ruthenium red, 99.9+/-11.0 mm(2)). A similar result was observed in rats pretreated with a neurotoxic dose of capsaicin. On the other hand, capsaicin (1-10 mg/kg, p.o., twice daily) inhibited antral ulcer formation (ulcer index: control, 99.2+/-20.6 mm(2); capsaicin 10 mg/kg, 37.0+/-11.7 mm(2)). A similar effect was obtained in rats treated with the novel antiulcer drug, lafutidine (3-10 mg/kg, p.o., twice daily), which has gastroprotective activity mediated by capsaicin-sensitive afferent nerves. The antiulcer effects of capsaicin and lafutidine were abolished by ruthenium red and by pretreatment with a neurotoxic dose of capsaicin. These results suggest that vanilloid receptors play a gastroprotective role in gastric antral ulcers. In addition, treatment with ruthenium red may be an alternative tool for defunctionalization of capsaicin-sensitive afferent nerves.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Cations; Ditiocarb; Famotidine; Ion Channels; Male; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Drug; Ruthenium Red; Stomach Ulcer

We investigated the recurrence of ulcers in rats after treatment with FRG-8813, (+/-)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyridyl] oxy-(Z)-2-butenyl] acetamide, a novel histamine H(2)-receptor antagonist. Chronic gastric ulcers were induced by serosa-searing with a hot metal bar, and the ulcer healing and recurrence after treatment with FRG-8813 or famotidine were evaluated by endoscopy for 160 days. At the dose of 30 mg/kg p. o., once daily, the treatment with FRG-8813 or famotidine for 60 days, which was stopped earlier if the ulcer had healed, accelerated the ulcer healing significantly. A subsequent follow-up study on the healed rats showed that the cumulative recurrence rate of rats healed by FRG-8813 was lower than that of naturally healed rats or rats healed by famotidine. In many cases of rats healed by FRG-8813, the regenerated mucosa was normal in contrast with the control of famotidine-healed animals. The mucosal regeneration index of the gastric ulcer after 10 days' administration of FRG-8813 was significantly higher than that obtained with famotidine. After cessation of the treatment with famotidine for 7 days, rebound hyperacidity was induced; but such rebound did not occur with FRG-8813. Considering the low recurrence rate of ulcers after FRG-8813 treatment, we suggest that FRG-8813 treatment may provide additional benefits in peptic ulcer therapy.

Topics: Acetamides; Animals; Disease Models, Animal; Endoscopy, Gastrointestinal; Famotidine; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Male; Outcome Assessment, Health Care; Piperidines; Pyridines; Rats; Rats, Wistar; Secondary Prevention; Stomach Ulcer

Many clinicians have believed that H2-blockers and proton pump inhibitors ameliorate gastric ulcers via their antacid function. We examined the effects of these antacids on granulocytes. Gastric ulcer patients were administered an H2-blocker or proton pump inhibitor for a week and the number of granulocytes and the superoxide production were examined. To determine the trafficking of granulocytes, mice were exposed to restraint stress for 24 hr. The H2-blocker decreased the number of granulocytes, while the proton pump inhibitor suppressed their superoxide production in humans and mice. The major function of H2-blockers and proton pump inhibitors in curing gastric ulcers seems to be their suppressive effects on granulocytes. In this case, stress accelerates the trafficking of granulocytes from the bone marrow to the gastric mucosa. If we demonstrate a role for granulocytes in gastric ulcer formation, an gap in the acid-pepsin theory and the Helicobacter pylori theory is filled in.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Animals; Anti-Ulcer Agents; Depression, Chemical; Granulocytes; Histamine H2 Antagonists; Humans; Lansoprazole; Leukocyte Count; Luminescent Measurements; Mice; Middle Aged; Omeprazole; Piperidines; Proton Pump Inhibitors; Stomach Ulcer; Stress, Physiological; Superoxides

To study the effects of piperine (Pip) on several experimental gastric ulcers in rats and mice.. The gastric mucosa damage was induced by stress, indometacin, HCl, and pyloric ligation in rats or mice. The number of gastric ulcers, the volume and acidity of gastric juices, and pepsin A activity were detected.. Pip 25, 50, 100 mg/kg ig protected animals from gastric ulceration in a dose-dependent manner. The inhibitory rates were 16.9%, 36.0%, and 48.3% in stress ulcers; 4.4%, 51.1%, and 64.4% in indometacin ulcers; 19.2%, 41.5%, and 59.6% in HCl ulcers; 4.8%, 11.9%, and 26.2% in pyloric ligation ulcers, respectively; Pip inhibited the volume of gastric juice, gastric acidity, and pepsin A activity.. Pip has the protective effects against gastric ulceration.

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastric Juice; Gastric Mucosa; Male; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Stomach Ulcer; Tyrosine

Neutrophils are considered to be involved in the pathogenesis of Helicobacter pylori-associated gastroduodenal diseases on account of their potent biological functions as effector cells. Troxipide, a new antiulcer compound used for patients with gastric ulcer or gastritis, has been shown to inhibit migration and activation of guinea pig neutrophils, but little is known about the pharmacological effects on human neutrophils.. To study the effects of troxipide on chemotactic migration and superoxide generation by human neutrophils.. The chemotactic response of neutrophils was determined in a multi-well chamber with a polycarbonate filter and the generation of O2- by neutrophils was measured using a chemiluminescence method. Concentrations of troxipide in gastric mucosa were measured by high-performance liquid chromatography.. Incubation of neutrophils with 10(-6) to 10(4) M troxipide caused inhibition of recombinant interleukin-8-induced migration. These concentrations of troxipide also inhibited superoxide generation by neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine or platelet activating factor. These phenomena were not simply due to the direct cytotoxic effects since the above concentrations of troxipide did not induce neutrophil apoptosis. The concentrations of troxipide detected in the gastric mucosa after oral administration were in the range able to inhibit chemotactic migration and superoxide generation by neutrophils in vitro.. These results suggest that troxipide may exert its therapeutic effect in patients with gastric ulcer or gastritis by inhibiting inflammatory responses and mucosal injury mediated by neutrophils in gastric mucosa.

Topics: Adult; Anti-Ulcer Agents; Cell Culture Techniques; Cell Movement; Chemotaxis; Chromatography, High Pressure Liquid; Helicobacter Infections; Humans; Inflammation; Intestinal Mucosa; Neutrophils; Piperidines; Stomach Ulcer; Superoxides

Since endogenous vasopressin has been reported to be an aggressor in the gastric mucosa and a vasoconstrictor in the gastric circulation, we investigated the gastric cytoprotective effects of OPC-21268, a newly developed, nonpeptide, orally active vasopressin-1 receptor antagonist, on ethanol-induced gastric injury in rats. The rats were treated with OPC-21268 or placebo 2 hr before ethanol administration, and the gastric mucosa was evaluated macroscopically for ulcer damage, and histologically for gastric mucosal injury. Gastric mucosal blood flow, erythrocyte volume, and erythrocyte velocity were also measured in groups given saline, ethanol alone, and ethanol after OPC-21268. To investigate the role of systemic or locally secreted vasopressin, we measured plasma and tissue (gastric mucosa) vasopressin concentrations after ethanol or vehicle administration. Prophylactic OPC-21268 treatment improved the gastric ulcer score in a dose-dependent manner, and histological examination demonstrated that the drug significantly ameliorated the gastric injury induced by ethanol. The hemodynamic values obtained in the OPC-21268-treated and ethanol-treated group were similar to those in the saline control group, but values were significantly (P < 0.05) higher for gastric mucosal blood flow and erythrocyte velocity and lower for erythrocyte volume compared to the group given ethanol alone. Plasma vasopressin concentrations were not significantly different in the control group and at 15, 30, and 60 min after administration of ethanol. However, ethanol administration caused a threefold increase in gastric tissue vasopressin level (P < 0.05) compared to the control group. These results suggested that OPC-21268 relieved congestive hyperemia in the gastric mucosa and ameliorated the mucosal injury caused by ethanol, probably as a result of inhibition of vasopressin-mediated actions on the stomach. The vasopressin involved was probably generated locally in the gastric mucosa after ethanol administration.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Ethanol; Gastric Mucosa; Male; Microcirculation; Piperidines; Quinolones; Rats; Stomach Ulcer; Vasopressins

Reactive oxygen-derived species and redox-active metals are implicated in mediation of the pathogenesis of gastric mucosal damage and ulceration. Therefore, common strategies of intervention employ metal chelators, antioxidative enzymes, and low-molecular-weight antioxidants (LMWA). The aim of the present study was to elaborate the mechanism(s) responsible for the protection provided by nitroxide radicals in the experimental model of gastric ulceration. Fasted male rats were treated ig with 1 ml 96% ethanol, with or without ig pretreatment with nitroxide or hydroxylamine. In several experiments, rats were injected ip or iv with iron(III) or iron(II) prior to ethanol administration. Rats were sacrificed 10 min after ethanol administration, the stomach was removed, washed and lesion area measured. Pretreatment with iron(III) complexed to nitrilotriacetate or citrate, aggravated the extent of the gastric injury. Conversely, iron(II) inhibited the formation of lesions. The nitroxides were rapidly reduced to their respective hydroxylamines and demonstrated antiulcerative activity for rats treated with iron. However, injecting the hydroxylamine resulted in a similar tissue distribution of nitroxide/hydroxylamnine but did not provide protection. The results show that: (a) the nitroxide radicals, rather than their respective non-radical reduced form, are the active species responsible for protection; (b) nitroxides protect by dismutating O2*- and possibly indirectly increasing the NO level; (c) unlike classical LMWA which are reducing agents, nitroxides inhibit gastric damage by acting as mild oxidants, oxidizing reduced metals and pre-empting the Fenton reaction; and (d) the nitroxides act catalytically as recycling antioxidants.

Topics: Animals; Anti-Ulcer Agents; Antioxidants; Copper; Cyclic N-Oxides; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Hydroxylamines; Iron Compounds; Male; Nitrogen Oxides; Oxidants; Piperidines; Rats; Rats, Sprague-Dawley; Spin Labels; Stomach Ulcer

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ammonia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsaicin; Central Nervous System Depressants; Ethanol; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Capsaicin; Cimetidine; Denervation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Famotidine; Food; Indomethacin; Male; Nitroarginine; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Wound Healing

Lafutidine ((+/-)-2-(furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyr idyl)oxy-(Z)-2-butenyl)acetamide) is a novel histamine H2-receptor antagonist and has been shown to exhibit a potent gastroprotective activity in addition to its antisecretory action. In the present study, we examined the effects of lafutidine on the mucosal ulcerogenic and potential difference (PD) responses induced by monochloramine (NH2Cl) in rat stomachs.. Oral administration of NH2Cl at 120 mmol/L produced haemorrhagic lesions in the stomach in unanaesthetized rats.. Lafutidine (3-30mg/kg), given p.o., showed a dose-dependent and significant inhibition against damage caused by NH2Cl: the effect was significant at 10 mg/kg or greater but disappeared almost totally in the sensory deafferented animals following capsaicin pretreatment. Likewise, capsaicin (10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.) exhibited a potent protection against NH2Cl-induced gastric lesions. Topical application of NH2Cl (10 mmol/L) reduced transmucosal PD in ex-vivo stomachs of anaesthetized rats, but this PD response was also prevented by pre-exposure to lafutidine, in a dose-dependent and sensory neuron-sensitive manner. Mucosal exposure to NH4OH (60 mmol/L) also caused PD reduction in ex-vivo stomachs made ischaemic by bleeding from the carotid artery (1 mL/100 g bodyweight), resulting in severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischaemia were attenuated by prior application of lafutidine as well as taurine, a scavenger of NH2Cl. The former effect was, again, dependent on the sensory neurons. Intraluminal capsaicin but not cimetidine was also effective in preventing a PD response to NH2Cl.. These results suggest that lafutidine, but not cimetidine, protects the stomach against NH2Cl, whether occurring endogenously or administered exogenously and that this action may be mediated by capsaicin-sensitive sensory neurons.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Chloramines; Cimetidine; Gastric Mucosa; Histamine H2 Antagonists; Ischemia; Membrane Potentials; Neurons, Afferent; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach; Stomach Ulcer

Effect of lafutidine ((+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl] oxy-(Z)-2-butenyl] acetamide, FRG-8813), a novel antiulcer agent, on the healing and relapse in acetic acid-induced gastric ulcer in rats was investigated. Lafutidine at 1, 3 or 10 mg/kg, twice daily for 10 days reduced the ulcer area in a dose-dependent manner, and the effect by 10 mg/kg of lafutidine was significant. The effect of famotidine at 1 mg/kg and cimetidine at 30 mg/kg, which have almost equal antisecretory activity to lafutidine at 10 mg/kg, on the ulcer area was not significant. Effect on the healing and relapse was assessed by endoscopy for 25 weeks after the induction of gastric ulcer. Drugs were administered twice daily for 11 weeks. Lafutidine at 3 mg/kg and famotidine at 1 mg/kg accelerated the healing, but cimetidine at 30 mg/kg did not. Cumulative relapse rate and inflammatory cell infiltration were significantly reduced in rats initially treated with lafutidine. Famotidine and cimetidine had no effect. In conclusion, lafutidine accelerated ulcer healing and prevented ulcer relapse in rats.

Topics: Acetamides; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Dose-Response Relationship, Drug; Famotidine; Histamine H2 Antagonists; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Recurrence; Stomach Ulcer

Apnea in the neonatal period frequently is associated with prematurity. Full-term infants who develop apnea usually have associated clinical conditions such as infection, shock, metabolic disorders, neonatal abstinence syndrome, intracranial pathology, and gastroesophageal reflux. Gastric ulcer also is a rare phenomenon in the neonatal period. We describe a full-term infant presenting with apnea. Upon investigation, a 6-channel pneumocardiogram revealed central apnea and multiple episodes of low esophageal pH (< 4), which is suggestive of gastroesophageal reflux. This was confirmed by an upper gastrointestinal series. A small antral ulcer crater also was demonstrated. When assessing the etiology of apnea in a full-term infant, gastroesophageal reflux and gastric ulcer should be considered.

Topics: Anti-Ulcer Agents; Apnea; Cisapride; Esophagus; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Male; Nose; Oxygen; Piperidines; Pulmonary Ventilation; Pulse; Ranitidine; Respiration; Stomach Ulcer

We have studied the effect of the newly synthesized agent, roxatidine bismuth citrate (N-[3-(3-(1-piperidinyl-methyl)phenoxy)propyl]-hydroxyacetamide-2- hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex), code name MX1, against acetylsalicylic acid (ASA)- and indomethacin-induced gastric mucosal damage in rats. Effects of MX1 (12.5, 50, 125, 184, 250 mg/kg) were compared to the effects of equimolar doses of roxatidine and bismuth subcitrate. Effect of MX1 (10(-6) M) on mucin biosynthesis measured by [3H] glucosamine incorporation in rat gastric corpus has been determined. MX1-pretreatment dose-dependently decreased the mean ulcer number and length in all doses used in an extent similar to that of roxatidine and more pronounced in comparison with bismuth subcitrate. The morphometrical results have been confirmed histomorphologically. The biosynthesis of mucin was found to be significantly enhanced after MX1 addition. The results of the present study suggest that MX1 has a gastroprotective effect against ASA- and indomethacin-induced ulcers which might be due both to its H2-blocking and mucus-stimulating activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Drug Combinations; Drug Evaluation, Preclinical; Gastric Mucosa; Indomethacin; Male; Organometallic Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer

The present study was performed to examine whether gastric prokinetic drugs may induce damage in the rat stomach under normal and prostaglandin (PG)-deficient conditions. Male SD rats fasted for 18 hr were administered subcutaneously with three different prokinetic drugs such as metoclopramide (3-60 mg/kg), ondansetron (0.3-3 mg/kg), and cisapride (3-30 mg/kg). Half the number of these animals were pretreated with indomethacin (5 mg/kg) subcutaneously for induction of PG deficiency in the stomach. Administration of these drugs increased gastric motor activity in a dose-dependent manner and expedited gastric emptying at lower doses than those affecting gastric motility; the potency of the hypermotility effect was in the following order: metoclopramide = ondansetron > cisapride. None of these drugs alone caused gross damage in the stomach, although whitish rough areas were observed in the gastric mucosa along the folds. In the rats pretreated with indomethacin, however, both metoclopramide and ondansetron provoked multiple hemorrhagic lesions in the gastric mucosa. Indomethacin at this dose showed over 90% inhibition of cyclooxygenase activity without causing any damage in the stomach, and this PG-deficient effect was not affected by coadministration with the prokinetic drugs. The mucosal ulcerogenic responses induced by metoclopramide in the presence of indomethacin were significantly inhibited by prior administration of atropine (1 mg/kg) or PGE2 (300 micrograms/kg) at doses that inhibited gastric hypermotility induced by metoclopramide. These results suggest that: (1) gastric prokinetic drugs induce damage in rat stomachs under PG-deficient conditions at the doses that enhance gastric motility and emptying but not at the doses that expedite gastric emptying only, and (2) gastric hypermotility has the potential to cause gross damage in the stomach, supporting the importance of gastric motility as a pathogenic element of gastric lesions.

Topics: Animals; Cisapride; Dose-Response Relationship, Drug; Gastric Acid; Gastric Emptying; Gastric Mucosa; Gastrointestinal Agents; Gastrointestinal Motility; Indomethacin; Male; Metoclopramide; Ondansetron; Piperidines; Prostaglandin Antagonists; Prostaglandins; Rats; Rats, Sprague-Dawley; Stomach; Stomach Ulcer

The biosynthesis of sulfated mucin in gastric tissue was investigated in cold-stress and indomethacin (CSI)-induced gastric ulcer models. To examine the synthesis of gastric sulfated mucin, [35S]H2SO4 (sulfate) incorporation into gastric mucin was measured. The treatment of CSI inhibited the incorporation of [35S]sulfate after 2 hr. The gastric acid hypersecretion or the formation of severe ulcer was observed at 1 or 4 hr after the CSI-treatment, respectively. Pibutidine hydrochloride (IT-066), a novel H2-receptor antagonist, (0.3 mg/kg, s.c.) inhibited the formation of ulcer and reversed the inhibition of mucin sulfation by the CSI-treatment, whereas atropine sulfate, a muscarinic receptor antagonist, (1.0 mg/kg, s.c.) did not inhibit the development of ulcer nor decrease in the mucin sulfation at 6 hr after the CSI-treatment. IT-066 inhibited the total acid output (T.A.O.) due to the reduction of the acidity in the gastric juice, whereas atropine inhibited the T.A.O. due to that of the volume. These results indicated that a different mode of action between IT-066 and atropine on gastric acid secretion influences their actions in the incorporation of [35S]sulfate and the formation of ulcer in the CSI-treated rat. Therefore, it is considered that the reduction of biosynthesis of gastric sulfated mucin following acid hypersecretion may be responsible for the formation of gastric ulcer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atropine; Cold Temperature; Ethanol; Gastric Mucins; Histamine H2 Antagonists; Indomethacin; Male; Muscarinic Antagonists; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological; Sulfates

The influence of KU-1257 on the recurrence and relapse of acetic acid ulcers in rats was investigated grossly and histologically in comparison with that of cimetidine. The ulcer was induced by topical application of glacial acetic acid at the junction of the corpus and antrum on the anterior wall of the stomach. The drug was administered from the 5th to the 153rd day after the ulcer induction and then discontinued to the 238th day. The healing rates of the control groups (control) rose until the 119th day after the ulcer induction, followed by ups and downs. The quality of healing in the regenerated mucosa and the granulation tissue of the healed ulcer was poor, resulting in the recurrence and relapse of ulcers. The recurrence and relapse of ulcers also occurred in the cimetidine groups (CIM). On the other hand, the KU-1257 groups (KU-1257) showed much lower recurrence and relapse rates of ulcers than the control and CIM groups. Moreover, KU-1257, unlike CIM, improved the quality of ulcer healing throughout the period of its administration and even after it was discontinued. These results suggest that KU-1257 improves the quality of ulcer healing, and this may contribute to the low recurrence and relapse rates of ulcers.

Topics: Acetates; Acetic Acid; Animals; Chronic Disease; Cimetidine; Histamine H2 Antagonists; Male; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar; Recurrence; Stomach Ulcer; Time Factors

The present study was designed to examine the role of endogenous sulphydryls (SHs) in the gastro-protection induced by cisapride (CIS) (10, 25 and 50 mg kg-1 i.p.), a potent benzamide stimulating gastrointestinal motility in mucosal injury induced by 50% v/v ethanol. Results were compared with those of 5-hydroxytryptamine (5-HT) (10mg kg-1). Ethanol mucosal damage was significantly reduced by treatment with CIS and 5-HT. On the contrary, administration of n-ethylmaleimide (NEM) (10 mg kg-1) an SH alkylator, markedly worsened lesion formation and counteracted the protective effect of CIS. Rats pretreated with CIS significantly increased the total sulphydryls as reflected in the non-protein and protein fractions however, 5-HT treatment showed a fall in the non-protein level. The present results suggest that 5-HT-ergic dependent mechanisms have no relation to the gastro-protection afforded by CIS in this experimental model. It is possible that mucosal SHs could be involved.

Topics: Animals; Anti-Ulcer Agents; Cisapride; Disease Models, Animal; Ethanol; Ethylmaleimide; Gastric Mucosa; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Piperidines; Rats; Rats, Wistar; Serotonin; Stomach Ulcer; Sulfhydryl Compounds; Sulfhydryl Reagents

MX1 (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ 2-hydroxypropane-1,2,3-tricarboxylate bismuth (3+) complex) is a novel salt of the active metabolite of H2-antagonist roxatidine with a complex of bismuth with citric acid. In a model of ethanol-induced ulcers in male Wistar rats, both roxatidine and the bismuth salt reduced the number and the total length of lesions. Comparison of roxatidine and MX1 at equimolar doses of 160 mumol kg-1 showed a more potent cytoprotective effect of MX1. The potency of anti-secretory and antiacidic effects of MX1 was more than twice that of roxatidine on histamine-stimulated secretion in female Wistar pylorus-ligated rats. Microbiological tests with the reference bismuth preparation De-Nol showed prominent anti-Helicobacter properties of MX1 in-vitro. Both test compounds had similar range of MICs to Helicobacter pylori, from 4 to 64 microgram bismuth mL-1. The cytoprotective, antisecretory, anti-acidic and anti-Helicobacter properties of the new agent MX1 warrant further more extensive pharmacological and clinical trials.

Topics: Animals; Anti-Ulcer Agents; Ethanol; Female; Gastric Mucosa; Helicobacter pylori; Histamine; Male; Microbial Sensitivity Tests; Organometallic Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer; Tricarboxylic Acids

Topics: Aged; Aged, 80 and over; Anti-Ulcer Agents; Drug Eruptions; Female; Histamine H2 Antagonists; Humans; Lichenoid Eruptions; Piperidines; Ranitidine; Stomach Ulcer

The antiulcer effects and protective mechanisms of cisapride, a prokinetic benzamide agonist of 5-HT3 and antagonist of 5-HT4 receptors, were investigated in gastric mucosal injury induced by pretreatment with 50% v/v ethanol in rats. The duration of the protective effect was also studied and the results were compared with those of 5-HT. 240 min after administration of cisapride (10, 25 and 50 mg/kg) the total area of gastric lesions decreased significantly, in macroscopical and histological evaluations, and the mucus, hexosamine, and sulphated glycoprotein content were significantly increased. Indomethacin partially reversed cisapride protection suggesting that the beneficial antiulcer effects of this drug could be mediated in part by prostaglandins. This study confirms that this benzamide, in this experimental model, enhances gastric PGE2 production. We also investigated the time course of action of 5-HT, 30-240 min before ethanol administration, and our study not only demonstrates the ulcerogenic action of the amine (30 min of pretreatment) but also its protective nature, shown macroscopic and microscopically, after 240 min of its administration, without any effect on PGs production. These findings suggest a new gastroprotective feature of cisapride partly explained through a prostaglandin-dependent mechanism and possibly independent of its 5-HT activity.

Topics: Animals; Anti-Ulcer Agents; Cisapride; Dinoprostone; Ethanol; Gastric Mucosa; Indomethacin; Male; Mucus; Piperidines; Rats; Rats, Wistar; Serotonin; Stomach Ulcer; Time Factors

1. The antiulcerogenic effects of cisapride, a potent benzamide-stimulating gastrointestinal motility agent, were studied on cold-resistant and pylorus-ligated gastric ulcers. Acidity, composition of gastric secretion, and quantitative and qualitative changes on mucus glycoprotein content were also determined. These effects were compared with those of ranitidine (50 mg/kg) and omeprazol (10 mg/kg). 2. Oral cisapride (10-100 mg/kg) dose-relatedly and significantly (P < 0.01, P < 0.05) decreased the severity of the lesions induced by cold-resistant stress. In stressed rats, cisapride increased the amount of mucus secretion and markedly enhanced the glycoprotein content. Morphometric evaluation of mucus secretion revealed a significant increase in both the PAS area (neutral glycoproteins) and Alcian blue area (sulfated glycoproteins). 3. In 4 h pyloric-ligated animals, cisapride (10-100 mg/kg) showed a significant reduction in the number and severity of ulcers (P < 0.01) and histamine concentration (P < 0.01, P < 0.001). In addition, at the highest doses (50-100 mg/kg), cisapride produced a significant decreases in acidity; however, it did not alter the gastric volume secretion or pepsin concentrations. 4. These results suggest that cisapride shows antiulcerogenic effects which could possibly be explained through antisecretory and cytoprotective mechanisms involving an enhancement of cuality and production of gastric mucus.

Topics: Animals; Anti-Ulcer Agents; Cisapride; Gastric Juice; Gastric Mucosa; Histamine Release; Ligation; Male; Mucus; Omeprazole; Pepsin A; Piperidines; Ranitidine; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological

FRG-8813 ((+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2- pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions against 1% NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl- and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11.1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection. Furthermore, prior administration of tetrodotoxin, the calcitonin gene-related peptide (CGRP) antagonist hCGRP or NG-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Drug Interactions; Gastric Mucosa; Gastrointestinal Motility; Histamine H2 Antagonists; Male; Omeprazole; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

The effects of IGN-2098 on the healing process of acetic acid-induced gastric ulcer was investigated in comparison with the other histamine H2-receptor antagonists, famotidine and roxatidine acetate HCl, in rats. Ulcer was induced by the injection of acetic acid solution (20%, 0.05 ml). From the 4th day to 17th day after the ulcer induction, drugs were orally administered twice a day. On the 18th day after the ulcer induction, rats were sacrificed to measure the ulcer index macroscopically and to take pictures of the stomachs. Judging from the photographs, the prominence of ulcer the edge was graded into 4 classes, which showed a significant correlation with the histological amount of connective tissue at the ulcer edge. All drugs accelerated the healing of the ulcer, and the effect of IGN-2098 was the most remarkable. In addition, IGN-2098-treatment exhibited more marked inhibition against the prominence of the ulcer edge as compared with the control group. Based on these results, it is concluded that IGN-2098 may be a useful drug for the clinical treatment of ulcer and that the healing acceleration by IGN-2098 without prominence of the ulcer edge may induce no relapse of the ulcer after healing.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Famotidine; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Flurbiprofen (FP) was esterified with a histamine H2-antagonist, PPA (N-[3-(3-(1-piperidinylmethyl)phenoxy)-propyl]-2-(2- hydroxyethylthio)acetamide), to yield a chimera drug, FP-PPA, and its protective effect toward gastric lesions, other toxicities and the disposition kinetics were investigated, as compared to those of FP, in multiple oral administration to rats for 2 weeks. FP-PPA scarcely formed any disorder of the gastric mucosa following multiple oral administration. The body weight changes and hematological and serum biochemical parameters were found to be similar to those in the control group. Some drug metabolizing enzyme activities tested were the same as those of the control group. Further, the pharmacokinetic parameters were found to be the same after both single and multiple oral administration. On the other hand, in the FP treated group, the inhibition of body weight increase and changes in serum biochemical and hematological parameters were observed due to malabsorption. The absorption rate constant was increased significantly after multiple administration as compared to that of single administration. It is suggested that these changes in the absorption process of FP are due to variations in gastrointestinal permeability derived from gastrointestinal damage. The results obtained here indicate clearly that the chimera drug FP-PPA scarcely forms any disorder of the gastric mucosa, even after multiple oral administration, and is thus a potential candidate for oral use.

Topics: Absorption; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Blood Cell Count; Body Weight; Cytosol; Flurbiprofen; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Piperidines; Rats; Rats, Wistar; Stomach Ulcer

It is not presently well understood whether the histamine H2 receptor antagonist has a function other than the inhibition of gastric acid secretion, such as the effect on the gastric mucosal defence mechanism. In this paper, we report the effect of FRG-8813 (N-[4-[4-(piperidinylmethyl)pyridyl-2-oxy]-(Z)-2-butenyl]-2- (furfurylsulfinyl) acetamide), a new histamine H2 receptor antagonist, on the rat gastric mucin content with or without 0.15N HCl-ethanol (60 %)-induced gastric damage. The prior administration of FRG-8813 significantly inhibited the occurrence of macroscopically observable hemorrhagic lesions induced by the acidified ethanol treatment. Using a newly developed biochemical method, the mucin content of the deep corpus and antral mucosa of the acidified ethanol-treated animals was significantly reduced to 50% and 32% of the control, respectively. These reductions were inhibited by the pretreatment with FRG-8813. Total mucin content in the entire stomach recovered to about 80% of the control value after pretreatment with FRG-8813. A single oral administration of FRG-8813 (30 mg/kg) caused no significant change in the total mucin content, but mucin in the adherent mucus gel layer selectively and significantly increased to 250% of the control. These results suggest that FRG-8813 not only inhibits acid secretion but may also affect the gastric mucosal defensive mechanism as well.

Topics: Acetamides; Analysis of Variance; Animals; Ethanol; Gastric Mucins; Gastric Mucosa; Histamine H2 Antagonists; Male; Piperidines; Premedication; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

It has been reported that time to peptic ulcer healing is shorter with proton pump inhibitors (PPI) than with H2-receptor antagonists (H2-RA). This study was designed to examine the difference in the healing process between gastric ulcers treated with PPI and those treated with H2-RA.. The healing of deep gastric ulcers treated with PPI (n = 11) or H2-RA (n = 13) was evaluated with endoscopic ultrasonography (EUS). Every 2 weeks during treatment EUS variables such as the width and the depth of the ulcer crater, the thickness and size of the low echoic area of the ulcer base, and the distance of the disrupted muscularis propria were measured. The contraction rates of EUS variables, the ratios of the contraction rate of the depth to that of the width of the ulcer crater (D/W ratio) and the contraction rate of the distance of the disrupted muscularis propria layer to that of the width of the ulcer crater (Dm/W ratio) were calculated.. Only at week 2 were the D/W ratio and Dm/W ratio significantly higher in the group receiving PPI (D/W ratio, 1.79 +/- 0.701; Dm/W ratio, 0.938 +/- 0.207) than in the group receiving H2-RA (D/W ratio, 1.10 +/- 0.559; Dm/W ratio, 0.641 +/- 0.166).. This study demonstrated that PPI therapy is associated with more rapid and stronger healing than obtained with H2-RA during the early treatment period.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Famotidine; Female; Gastroscopy; Histamine H2 Antagonists; Humans; Lansoprazole; Male; Middle Aged; Nizatidine; Omeprazole; Piperidines; Proton Pump Inhibitors; Stomach Ulcer; Ultrasonography, Interventional; Wound Healing

We have developed a unique rat AGML model produced by ischemia/reperfusion plus 0.2% ammonia (I/R.NH3), either treatment which would not induce mucosal injury when used alone. The effects of troxipide and other gastric mucosal defensive drugs were investigated with this I/R.NH3-induced AGML model and other AGML models in rats. The following results were obtained: 1) Like allopurinol, troxipide at 50-200 mg/kg, p.o. dose-dependently prevented I/R.NH3-induced development of AGML and also the ischemia/reperfusion-induced increase of gastric mucosal thiobarbituric acid (TBA)-reactive substances; 2) Troxipide at 10(-6)-10(-4) M, like allopurinol, inhibited concentration-dependently in vitro xanthine oxidase activity in gastric mucosal homogenates; 3) Troxipide at 50-200 mg/kg, p.o. inhibited AGMLs induced by bleeding plus 0.2% ammonia and by 1.0% ammonia alone; and 4) Troxipide and sofalcone were similar in preventing all AGMLs tested and also the increase of mucosal TBA-reactive substances, but somewhat differed from teprenone, cetraxate hydrochloride, azulene plus L-glutamine and sucralfate. These findings suggest that troxipide may inhibit I/R.NH3-induced AGML development by preventing generation of oxygen free radicals and by protecting against mucosal fragility due to reduced energy metabolism from poor blood flow and also against ammonia-induced disruption of the gastric mucosal barrier. Therefore, troxipide may be highly effective for various AGMLs with multifactor involvement.

Topics: Acute Disease; Ammonia; Animals; Disease Models, Animal; Gastric Mucosa; Male; Piperidines; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Stomach Ulcer

The effects of KU-1257 (N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]urea, CAS 120958-90-9) on gastric lesions and duodenal ulcers in rats were compared with those of various antiulcer drugs. KU-1257 prevented the formation of gastric lesions induced by necrotizing agents. The ID50 values against 0.6 N HCl-induced gastric lesions were 18.6 mg/kg, p.o. and 6.0 mg/kg, i.p. The ID50 values against absolute ethanol- and 1% NH3-induced gastric lesions were 12.4 and 9.2 mg/kg, p.o., respectively. Roxatidine acetate, troxipide and teprenone at doses of 100-200 mg/kg p.o. also significantly prevented the formation of gastric lesions by these necrotizing agents. Cimetidine, ranitidine and famotidine had no protective effect against these gastric lesions even at a dose of 200 mg/kg p.o. KU-1257, roxatidine acetate and famotidine inhibited acetylsalicylic acid- and water-immersion stress-induced gastric lesions. KU-1257, roxatidine acetate and famotidine inhibited mepirizole-induced duodenal ulcers, but not troxipide and teprenone. These results suggest that KU-1257 is more potent in the mucosal protective action than troxipide, teprenone, roxatidine acetate and other histamine H2-receptor antagonists.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Cyanides; Duodenal Ulcer; Epirizole; Ethanol; Gastric Mucosa; Histamine H2 Antagonists; Hydrochloric Acid; Immersion; Intestinal Mucosa; Male; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer; Stress, Psychological

Healing-promoting actions of KU-1257 (N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]urea, CAS 120958-90-9) were investigated in chronic gastric and duodenal ulcer models induced by acetic acid in rats and the effects were compared with those of famotidine and roxatidine acetate by gross or histological evaluation. KU-1257 markedly promoted the well-balanced healing of gastric ulcer at oral doses of 10-50 mg/kg x 2/day, as evidenced by the reduction of ulcer, regeneration of mucosa and proliferation of connective tissue. KU-1257 caused an increase in gastric mucus secretion in the regenerated mucosa around the gastric ulcers. Famotidine and roxatidine acetate failed to promote the healing of gastric ulcers even at 100 mg/kg x 2/day p.o. KU-1257 also significantly accelerated the healing of acetic acid-induced duodenal ulcers as well as famotidine and roxatidine acetate. These results indicate that KU-1257 is characterized by a potent promoting action on the healing of chronic ulcers, suggesting that the increase in gastric mucus secretion might be associated with the antiulcer actions of KU-1257 in part.

Topics: Acetates; Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Famotidine; Gastric Mucosa; Histamine H2 Antagonists; Intestinal Mucosa; Male; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer

Omeprazole is an inhibitor of gastric H+,K(+)-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H(+)-ATPase which is different from the gastric H+,K(+)-ATPase, in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2-blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Biomarkers; Body Weight; Bone Resorption; Calcium; Child; Cimetidine; Female; Histamine H2 Antagonists; Humans; Hydroxyproline; Male; Middle Aged; Omeprazole; Osteocalcin; Piperidines; Proton Pump Inhibitors; Stomach Ulcer

Effects of troxipide (Ku-54) on various experimental gastric ulcers in rats were studied. Ku-54 showed a dose-dependent antiulcerous action at 100, 200 and 300 mg/kg (particularly 300 mg/kg) p.o. in water-immersion stress, pylorus ligated and acetic acid reduced rats. The effect of cimetidine (CIM) (600 mg/kg) on water-immersion stress rats was significantly higher than that of Ku-54(300 mg/kg). On the other hand, the effect of Ku-54 (300 mg/kg) was higher than that of CIM (600 mg/kg) on the pylorus ligated and acetic acid reduced groups. The antiulcerous action of Ku-54 (300 mg/kg) was not related with the content and the pH of gastric juice.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Female; Male; Piperidines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Stress, Physiological

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.

Topics: Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Juice; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Stomach Ulcer

We examined the anti-ulcer effects of FRG-8813, a new type histamine H2-receptor antagonist, on various experimental gastric and duodenal lesions in rats. FRG-8813, administered orally, inhibited the formation of lesions dose-dependently in experimental models with the exception of the Shay ulcer model. The anti-ulcer potency of FRG-8813 was 4 approximately 10 times greater than that of cimetidine when the ED50 values of both compounds were compared. Famotidine and cimetidine inhibited lesion formation at higher doses than the anti-secretory doses. The anti-ulcer action of FRG-8813, however, appeared at even lower doses than those of anti-secretory action. These results suggest that FRG-8813 is able to prevent lesion formation with anti-secretory action plus other mechanisms unlike typical histamine H2-receptor antagonists.

Topics: Acetamides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

We examined the anti-ulcer effects of FRG-8813, a new-type histamine H2-receptor antagonist, in chronic ulcer models of rats and mice (W/WV). FRG-8813, given orally twice a day for 7 days, accelerated the healing of gastric or duodenal ulcer induced by acetic acid injection or application at the non-antisecretory doses (0.3 approximately 3 mg/kg). Administration of FRG-8813 to rats with ulcers increased the amounts of mucus in the gastric mucosa. These actions of FRG-8813 were more potent than those of famotidine or cimetidine. In W/WV mice, several ulcers spontaneously developed on gastric mucosa during the 8 weeks after the birth. The ulcers were aggravated by several unknown factors after the ulcer generation in W/WV mice. The aggravation of ulcers was inhibited by the 4-week administration of FRG-8813 with diet at the dose of 1 or 10 mg/kg/day, but was not inhibited by cimetidine at the dose of 100 mg/kg/day. From these results, we suggest that FRG-8813 is able to accelerate the healing of ulcers by antisecretory plus increasing actions on the integrity of the gastric mucosal defense mechanisms; therefore FRG-8813 is expected to be a useful drug for the treatment of gastric or duodenal ulcers in humans.

Topics: Acetamides; Animals; Chronic Disease; Disease Models, Animal; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Mice; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Topics: Acetamides; Administration, Oral; Animals; Dogs; Duodenum; Female; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Male; Peptic Ulcer; Piperidines; Rats; Rats, Inbred Strains; Stomach; Stomach Ulcer

The effect of 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis- 2-butenylamino]-3-cyclobutene-1,2-dione hydrochloride (IT-066), a new H2-receptor antagonist, on gastric acid secretion and on various experimental ulcers was investigated. IT-066 showed very potent and long lasting antisecretory action in pylorus ligated rats. The inhibitory potency of IT-066 given subcutaneously for gastric acid secretion was 1285 and 44 times higher than for cimetidine and famotidine, respectively. The duration of the inhibitory action of IT-066 was significantly longer than that of famotidine and cimetidine. In pylorus ligated rats, IT-066 showed almost 20 times higher potency than omeprazole with intraduodenal administration, and almost the same duration of action as omeprazole with one tenth the dose in oral administration. IT-066 showed a powerful protective effect on various experimental ulcer models. The potency of IT-066 administered subcutaneously was significantly higher compared with that of cimetidine, famotidine and omeprazole. IT-066 given orally also showed a more powerful antiulcer effect than cimetidine and omeprazole, and was comparable with that of famotidine in restraint and water immersion stress and cold-stress plus indometacin induced ulcer models in rats. These results suggest that IT-066 has powerful and long lasting antisecretory and antiulcer effects and is a useful antisecretory drug for treatment of peptic ulcer diseases.

Topics: Animals; Anti-Ulcer Agents; Cold Temperature; Cysteamine; Duodenal Ulcer; Gastric Acid; Histamine; Histamine H2 Antagonists; Indomethacin; Male; Omeprazole; Piperidines; Pylorus; Pyridines; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

We examined the effects of a new histamine H2-receptor antagonist, 3-amino-4-(4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino)-3- cyclobutene-1,2-dione hydrochloride (IT-066), on gastric acid secretion and the healing process of experimental ulcers in rats and dogs. Famotidine, a well-established H2-receptor antagonist, was used as the reference drug. Male Donryu rats (240-260 g) and Beagle dogs of both sexes (8-10 kg), having Heidenhain pouches, were used. IT-066 dose-dependently inhibited the basal gastric acid secretion of rats, and this inhibition significantly persisted for 12 hr. In addition, the agent significantly inhibited histamine-stimulated acid secretion in both normal rats and rats with acetic acid ulcers. IT-066, given p.o. twice daily for 2 and 3 weeks after ulceration, significantly accelerated both spontaneous and delayed healing (with indomethacin) of acetic acid-induced gastric ulcers in rats. The effects of IT-066 on acid secretion and ulcer healing were almost the same or slightly more potent than those observed with famotidine. IT-066, when given i.v. or p.o., dose-dependently inhibited the gastric acid secretion stimulated by histamine, pentagastrin, or carbachol in dogs. The antisecretory effects of the agent on histamine-stimulated acid secretion significantly persisted for more than 6 hr. These results indicate that IT-066 appears to be a promising antisecretory and anti-ulcer agent.

Topics: Acetates; Animals; Anti-Ulcer Agents; Carbachol; Depression, Chemical; Dogs; Famotidine; Female; Gastric Acid; Histamine Antagonists; Histamine H2 Antagonists; Male; Pentagastrin; Piperidines; Pyridines; Rats; Rats, Inbred Strains; Stomach Ulcer

Effects of FRG-8701, a new histamine H2-receptor antagonist, on gastric acid secretion, necrotizing agents-induced gastric lesions and acute gastric or duodenal ulcer in rats were studied. In lumen-perfused rats, intravenous injection of FRG-8701 reduced gastric acid secretion, and its antisecretory effect was almost equipotent to that of famotidine but the duration of action was substantially longer. In pylorus-ligated rats, the antisecretory effect of intraduodenal FRG-8701 administration was about 7 times more potent than that of cimetidine. FRG-8701 effectively inhibited macroscopic gastric hemorrhagic lesions induced by various kinds of necrotizing agents. Intraperitoneal injection was effective in preventing the lesions as well as oral treatment. The oral ED50 values for these lesions ranged from 1.1 to 9.4 mg/kg. On the other hand, famotidine failed to reduce these lesions, and the cytoprotective effect of cimetidine was observed only in high doses compared with the doses for antisecretory activity. In addition, the cytoprotective effect of FRG-8701 was not affected by the treatment of indomethacin or N-ethylmaleimide. FRG-8701 showed antiulcer activity against stress and indomethacin gastric ulcer and mepirizole duodenal ulcer. Its antiulcer effect was 5-15 times more potent than that of cimetidine. These results indicate that FRG-8701 is a new antiulcer drug that exerts a potent cytoprotective effect in addition to its gastric antisecretory activity.

Topics: Acetamides; Animals; Cimetidine; Duodenal Ulcer; Famotidine; Gastric Acid; Gastric Mucosa; Guinea Pigs; Heart Atria; Heart Rate; Histamine H2 Antagonists; Ileum; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Piperidines; Pylorus; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Capsaicin; Diterpenes; Ethanol; Female; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Stomach Ulcer

BMY-25368, 1-amino-2-[3-(3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3,4-dione, a new histamine H2-receptor antagonist, has been compared to ranitidine as an inhibitor of gastric acid secretion in the Heidenhain pouch dog. Intravenous infusion of BMY-25368 antagonized histamine-stimulated gastric secretion in a competitive manner. BMY-25368 also antagonized gastric secretion stimulated by pentagastrin, bethanechol and food. When compared to ranitidine in histamine-stimulated dogs, BMY-25368 was nine times more potent after bolus intravenous administration. Oral potency relative to ranitidine and ranged from 2.8 to 4.4, depending on the secretagogue used. BMY-25368 also exhibited a significantly longer duration of action than ranitidine. Thus, its potency relative to ranitidine after oral administration, in histamine-stimulated dogs, increased from 3.2 to 28 when determined 1-3 and 10-12 h post dose, respectively. BMY-25368 administered orally also antagonized aspirin-induced gastric lesions in the dog and was nine times more potent than ranitidine in this respect.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Bethanechol Compounds; Dogs; Dose-Response Relationship, Drug; Female; Food; Gastric Acid; Histamine H2 Antagonists; Pentagastrin; Piperidines; Ranitidine; Stomach Ulcer

A non-comparative multicentre study of 78 patients with healed gastric ulcers who had received roxatidine acetate was conducted to determine the ulcer recurrence rates during 6 months' maintenance therapy with roxatidine acetate 75 mg at night. Gastric ulcer relapses occurred in 35% of patients, representing a worst possible outcome estimate, with no significant differences between smokers and non-smokers although heavy smoking appeared to increase the rate of relapse. The incidence of epigastric pain did not significantly increase over the duration of therapy and while some patients complained of mild pain at the start of the trial all subjects had endoscopically confirmed healed ulcers. The consumption of antacids for symptom relief was low, reaching an average of 0.75 tablets a day which was insufficient to influence intragastric pH. Continuous poor appetite and pyrosis were reported by about 5% of subjects. Of 2 patients who complained of mild to moderate side effects, 1 discontinued treatment. In addition, there were no clinically significant changes in haematological and biochemical variables. Thus, maintenance therapy with roxatidine acetate 75 mg at night is safe and generally effective in preventing symptomatic relapse.

Topics: Adult; Aged; Aged, 80 and over; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Recurrence; Smoking; Stomach Ulcer

Topics: Animals; Anti-Inflammatory Agents; Female; Male; Peptic Ulcer Hemorrhage; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer; Structure-Activity Relationship

Effects of KU-54 on the biosynthesis of glycoprotein in the gastric mucosa and the liver, as measured by the rate of incorporation of 14C-glucosamine, were investigated in rats under various conditions after a single administration of 14C-glucosamine of (9.88 microCi/animal, ip). 14C-glucosamine was incorporated with relative ease in the acid-insoluble fraction of the gastric mucosa. KU-54 at 100 mg/kg was orally administered twice daily for 5 days in rats (though it was given once on the 5th day) before injection of 14C-glucosamine. The rate of 14C-glucosamine incorporation into the acid-insoluble fraction of the gastric mucosa was significantly increased by KU-54, but that of the hepatic tissue was not increased. In addition, hydrocortisone (20 mg/kg) also produced a drop of incorporation of 14C-glucosamine in the gastric mucosa, but oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given once on the 5th day) significantly inhibited the drop of incorporation of 14C-glucosamine in the gastric mucosa, but that in the hepatic tissue was not inhibited. Therefore, the effects of KU-54 were greater in the gastric mucosa than in the hepatic tissue. On the 5th day of the ulcer produced by acetic acid in rats, the specific radioactivity in the mucosa of the margin of the ulcer increased significantly compared with that in the normal (non-ulcerative) mucosa, but this phenomenon was not affected by KU-54.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Gastric Mucosa; Glucosamine; Glycoproteins; Hydrocortisone; Injections, Intraperitoneal; Liver; Male; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer

New thioureas and ureas with an interesting anti-ulcer and antisecretory activity are disclosed. The chemical synthesis, determination of the structure, and structure-activity relationships of the compounds are discussed.

Topics: Animals; Anti-Ulcer Agents; Chemical Phenomena; Chemistry; Gastric Juice; Male; Parasympatholytics; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer; Structure-Activity Relationship

Effects of 3,4,5-trimethoxy-N-(3-piperidyl) benzamide (KU-54), an antiulcer drug, on the tissue respiration of the gastric mucosa and the liver were studied in rats. Oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given only once on the 5th day) caused an increase in oxygen consumption of the gastric mucosa in rats, but did not affect that of the liver. Thus the principal active site of KU-54 on tissue respiration was found to be the gastric mucosa. Oral KU-54 at 100 mg/kg once daily for 11 days significantly accelerated the oxygen consumption of marginal gastric mucosa of acetic acid ulcer in rats. The effect of oral gefarnate at 200 mg/kg was about half that of KU-54 at 100 mg/kg, but it was not significant. In addition, oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given only once on the 5th day) significantly inhibited the decrease of oxygen consumption of the gastric mucosa in hemorrhagic shocked rats. The effect of oral gefarnate at 100 mg/kg was not like that at KU-54 at 100 mg/kg in conscious rats. When KU-54 was added in the incubation medium with small gastric mucosal fragments of rats, the increase of oxygen consumption of the gastric mucosa did not occur. Oral KU-54 at 100 mg/kg significantly accelerated a glycogen consumptive stimulation of the gastric mucosa of the corpus in ischemic rats, but the respiration of the antral mucosa was not accelerated under anaerobic incubating conditions. Oral gefarnate at 200 mg/kg accelerated an anaerobic glycolysis of the gastric antral mucosa in rats.

Topics: Animals; Anti-Ulcer Agents; Gastric Mucosa; Gefarnate; Glycolysis; In Vitro Techniques; Liver; Male; Oxygen Consumption; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Albuterol; Anaphylaxis; Animals; Anura; Bronchial Spasm; Cardiovascular System; Chlorpheniramine; Dogs; Drug Evaluation, Preclinical; Female; Gastric Juice; Guinea Pigs; Histamine H1 Antagonists; Inflammation; Male; Mice; Muscle, Smooth; Piperidines; Pizotyline; Rats; Respiration; Stomach Ulcer; Thiophenes

Topics: Animals; Antiemetics; Guinea Pigs; Male; Piperidines; Pyrrolidines; Rats; Stomach Ulcer

Pharmacological properties and acute toxicity of 2-tolyl 1-phenyl-3-(2-methylpiperidino) propyl ether methyl bromide (R111) and 2-chlorophenyl 1-phenyl-3-(2-methylpiperidino) propyl ether methyl iodide (R97) were examined. The results obtained were as follows: (1) In the analgesic effects, RIII and R97 inhibited markedly the acetic acid-induced writhing in mice, but in reducing pain induced by heat, R111 and R97 showed negative results. The local anesthetic effect of R111 was approximately equal to that of procaine. R111 and R97 showed no effects on spontaneous locomotion, the convulsion induced by strychnine or pentetrazol, and normal body temperature. (2) R111 and R97 antagonized acetylcholine, barium chloride, nicotine and serotonine-induced spasm, but not that of histamine and bradykinin. In particular they possessed marked anti-barium chloride activity, where their effects were 20 to 30 times more active than that of papaverine. (3) R111 and R97 indicated weak mydriatic activity. (4) R111 and R97 showed inhibitory effects on the pilocarpine-induced sialic secretion and the propulsive movements of the small intestine, but their inhibitory effects on the gastric secretion were relatively weak. (5) R111 and R97 displayed protective effects in Shay's ulcer, but had no curative effects on acetic acid ulcer. (6) R111 and R97 induced temporary reduction of arterial blood pressure and blood flow immediately after the administration of the test compounds in anesthetized rabbits. However, these agents induced no change in ECG, heart rate and respiration. (7) Intraperitoneally administered R111 and R97 were effective in inhibiting the carrageenin-induced edema in the hind paw of rats. From the above results, it may be considered that R111 and R97 have together strong cholinergic blocking and muscotropic antispasmodic effects, moreover, no significant effects on the central nervous system.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Central Nervous System; Female; Gastric Juice; Gastrointestinal Motility; Guinea Pigs; Hemodynamics; In Vitro Techniques; Male; Mice; Muscle Contraction; Parasympatholytics; Piperidines; Pupil; Rabbits; Rats; Respiration; Sleep; Stomach Ulcer; Uterine Contraction

Topics: Anesthetics, Local; Animals; Cardiovascular System; Cats; Depression, Chemical; Female; Ganglia, Autonomic; Gastric Juice; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Irritants; Male; Methemoglobin; Methyl Ethers; Mice; Muscle Contraction; Muscle, Smooth; Mydriatics; Parasympatholytics; Piperidines; Rats; Respiration; Salivation; Stomach Ulcer; Thiophenes

Topics: Animals; Anti-Allergic Agents; Histamine H1 Antagonists; Peptic Ulcer; Piperidines; Rats; Reserpine; Serotonin; Stomach Ulcer