piperidines and Duodenal-Ulcer

An 86-year-old man was admitted with a 3-day history of melaena and syncope. He was haemodynamically compromised and anaemic on presentation. His only medical history was mild Alzheimer's disease diagnosed 6 months prior. For this, he was on donepezil, a cholinesterase inhibitor (ChEI), with a recent dose increase 3 months earlier. After fluid resuscitation with packed red cells, an endoscopy was performed, which showed an acute duodenal ulcer. This was treated with a high-dose proton pump inhibitor. The patient recovered well and was discharged on donepezil with the addition of a gastro-protective proton pump inhibitor. In view of other absent risk factors of upper gastrointestinal haemorrhage, donepezil was the likely causative agent. ChEIs are associated with frequent side effects and increased hospitalisation due to central and peripheral increase in acetylcholine. With this case report, we review the literature of side effects related to ChEIs, where the mechanisms of action, complications and appropriate management are discussed.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Duodenal Ulcer; Endoscopy; Gastrointestinal Hemorrhage; Humans; Indans; Lansoprazole; Male; Piperidines; Proton Pump Inhibitors; Syncope

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

This study was conducted using roxatidine acetate or Mylanta combined with metronidazole and amoxicillin to evaluate the role of acid and Helicobacter pylori in the natural course of the duodenal ulcer. Eighty-three patients with H. pylori positive duodenal ulcers were randomly allocated into one of four treatment groups. Group A: roxatidine 75 mg hs for 8 weeks; Group B: the same as group A + metronidazole 250 mg and amoxicillin 250 mg qid for 1 week on the 3rd week; Group C: Mylanta (combined hydroxide of magnesium and aluminum) 20 ml qid for 8 weeks; Group D: the same as group C + metronidazole 250 mg and amoxicillin 250 mg qid for 1 week on the 3rd week. Repeated endoscopies were performed on the 8th week post the initial treatment and the sixth and 12th month post the termination of treatment, or, at the earliest recurrence of symptoms. Eradication of H. pylori was considered to be successful if the culture, histology and CLO test all showed negative. The ulcer healing rates of Groups A, B, C and D were 95%, 100%, 61% and 86%, respectively, with a significant difference between A and C. The eradication rates of groups B and D were 81% and 62%, respectively, without any significant difference. The 12 months cumulative ulcer recurrence rates were 72%, 15%, 80% and 22%, respectively, with a significant difference between each paired groups with and without antibiotics. In conclusions, roxatidine is effective in the healing of duodenal ulcer. One-week roxatidine-based triple therapy is powerful in the eradication of H. pylori. Potent acid suppression is sufficient to heal the duodenal ulcer. Eradication of H. pylori can potentiate ulcer healing under insufficient acid suppression. A causal role for H. pylori in recurrent duodenal ulcer is strongly supported by a much lower recurrence of ulcer in H. pylori free patients.

Topics: Adolescent; Adult; Aged; Aluminum Hydroxide; Drug Combinations; Duodenal Ulcer; Female; Gastric Acid; Helicobacter pylori; Humans; Magnesium Hydroxide; Male; Middle Aged; Piperidines; Prospective Studies; Recurrence; Simethicone

To assess the usefulness of early evening administration of roxatidine 150 mg as an alternative to the traditional bedtime regimen.. Twenty-four patients with healed duodenal ulcer were dosed according to a balanced incomplete-block design, with two of the following regimens: placebo, roxatidine 150 mg at 07.30 h (early evening) or roxatidine 150 mg at 22.00 h (bedtime). Twenty-four-hour intragastric pH-metry was started at 18.00 h on the first day of dosing. Median pH was determined for the 24-h period, and for the following time intervals: 20.00-00.00 h, 00.00-08.00 h and 08.00-18.00 h. Percentage time in the 24-h period with pH greater than 4.0 was also calculated.. The two roxatidine regimens proved significantly superior to the placebo, decreasing 24-h acidity for all the time intervals, except the 20.00-00.00 h period, when mean intragastric pH with the early evening regimen (4.5 +/- 1.1) proved significantly higher than after placebo (2.2 +/- 1.0) or when roxatidine was taken at bedtime (2.4 +/- 1.1).. Early evening administration of roxatidine may afford satisfactory control of 24-h acidity, offering a useful alternative to conventional bedtime administration.

Topics: Administration, Oral; Adult; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Gastric Acid; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines

There is much experimental work on the occurrence of tolerance to the antisecretory effect of H2-receptor antagonists in healthy subjects, while data on its development in patients with duodenal ulcer are poor and conflicting. Moreover, this phenomenon has not been studied previously with 24 h gastric pH-metry in patients with active duodenal ulcer. For these reasons, we carried out a prospective pharmacodynamic investigation in 48 patients with endoscopically proven duodenal ulcer using the well-established once daily dosing schedule of H2 blockers. They were studied by means of 24 h continuous endoluminal pH-metry which was performed before, on d1 and d28 after receiving an oral bedtime dose (2200 hours) of either roxatidine 150 mg or ranitidine 300 mg, given in randomized and single-blind fashion. Eight patients did not complete the study for various reasons and 82% of ulcers healed after 4 weeks of therapy. Gastric pH was higher (P < 0.001) on d1 and d28 than basal values during all time periods, but the evening, with both H2 blockers. There was no significant difference between pH values of d1 and d28 in any time interval with both roxatidine and ranitidine. There was also no difference in pharmacodynamic data between the two active treatments. We conclude that tolerance does not develop after 1 month's treatment with a bedtime dose of H2 antagonist in patients with active duodenal ulcer and therefore data gathered on this phenomenon in healthy subjects are not applicable to ulcer patients.

Topics: Adult; Analysis of Variance; Drug Tolerance; Duodenal Ulcer; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Prospective Studies; Ranitidine; Single-Blind Method

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

To compare the efficacy and tolerability of early evening (19.00-21.00 hours) vs. bedtime (22.00-00.00 hours) oral administration of roxatidine 150 mg in the short-term treatment of active duodenal ulcer.. The trial was randomized, double-blind and double-dummy, with parallel groups. A total of 276 patients were recruited and randomly assigned either to roxatidine in the early evening (n = 139) or roxatidine at bedtime (n = 137).. After 4 weeks, 78% of patients receiving roxatidine in the early evening and 74% of those treated at bedtime had achieved complete healing, as determined by per-protocol analysis. With intention-to-treat analysis the healing rates were 70.5% and 70.8%, respectively. After 8 weeks the healing rates in the early evening and bedtime treatment groups were 92% and 95% (per-protocol analysis) and 78% and 84% (intention-to-treat analysis). Both treatments proved effective in reducing the frequency and severity of daytime and nocturnal epigastric pain, as well as other ulcer-related symptoms.. This study confirmed the healing and analgesic properties of roxatidine in duodenal ulcer disease. Early evening or bedtime dosing with roxatidine 150 mg resulted in similar 4- to 8-week rates of duodenal ulcer healing.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Ulcer Agents; Double-Blind Method; Duodenal Ulcer; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Time Factors; Treatment Outcome

Roxatidine acetate is a novel H2-receptor antagonist and several studies have shown that it is effective in healing duodenal ulcers. We evaluated the efficacy of roxatidine in a non-western society with particular different features and its healing of duodenal ulcers was compared in Thailand with that of ranitidine.. The design was controlled, randomized, double-blind, and multicenter. The study recruited a total of 215 patients who were endoscoped at the start of the trial and then randomized to receive a single capsule of roxatidine acetate, 150 mg, or an identical capsule containing ranitidine, 300 mg, both to be taken at night. Patients were evaluated at 1, 2, and 4 weeks, including endoscopy at the last session, as well as at 6 weeks with repeat endoscopy if the ulcer had not healed.. Both drugs relieved pain rapidly, usually within a week, and at repeat endoscopy at 4 weeks most ulcers (78%) were healed, 77.0 and 79.5 per cent in ranitidine and roxatidine, and in those patients in whom healing was not completed the healing rate had risen appreciably to 89.8 and 93.8 per cent respectively at 6 weeks. Small ulcers tended to heal quicker than larger ones, but smoking and alcohol intake had no negative effects on the results.. The study was valid proof that roxatidine, in a single evening dose of 150 mg, was found to be both safe and effective in the rapid healing of duodenal ulcers when compared with 300 mg ranitidine.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain Measurement; Piperidines; Ranitidine; Risk Factors; Thailand; Treatment Outcome

A double blind randomised trial, comparing a new H2-receptor antagonist, Roxatidine acetate, with Cimetidine was carried out in 47 patients of uncomplicated, endoscopically proven duodenal ulcer. Twenty seven patients were treated with Roxatidine 75 mg twice daily and 20 patients were treated with Cimetidine 200 mg 3 times a day and 400 mg at bed time for 4 weeks. At the end of 4 weeks, total pain relief was obtained in 74% and 70% patients receiving Roxatidine and Cimetidine respectively. Complete endoscopic healing at the end of 4 weeks was observed in 92.3% patients receiving Roxatidine and 85% patients receiving Cimetidine. These differences were statistically not significant. No significant side effects were observed in either group. We conclude that Roxatidine acetate is comparable to cimetidine in relieving pain and endoscopic healing of duodenal ulcer and has an excellent safety profile.

Topics: Cimetidine; Double-Blind Method; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Piperidines

In a multicenter, placebo-controlled, comparative trial with 196 general practitioners and internists 730 18 to 70 year-old patients with endoscopic evidence of a duodenal ulcer were enrolled. Each group of 365 patients received 150 mg Roxatidine acetate once daily, either late in the evening (bedtime administration, between 10.00 p.m. and 11.00 p.m.) or early in the evening (after dinner, between 6.00 p.m. and 7.00 p.m.). The endoscopic control revealed that the ulcers healed after four weeks of treatment in 74% (bedtime administration) and 77% (administration early in the evening), respectively. There was no significant difference ascertained between both groups. At the last visit, epigastric pain was removed during the day in 86% and during the night in 90% in both groups.

Topics: Adolescent; Adult; Aged; Drug Administration Schedule; Duodenal Ulcer; Duodenoscopy; Female; Histamine H2 Antagonists; Humans; Intestinal Mucosa; Male; Middle Aged; Piperidines

In a single centre double blind study of 66 patients, the value of cisapride (10 mg twice daily) was compared with placebo in the prevention of duodenal ulcer relapse. Patients who remained ulcer free attended for clinical review every two months and had a mandatory endoscopy at 0, 4, 8, and 12 months or if symptoms suggestive of ulcer recurrence developed. The 12 month crude relapse rates (that underestimate the probability of ulcer recurrence) showed that cisapride was superior to placebo (34% (11/32) relapsed on cisapride v 68% (23/34) on placebo, p = 0.007). This finding was confirmed using lifetable analysis, with a 35% reduction (95% confidence intervals 10-59%, p < 0.05) in the proportion of ulcer relapses in patients who had received cisapride compared with those treated with placebo. These results are similar to those reported in maintenance trials of H2 receptor antagonists analysed by the same method. Drug related adverse clinical events were mainly trivial, but led to three patients on cisapride and one on placebo withdrawing from the trial.

Topics: Adolescent; Adult; Aged; Anti-Ulcer Agents; Cisapride; Confidence Intervals; Double-Blind Method; Duodenal Ulcer; Duodenoscopy; Female; Follow-Up Studies; Gastric Acid; Gastrointestinal Motility; Humans; Life Tables; Male; Middle Aged; Piperidines; Recurrence; Treatment Outcome

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

Topics: Abdominal Pain; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Logistic Models; Male; Middle Aged; Piperidines; Severity of Illness Index

Roxatidine acetate is a new histamine H2-antagonist of about twice the potency of ranitidine on a weight-for-weight basis. Two hundred and thirty-two patients participated in a double-blind randomized trial of duodenal ulcer healing comparing 300 mg ranitidine nocte with 150 mg roxatidine nocte. Endoscopy was repeated fortnightly to 4 weeks in each of four participating centres. Usual exclusion criteria applied but NSAID users were allowed. There were no important demographic differences between treatment recipients. Three analyses were used: protocol (dropouts and violators not included), intention-to-treat I (dropouts considered failures), and intention-to-treat II (dropouts considered failures, but violators outcome included). Healing rates differed markedly (but not significantly) with each analysis. After 2 weeks of treatment ulcers had healed in 51% versus 45% using the intention to treat I analysis with roxatidine and ranitidine, respectively; by the protocol analysis the healing proportions were 60% and 55%. These differences between treatments were not significant. After 4 weeks of treatment healing rates ranged from 71% to 83% on roxatidine and between 69% and 84% on ranitidine depending on the analysis. Differential healing proportions of smokers and non-smokers were non-significant (83% vs. 79%). Both drugs were well tolerated and adverse events were similar with each agent. Roxatidine should prove as effective as ranitidine for acute duodenal ulcer treatment.

Topics: Adult; Aged; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Ranitidine

In a double blind study, 24 hour intragastric acidity and 24 hour plasma gastrin concentrations were measured simultaneously in seven duodenal ulcer subjects on the fifth day of receiving either sufotidine 600 mg bd or placebo. Compared with placebo, during treatment with sufotidine 600 mg bd the median integrated 24 hour intragastric acidity was decreased by 95% (range 74% to 99%) from 1000 to 51 mmol/h/l, whilst the median integrated 24 hour plasma gastrin concentration increased from 416 to 927 pmol/h/l.

Topics: Adult; Circadian Rhythm; Double-Blind Method; Duodenal Ulcer; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Triazoles

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 double-blind study was conducted to compare the efficacy of roxatidine acetate 75 mg twice daily with ranitidine 150 mg twice daily in 308 patients with endoscopically confirmed uncomplicated duodenal ulcers. After 6 weeks of treatment ulcer healing was found in 93.5% of the roxatidine acetate group and 89.2% of the ranitidine group, with no significant differences between treatment groups. The relief of day and night-time epigastric pain assessed at clinic visits or on diary cards by patients was comparable for both treatment groups, as was the consumption of antacid tablets for relief of symptoms of dyspepsia. There were no significant differences in the healing rates of smokers and non-smokers for either roxatidine acetate or ranitidine treatment, and no clinically significant alterations in laboratory values. Eight patients in the roxatidine acetate group and 1 in the ranitidine group complained of mild side effects, which included diarrhoea, constipation and headache. One patient on roxatidine acetate withdrew from treatment because of a mild skin rash. The results confirm that roxatidine acetate is a safe and effective treatment for duodenal ulcer disease.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Random Allocation; Ranitidine

A randomised multicentre, double-blind study of the efficacy and safety of roxatidine acetate 150 mg at bedtime or 75 mg twice a day was conducted in 300 outpatients with endoscopically confirmed duodenal ulcers. After 14 days' treatment with roxatidine acetate substantial reductions in ulcer sizes had been obtained, in addition to healing rates of 87 to 89%, with no significant differences between the dosage regimens. There were graded reductions in day and night-time assessment of epigastric pain for both treatment groups and no differences in the mean numbers of antacid tablets consumed. In addition, cigarette smoking did not influence the healing rates produced by either treatment schedule. 11 patients reported 12 mild adverse reactions, with gastrointestinal symptoms the most frequent, and no clinically significant alterations in laboratory values. The present data suggests that a single bedtime dose of roxatidine acetate 150 mg produces effective duodenal ulcer healing and pain relief equivalent to that produced by a twice daily dosage regimen.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Random Allocation; Smoking

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

Domperidone (5 mg i.v.) was given singly or together with apomorphine (0.25 mg i.v.) to healthy volunteers. The gastric emptying rate of a test meal of 750 ml of water was then measured using a dye dilution and double sampling technique. The effect of domperidone on gastric secretion was evaluated in patients with duodenal ulcer who received domperidone (5 mg i.v.) prior to continuous aspiration of the stomach contents for 120 minutes. Domperidone markedly increased the rate of emptying of the test meal. Following apomorphine the gastric emptying rate decreased and domperidone antagonized this slowing effect. The composition of gastric juice was not affected by an intravenous dose of domperidone. Domperidone appears to modulate gastric contractile activity without affecting gastric secretion.

Topics: Antiemetics; Apomorphine; Benzimidazoles; Duodenal Ulcer; Gastric Emptying; Gastric Juice; Humans; Male; Piperidines; Secretory Rate; Stimulation, Chemical

The effect of domperidone and metoclopramide on antral motility was studied by measuring the intraluminal pressure in the antrum of 10 normal persons and of 8 patients suffering from duodenal ulcer. Both drugs stimulated the rhythmic activity of the antrum. The antiemetic effect and the therapeutic effect of domperidone on complaints by gastrointestinal retention was the result of the influence on gastrointestinal motility, which is similar to that of metoclopramide.

Topics: Antiemetics; Benzimidazoles; Clinical Trials as Topic; Drug Evaluation; Duodenal Ulcer; Gastrointestinal Motility; Humans; Male; Metoclopramide; Piperidines; Pyloric Antrum

Topics: Adolescent; Adult; Aged; Benzilates; Clinical Trials as Topic; Duodenal Ulcer; Gastric Juice; Humans; Middle Aged; Parasympatholytics; Piperidines; Placebos; Secretory Rate

Topics: Atropine; Codeine; Diarrhea; Duodenal Ulcer; Humans; Piperidines; Placebos; Postoperative Complications; Pylorus; Vagotomy

(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenitis; Intestine, Small; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Tumor Necrosis Factor-alpha

We examined the prophylactic effect of lafutidine, a novel histamine H(2)-receptor antagonist [(+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl]oxy- (Z)-2 butenyl]acetamide], on indomethacin-induced small intestinal ulcers in rats and investigated the relation of this action to capsaicin-sensitive sensory neurons.. Subcutaneously administered indomethacin (10 mg/kg) provoked ulceration in the small intestine, mainly the jejunum and ileum, accompanied by increases in myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well as the enterobacterial numbers invading the mucosa. Intestinal ulcerogenic response to indomethacin was prevented by 16,16-dimethyl prostaglandin E(2) (10 microg/kg, p.o.) and capsaicin (10 mg/kg, p.o. ) as well as ampicillin (800 mg/kg, p.o.), but not omeprazole (100 mg/kg, p.o.). Likewise, lafutidine (1-10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.), reduced the occurrence of intestinal ulcers in response to indomethacin in a dose-dependent manner, and a significant effect was observed at 3 mg/kg or greater. The protective action of lafutidine as well as capsaicin was almost totally abolished by chemical ablation of capsaicin-sensitive sensory neurons. Both lafutidine and capsaicin significantly suppressed the increases in MPO and iNOS activities as well as enterobacterial numbers in the mucosa. These agents also significantly enhanced mucus secretion in the small intestine.. These results suggest that lafutidine protects the small intestine against ulceration via stimulation of capsaicin-sensitive sensory neurons. This action may be attributable to inhibition of enterobacterial invasion in the intestinal mucosa, probably by increasing the mucus secretion.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Capsaicin; Dose-Response Relationship, Drug; Duodenal Ulcer; Histamine H2 Antagonists; Indomethacin; Intestinal Mucosa; Male; Neurons, Afferent; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley

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

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

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

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: Adult; Dose-Response Relationship, Drug; Duodenal Ulcer; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Monitoring, Physiologic; Piperidines

A non-comparative multicentre study of 105 patients with healed duodenal ulcers was conducted to determine the effect on ulcer recurrence of 6 months' maintenance treatment with roxatidine acetate 75 mg daily. All patients had previously received roxatidine acetate treatment. 31 patients out of 89 had 32 relapsed ulcers after 6 months of treatment, which represents an overall relapse rate of around 30%; the relapse rate in smokers was double that of non-smokers. The overall incidence of epigastric pain did not increase significantly over the period of the trial, although some patients complained of mild pain when they entered the study despite having endoscopically confirmed healed ulcers. At the end of the study continuous poor appetite and pyrosis were reported by 17% and 6% of patients, respectively. Side effects, which included constipation and diarrhoea, were reported by 4 patients, 1 of whom withdrew from therapy. There were no clinically significant changes in laboratory values. Thus, maintenance treatment with roxatidine acetate 75 mg daily proved a safe and effective method of preventing symptomatic duodenal ulcer relapse.

Topics: Adult; Aged; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain; Piperidines; Recurrence; Time Factors

Topics: Adolescent; Adult; Duodenal Ulcer; Female; Gastric Juice; Gastrointestinal Motility; Humans; Indoles; Isoindoles; Male; Middle Aged; Parasympatholytics; Piperidines; Pyloric Antrum; Scopolamine

Topics: Benzilates; Drug Interactions; Duodenal Ulcer; Duodenum; Gastric Acidity Determination; Gastric Juice; Humans; Hydrogen-Ion Concentration; Injections, Intravenous; Metoclopramide; Parasympatholytics; Pentagastrin; Piperidines; Secretory Rate

Topics: Adult; Alkynes; Duodenal Ulcer; Female; Humans; Male; Middle Aged; Parasympatholytics; Peptic Ulcer; Piperidines

Topics: Duodenal Ulcer; Humans; Peptic Ulcer; Piperidines

Topics: Duodenal Ulcer; Parasympatholytics; Peptic Ulcer; Piperidines

Topics: Disease Management; Duodenal Ulcer; Parasympatholytics; Peptic Ulcer; Piperidines