Comparison of antisecretory potency and duration of action of the H2-receptor antagonists AH 22216, cimetidine, ranitidine and SK & F 93479 in the dog

The antisecretory potency and duration of action of the new histamine H2-receptor antagonist AH 22216 have been compared with those of cimetidine, ranitidine and SK & F 93479 against histamine-induced gastric acid secretion in the conscious Heidenhain pouch dog. Ranitidine was 4-6 times more potent than cimetidine, with a similar duration of action. SK & F 93479 was approximately twice as potent as ranitidine and had a slightly longer duration of action. AH 22216 was most potent of the four H2-antagonists, some 20-30 times more active than cimetidine, and had an extremely prolonged duration of action.     

Alendronate gastric ulcers

BACKGROUND: It appears likely that drugs other than NSAIDs may cause ulcers and ulcer complications (e.g. potassium chloride). Alendronate (Fosamax) is used in the treatment and prevention of metabolic bone disease and has also been associated with severe oesophageal damage and stricture. We have previously shown that the dose of alendronate used for Paget's disease (40 mg) causes gastric damage similar to NSAIDs. The usual dose for the treatment of postmenopausal osteoporosis is 10 mg per day. AIM: To investigate whether the 10 mg dose of alendronate causes gastric ulcers. METHODS: We performed an endoscopist-blind, crossover, randomized, single-centre comparison of 10 mg of alendronate/day and placebo in volunteers aged 40 years or more. Video-endoscopy was used to evaluate the presence and degree of mucosal damage to the oesophagus, stomach, or duodenal bulb after 7 and 14 days of treatment. RESULTS: Twenty-four healthy volunteers participated, including 15 women and nine men, ranging in age from 41 to 52 years. Visible gastric mucosal damage was present in nine (38%) who received alendronate compared to three (13%) in the placebo group. There was a marked difference in the severity of mucosal damage; there were no ulcers or large erosions in those receiving placebo. In contrast, potentially clinically significant gastric mucosal injury was seen in six subjects receiving alendronate (two developed antral ulcers and four had large (4-8 mm) superficial antral erosions) compared to none in the placebo group (P = 0.0219). One subject developed oesophageal damage in the form of multiple linear superficial erosions in the mid and distal oesophagus. Duodenal injury was not seen. CONCLUSION: Alendronate causes gastric ulceration, suggesting that alendronate use may be associated with ulcer complications such as acute upper gastrointestinal bleeding. The results of this study suggest the need for post-marketing surveillance to clarify the nature, frequency and magnitude of any potential gastrointestinal side-effects associated with the use of this drug.     

Effect of histamine H2-receptor antagonists on acute inflammatory of the rat paw oedema

The effect of three histamine H2-antagonists, cimetidine, ranitidine, and loxtidine, on acute rat paw oedema induced by histamine, carrageenan or complete Freund's adjuvant, have been examined. Administered intraperitoneally, all three antagonists inhibited histamine-induced paw oedema dose-dependently in the range 0.5-15 mumol kg-1. The highest dose of cimetidine produced an inhibition of 92% as against 38% with the same dose of mepyramine. Analysis of the concentration-effect curves produced IC50 values of 1.66, 5.12 and 12.30 mumol kg-1 for cimetidine, loxtidine, and ranitidine, respectively, on histamine-induced oedema. In carrageenan-induced inflammation 12.3 mumol kg-1 of each of the three drugs produced significant inhibition, whereas in adjuvant-induced inflammation, (acute phase), cimetidine was very active, loxtidine less so and ranitidine inactive. Thus the relative effectiveness of the antagonists (cimetidine greater than loxtidine greater than ranitidine) appears to differ from their known potency relationship (loxtidine greater than ranitidine greater than cimetidine) on H2-mediated effects. We conclude that H2-receptors are involved in the induction of rat paw oedema, especially those induced by histamine and carrageenan, but that their relative effectiveness appears atypical.     

Role of pepsin in the development of indomethacin-induced antral ulceration in the rat

Aims: To examine the effects of a pepsin inhibitor, pepstatin-A, a long acting H₂-receptor blocker, loxtidine, exogenous pepsin and exogenous acid against indomethacin-induced antral ulceration in the rat. Results: Indomethacin (60 mg/kg s.c.) caused antral ulceration in fasted/re-fed rats over a period of 4 h. Ulceration was prevented in a dose-dependent manner by treatment with pepstatin-A (0.1–1 mg.kg hourly) or loxtidine (3 mg/kg) given orally. Acidified methylcellulose (1 mL hourly per os) enhanced damage and also prevented protection by loxtidine (3 mg/kg per os). The protection by pepstatin-A was not altered by treatment with acidified methylcellulose but was reversed by treatment with a 10-fold excess of pepsin. Conclusion: These studies suggest that mucosal degradation by pepsin, rather than direct damage by luminal acid, was the major factor in the development of indomethacin-induced antral ulceration in the rat.     

Ranitidine: a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases

Ranitidine is a new histamine H2-receptor antagonist which, unlike cimetidine, does not contain an imidazole group. On a weight basis, ranitidine is 4 to 10 times more potent than cimetidine in inhibiting stimulated gastric acid secretion in humans. Therapeutic trials comparing ranitidine and cimetidine have demonstrated that ranitidine 150 mg twice daily is an effective alternative to cimetidine 1000 mg daily in 4 divided doses in increasing the rate of healing of duodenal and gastric ulcers over a period of 4 to 6 weeks. Ranitidine, given as a single 150 mg dose at night, decreases the incidence of ulcer recurrence. Preliminary studies in the Zollinger-Ellison syndrome and in patients intolerant of, or unresponsive to cimetidine, indicate that ranitidine controls the gastric hyperacidity and heals most ulcers, including those which failed to respond to months of treatment with cimetidine 1 to 1.6 g daily. Ranitidine, unlike cimetidine, has no antiandrogenic effects and does not alter hepatic metabolism of drugs. Ranitidine is well tolerated. Preliminary reports of the resolution of cimetidine-induced adverse effects following substitution of ranitidine, suggest that ranitidine may be of value in patients intolerant of cimetidine. However, wider clinical experience with ranitidine is needed to determine the clinical relevance of these reports.     

Oxyntic lesions may be provoked in the rat both by the process of acid secretion and also by gastric acidity

BACKGROUND: Gastric ischaemia appears to be a common pathogenetic factor for stress ulcers. These ulcers occur predominantly in the oxyntic mucosa, suggesting that the acid secretory process or its stimulation is involved in the pathogenesis. METHODS: We examined separately the role of the acid secretory process and gastric luminal acidity in the pathogenesis of gastric lesions using the isolated vascularly perfused acid-secreting rat stomach. RESULTS: Pentagastrin-stimulated acid secretion induced submucosal bleeding in the oxyntic mucosa whether accompanied by perfusion of the gastric lumen with saline or a phosphate buffer at pH 7.0. On the other hand, acidity, whether endogenous or introduced by luminal perfusion, induced erosions in both the oxyntic and antral mucosa. CONCLUSION: It is concluded that the acid secretory process itself contributes to the particular vulnerability of the oxyntic mucosa to ischaemia. Histamine released upon stimulation of gastric acid secretion or shortage of energy due to the requirements for acid secretion may both contribute to this vulnerability. Furthermore, these findings suggest that inhibition of gastric acid secretion should be superior to antacids in preventing stress ulcers.     

Famotidine. Pharmacodynamic and pharmacokinetic properties and a preliminary review of its therapeutic use in peptic ulcer disease and Zollinger-Ellison syndrome

Famotidine is a new histamine H2-receptor antagonist. On a weight basis, famotidine is 20 times more potent than cimetidine and 7.5 times more potent than ranitidine in inhibiting basal and pentagastrin-stimulated gastric acid secretion in humans. Therapeutic trials have shown that famotidine 20 mg twice daily or 40 mg at bedtime may be an effective alternative to standard doses of cimetidine for healing gastric ulcers and to standard doses of cimetidine and ranitidine for healing duodenal ulcers. When used prophylactically, a single 20 mg dose of famotidine at night decreases the incidence of duodenal ulcer recurrence (versus placebo). However, further study is needed to clarify the comparative efficacy of the H2-receptor antagonists, in particular as maintenance therapy for healed peptic ulcer. Preliminary results in a few patients with Zollinger-Ellison syndrome indicate that famotidine, alone or in combination with an anticholinergic agent, gives good control of gastric acid hyperacidity with no evidence of biochemical or haematological toxicity. Famotidine appears to be well tolerated. Unlike cimetidine, it does not have antiandrogenic effects or alter hepatic metabolism of drugs. However, wider clinical experience with famotidine is needed to accurately determine its relative tolerability compared with other anti-ulcer drugs. Thus, famotidine appears to be a suitable and well tolerated alternative to cimetidine and ranitidine for healing peptic ulcers, but wider clinical experience is needed to assess its relative efficacy and tolerability in the long term maintenance treatment of patients with healed ulcers as well as in patients with Zollinger-Ellison syndrome.     

Cimetidine, ranitidine and mifentidine in specific gastric and duodenal ulcer models

The protective effect of cimetidine, ranitidine and a newer H2-receptor antagonist, mifentidine (proposed INN), on models of gastric and duodenal damage, caused by activation of H2 receptors, was studied. Gastric erosions were induced in rats by intravenous dimaprit (100 mg/kg) while duodenal damage was investigated in guinea pigs following subcutaneous administration of dimaprit (2 mg/kg, 6 doses). All the compounds reduced or abolished gastric and duodenal damage in rats and guinea pigs, mifentidine being more potent than both cimetidine and ranitidine. The antiulcer effect of the H2-receptor antagonists was related to the dose and to their ability to inhibit dimaprit-induced gastric acid secretion. The duration of action proved to be different for the three compounds. According to the two dosing schedules adopted to evaluate the duration of action, mifentidine, compared to cimetidine and ranitidine, required considerably lower oral dosages to display its protective effect.     

Pharmacological basis for the induction of gastric carcinoid tumours in the rat by loxtidine, an insurmountable histamine H2-receptor blocking drug.

The very late occurrence of gastric carcinoids in a life-span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long-acting unsurmountable histamine H2-antagonist. The nature of the anti-secretory activity of loxtidine was compared with that of ranitidine on histamine-induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation. Ranitidine and loxtidine had qualitatively different inhibitory effects on acid secretion, ranitidine being a competitive antagonist of histamine even at high concentrations, whereas the effect of loxtidine on both preparations was unsurmountable at relatively low concentrations. These results support the hypothesis that the late formation of gastric carcinoids in rats receiving loxtidine is a consequence of persistent achlorhydria caused by unsurmountable blockade of parietal cell H2-receptors.     

Ranitidine. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer disease and other allied diseases

Ranitidine, a histamine H2-receptor antagonist, is now well established as a potent inhibitor of gastric acid secretion effective in the treatment and prophylaxis of gastrointestinal lesions aggravated by gastric acid secretion. Therapeutic trials involving several thousands of patients with peptic ulcer disease confirm that ranitidine 300mg daily administered orally in single or divided doses is at least as effective as cimetidine 800 to 1000mg daily in increasing the rate of healing of duodenal and gastric ulcers. Similar dosages of ranitidine have been shown to relieve the symptoms of reflux oesophagitis and heal or prevent gastrointestinal damage caused by ulcerogenic drugs. Ranitidine 150mg orally at night maintains ulcer healing in the long term. Ranitidine has also demonstrated good results in the treatment of Zollinger-Ellison syndrome and in the prevention of aspiration pneumonitis when given prior to surgery and to pregnant women at full term. It may also have a place in the management of acute upper gastrointestinal bleeding and in the prevention of stress ulcers in the intensive care setting, although these areas require further investigation. Ranitidine has been used safely in obstetric patients during labour, in children, the elderly, and in patients with renal impairment when given in appropriate dosages. The drug is very well tolerated and is only infrequently associated with serious adverse reactions or clinically significant drug interactions. Even at high dosages, ranitidine appears devoid of antiandrogenic effects. Ranitidine is clearly comparable or superior to most other antiulcer agents in the treatment and prevention of a variety of gastrointestinal disorders associated with gastric acid secretion. With its favourable efficacy and tolerability profiles, ranitidine must be considered a first-line agent when suppression of gastric acid secretion is indicated.     

Antiulcer effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl] carbamoyl]methyl]-amino-N-methylbenzamide in experimental gastric and duodenal ulcers

Effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl] methyl]-amino-N-methylbenzamide (DQ-2511), a newly synthesized compound, were evaluated using various types of experimental gastric and duodenal ulcers in rats. Pretreatment with DQ-2511, over the dose range 30-300 mg/kg p.o., resulted in a dose-related inhibition of water-immersion stress-, serotonin-, acetylsalicylic acid (ASA)-, indometacin-, ethanol-, and 2-deoxy-D-glucose(2DG) plus indometacin-induced gastric ulcers as well as cysteamine-induced duodenal ulcers. The antiulcer potencies of DQ-2511 were equal to or greater than those of H2-receptor antagonist cimetidine in these ulcer models except for ASA- and 2DG plus indometacin-induced ulcers. The rate of healing of chronic gastric ulcers induced by acetic acid was significantly accelerated by DQ-2511 (100 and 300 mg/kg p.o.) but not by the same doses of cimetidine. DQ-2511, at doses of 30 mg/kg p.o. and above, produced a significant decrease in gastric acid and pepsin output in pylorus-ligated rats. In anesthetized rats with acute gastric fistulae, 30 mg/kg i.v. of DQ-2511 significantly inhibited gastric acid secretion stimulated by 2DG, whereas it did not affect gastric hyperacidity evoked by either carbachol, histamine or pentagastrin. At effective antiulcer doses, this compound produced a sustained increase in gastric mucosal blood flow in conscious, restrained rats. Based on these observations, DQ-2511 is characterized as a new antiulcer compound with beneficial effects on both gastric aggressive and defensive factors. Furthermore, these results indicate a possible superiority of DQ2511 over cimetidine in regard to its antiulcer potency and spectrum.     

Byciclic compounds with potential antiulcer and/or antisecretory activity. III--2-substituted tetrahydrothiazolo-[5,4-c]pyridines

As the ultimate result of a long-term search for new bicyclic molecules potentially endowed with antiulcer and/or antisecretory activity, simple urea derivatives of 2-guanidino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine [(VIII), Fig. 1; X = 0, R = alkyl], displaying a strong inhibition of stress- and ASA-induced gastric ulcers and of basal gastric secretion, were found. Their potency does compare very favourably with that of cimetidine and ranitidine and approaches that of famotidine. On spontaneously beating guinea pig atria they behaved as inhibitors of the histamine H2-receptor. In contrast with cimetidine and ranitidine but like other recently described inhibitors (famotidine included), the most active compounds (VIII) caused a surmountable antagonism only at low concentrations and an unsurmountable antagonism at higher concentrations. The onset of action was slow, while the inhibitory effect was hardly reversed by washing. The rational development of the research and the synthetic approach, as well as a quantitative assessment of both in vitro and in vivo potencies in comparison with the best known, clinically used drugs, are shown in detail.     

Histamine is able to suppress the inhibitory effect of somatostatin on exogenous gastrin: comparison between extractive antral histamine and synthetic histamine

In view of examining inhibition by somatostatin of gastrin-induced gastric secretion, antral histamine (AH) and synthetic histamine (SH) were comparatively studied in dogs. Both AH and SH were able to antagonize somatostatin: their potencies did not differ significantly as regards acid secretion, but AH is more potent than SH on pepsin secretion. The dose-dependent activity of AH was limited for the period of infusion. The denervated pouch is more sensitive than the innervated stomach. We suggest that antral histamine might intervene in the complex regulation of gastric secretion where somatostatin and gastrin act antagonistically and where the stimulatory as well as inhibitory fibers of the vagus intervene.     

Effects of the new anti-ulcer drug nizatidine on prostaglandins in the rat gastric mucosa.

The effects of nizatidine (N-[2-[[[2-[(dimethylamino)methyl]- 4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine , CAS 76963-41-2), a new histamine H2-receptor antagonist, on the content of prostaglandins (PGs) in the rat gastric mucosa at doses that inhibit basal gastric acid secretion were compared with those of two other histamine H2-receptor antagonists, cimetidine and ranitidine. Nizatidine did not inhibit basal gastric acid secretion at a dose of 0.4 mg/kg but showed dose-dependent inhibition at doses of 10, 30, and 100 mg/kg. This drug had no effects on the content of PG in the gastric mucosa when subcutaneously administered at doses of 0.4, 10, 30 and 100 mg/kg once daily for 5 days. Cimetidine and ranitidine administered at doses that markedly inhibit basal gastric acid secretion (250 and 100 mg/kg/d, respectively) had no effects on the content of PG in the gastric mucosa. On the other hand, nizatidine, cimetidine, or ranitidine at concentrations of 1-100 mumols/l did not inhibit in vitro PGE2 synthesis using sheep seminal vesicle microsomes. These results suggest that nizatidine did not affect in vitro PGE2 synthesis and even doses that markedly inhibit gastric acid secretion had no effects on the content of PGs in the gastric mucosa.     

In-vitro potencies of histamine H2-receptor antagonists on tetraethylammonium uptake in rat renal brush-border membrane vesicles

Abstract— The histamine H₂ antagonists cimetidine, ranitidine and famotidine are organic bases that are cleared from the body by active renal tubular secretion involving the organic cation transporter in the proximal tubule. To determine the potential for competition for the transporter between these drugs and other drugs, their inhibitory potencies were assessed in-vitro, using rat renal brush-border membrane vesicles and tetraethylammonium as the substrate. The concentration-dependent effect of cimetidine, ranitidine and famotidine on the 15-s proton-stimulated uptake of tetraethylammonium into the membrane vesicles was studied using five different rat kidneys. The order of inhibition potencies was: cimetidine (mean IC50= 1·07 μm ) > famotidine (2·43 μm ) > ranitidine (55·4 μm ). The results indicate the potential for drug interactions in the kidney, especially for cimetidine and famotidine.     

Current concepts in clinical therapeutics: peptic ulcer disease

The epidemiology, pathophysiology, diagnosis, clinical presentation, and treatment of peptic ulcer disease (PUD) are reviewed. PUD occurs commonly, with about 4 million Americans affected in a year. Cigarette smoking, aspirin use, and prolonged corticosteroid use are associated with PUD. The disease's etiology is multifactorial; the long-held assumption that ulcers develop solely because of increased gastric acid secretion is no longer valid. Although duodenal ulcer patients are frequently hypersecretors of acid, gastric ulcer patients more commonly have defective mechanisms for protecting the mucosal lining from acid, pepsin, and other agents. PUD is best diagnosed using an upper gastrointestinal roentgenographic series or using endoscopy. The clinical presentations, which involve epigastric abdominal pain that is relieved by food, milk, or antacids, may aid in diagnosis but are not usually definitive. Treatment is designed to relieve symptoms, heal the ulcer, prevent recurrences, and prevent complications. Of the four currently available drug treatments (cimetidine, ranitidine, antacids, and sucralfate), the treatment of first choice is cimetidine or ranitidine for four or six weeks, respectively, for duodenal and gastric ulcer patients. Antacids should be used as needed for pain, and the patient should be reassessed at the end of this period. For most patients, neither cimetidine nor ranitidine is demonstrably superior to one another. Several agents are under investigation in the U.S., including other H2-receptor antagonists (famotidine and nizatidine), proton-pump inhibitors (omeprazole), prostaglandins (misoprostol, arbasprostil, enprostil, and trimoprostil), antimuscarinic agents (pirenzepine), and tricyclic antidepressants (doxepin and trimipramine). peptic ulcer disease is an important disease. It is best treated with H2-receptor antagonists supplemented with antacids as needed for pain.     

Omepmazole or high-dose ranitidine in the treatment of patients with reflux oesophagitis not responding to ''standard doses''of H2-receptor antagonists

Ninety-eight patients (26 females), who presented with erosive and/or ulcerative oesophagitis, despite at least a 3-month period of treatment with standard doses of cimetidine (greater than or equal to 1200 mg daily) or ranitidine (greater than or equal to 300 mg daily), were included in a double-blind, randomized trial to compare omeprazole (40 mg o.m.) with a high dose of ranitidine (300 mg b.d.). The treatment was given for 4-12 weeks; endoscopy assessment and laboratory screening were performed on entry to the trial and thereafter every fourth week. Endoscopic healing was defined as complete epithelialization of all macroscopic erosions or ulcers in the squamous epithelium. An 'intention-to-treat' analysis of the clinical data revealed omeprazole to be superior to ranitidine: 63% of those patients who were given omeprazole were healed endoscopically after a 4-week period of treatment, compared with only 17% of those given ranitidine. This difference in healing rate persisted during the 12-week study period (90% vs 47% after 12 weeks; P less than 0.0001). Reflux symptoms were more rapidly and completely relieved with omeprazole: heartburn resolved completely in 86% of patients treated with omeprazole for 4 weeks compared with 32% in the ranitidine group (P less than 0.0001). The mean basal gastrin concentrations increased only in those given omeprazole from 18.9 pmol/L at pre-entry to a mean value of 31.7 pmol/L on the last day of omeprazole administration. In ranitidine-treated patients no significant increase in basal gastrin concentration was observed. Both drugs were well tolerated with few adverse events, which were mainly mild and transient. These results demonstrate the superiority of omeprazole over a high dose of ranitidine in the treatment of resistant reflux oesophagitis.     

Omeprazole. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome

Omeprazole is a substituted benzimidazole derivative which markedly inhibits basal and stimulated gastric acid secretion. It has a unique mode of action, irreversibly blocking the so-called proton pump of the parietal cell which is supposedly the terminal step in the acid secretory pathway. In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidine in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochromaffin-like cells and carcinoids, a few with proliferations into the submucosa. The significance of such findings to the clinical situation is wholly speculative and requires further research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syndrome have found no mucosal changes which would suggest that the drug represents a risk for development of carcinoid tumours at therapeutic dosages. In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily, produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and 100% after 4 weeks, even in patients resistant to treatment with H2-receptor antagonists. Comparative trials clearly demonstrated that omeprazole 20 to 40 mg administered once daily was significantly more effective than usual dosage regimens of cimetidine and ranitidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data are available evaluating omeprazole as maintenance therapy once ulcers have healed. Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers, ulcerative peptic oesophagitis, and Zollinger-Ellison syndrome. In patients with Zollinger-Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may make it the drug of choice for treating the massive acid hypersecretion associated with the disease, especially when H2-receptor antagonists are ineffective. During clinical trials reported to date omeprazole has been very well tolerated but further clinical experience is essential to fully evaluate its safety profile. Thus, omeprazole represents a pharmacologically unique antisecretory drug which is very effective for rapidly healing peptic ulcers and peptic oesophagitis, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent absence of undesirable mucosal morphological changes during treatment with usual doses in patients with peptic ulcer disease is confirmed, it may be a major advance in the treatment of these diseases.     

Effects of FPL-52694, a new mast cell stabilizer, on gastric secretion and various acute gastric lesions in rats

Oral FPL-52694 [5-(2-hydroxypropoxy)-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid Na], a new mast cell stabilizer, dose-dependently inhibited gastric acid secretion but increased the volume and pepsin output in pylorus-ligated rats. Intraduodenal FPL-52694 significantly inhibited all of the volume, acidity, acid output and pepsin output. Concerning the acidity, oral administration of the agent showed much more potent inhibition than intraduodenal administration. Oral FPL-52694 markedly inhibited the development of pylorus-ligated ulcers, water-immersion stress- and aspirin-induced gastric erosions and moderately inhibited the formation of reserpine-induced gastric erosions in rats. Intraduodenal FPL-52694 also inhibited pylorus-ligated ulcers whereas it had no effect on aspirin-induced gastric erosions. Histamine-induced gastric erosions were not affected by oral FPL-52694. These effects of FPL-52694 were almost the same as those of cimetidine, except that cimetidine tended to inhibit histamine-induced gastric erosions. Although the precise mechanism of action of FPL-52694 remains unknown, oral FPL-52694 appears to be a promising agent for the treatment of peptic ulcers.