Effects of NC-1300, a gastric proton pump inhibitor,on healing of acetic acid-induced gastric ulcers in rats

Effects of NC-1300 (a gastric proton pump inhibitor) on healing of experimental chronic gastric ulcers induced in rats were studied. Gastric ulcers were induced by the submucosal injection of 20% acetic acid (0.03 ml) into the antral-oxyntic border of the anterior wall of male Donryu rats (260–280 g). The healing of acetic acid ulcers was delayed by the daily subcutaneous administration of indomethacin (1 mg/kg) for two or four weeks after ulceration. Aggravation of healed ulcers was evoked by subcutaneous administration of indomethacin (1 mg/kg) once daily for four weeks to rats with four-week-old ulcers. Oral administration of NC-1300 (10, 30, or 100 mg/kg) once daily for two or four weeks after ulceration dose-dependently accelerated both natural and delayed healing of acetic acid ulcers. When the period of administration was extended from two to four weeks, the ED₅₀ values (the dose reducing the ulcerated area by 50%) were decreased from 36.5 to 13.5 mg/ kg in natural healing and from 76.0 to 23.0 mg/kg in delayed healing. Aggravation of four-week-old ulcers by indomethacin was significantly prevented by daily administration of NC-1300 (30 or 100 mg/kg) for four weeks. Acetic acid ulcers that were healed with NC-1300 given for four weeks after ulceration remained healed for four to eight weeks after the cessation of drug administration. A single administration of NC-1300 to normal rats and repeated administration of NC-1300 to rats with acetic acid ulcers for four weeks after ulceration caused the same degree of inhibition of gastric acid secretion. Reduction in the area of ulceration and inhibition of gastric acid secretion by NC-1300 were significantly correlated in the indomethacin-treated animals. We conclude that NC-1300 markedly accelerates the healing of chronic gastric ulcers and prevents aggravation of the healed ulcers, presumably through antisecretory activities.     

Effects of a proton pump inhibitor,omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats

The effects of omeprazole, a proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions in rats were studied. Omeprazole, given intraduodenally, dose-dependently inhibited the gastric secretion (volume, acid and pepsin output) of pylorus-ligated rats. The antisecretory activity of omeprazole at 100 mg/kg persisted for 14 hr after treatment. Acutely induced gastric ulcers or erosions such as Shay ulcers, water-immersion stress-, indomethacin-, aspirin-, or prednisolone-induced erosions were all markedly inhibited by oral or intraduodenal administration of 10–100 mg/kg of omeprazole. The development of duodenal ulcers and gastric erosions caused by mepirizole was also potently inhibited by omeprazole at 3–10 mg/kg given orally. Repeated administration of omeprazole, 200 mg/kg/day in two divided doses for 14 days, significantly accelerated the spontaneous healing of acetic acid-induced gastric ulcers. The mechanism by which omeprazole inhibits the development of acute ulcers and accelerates healing of preexisting ulcers appears to be mainly due to its potent and longlasting antisecretory activity. The antisecretory and antiulcer activities of omeprazole are equal to or exceed those of cimetidine, both in the maximum inhibitory response and ED₅₀ values.     

The effect of a new gastric proton pump inhibitor on serotonin-induced gastric mucosal lesions in rats

The anti-ulcer effect of NC-1300, a new proton pump inhibitor, and its effect on gastric mucosal blood flow were studied in rats. Acute gastric mucosal lesions were induced by the subcutaneous administration of serotonin, 20 mg/kg. Using the electrolytically generated hydrogen gas clearance technique, it was determined that such gastric ulceration resulted mainly from a decrease in gastric mucosal blood flow. These lesions could be inhibited to a statistically significant extent by the intravenous administration of NC-1300, 20 mg/kg, which markedly inhibited gastric acid secretion. However, the serotonin-induced decrease in gastric mucosal blood flow could not be prevented by pretreatment with 20 mg/kg of NC-1300. It was concluded that protection against serotonin-induced gastric ulceration can be achieved by markedly inhibiting gastric acid secretion.     

Inhibition of canine gastric secretion by the prostanoid Ro 22-6923

The synthetic prostanoid, Ro 22-6923, was studied for its effects on canine gastric secretion. Histamine-stimulated acid secretion was inhibited for up to 8 hr after an orally administered dose of 0.25 mg/kg Ro 22-6923. In the Amdrup (modified Pavlov) pouch model, Ro 22-6923 significantly inhibited food-stimulated acid secretion at an oral dose of 0.5 mg/kg. The effect lasted for 4 hr and was of greater intensity than that observed with 5 mg/kg cimetidine. The ED ₅₀ for Ro 22-6923 in this model was 0.25 mg/kg and 0.09 mg/kg for oral and intrapouch administration, respectively. Natural prostaglandin E ₂ was inactive up to 1 mg/kg orally, but had an ED ₅₀ of 0.08 mg/kg when administered directly into the pouch. The results indicate that Ro 22-6923 is a potent, long-acting antisecretory drug that may be useful in the therapy of peptic ulcer disease in man.     

Effect of intraduodenally administered histamine on gastric acid secretion in rats and guinea pigs

We examined the effect of histamine administered intraduodenally as well as subcutaneously or intravenously on the gastric acid secretion in rats and guinea pigs, using a newly devised cannula. Intraduodenally administered histamine dihydrochloride caused a significant dose-dependent increase in the gastric acid secretion in rats. The maximal acid secretion, which corresponded to that after subcutaneous (20 mg/kg) or intravenous (10 mg/kg/hr) administration of histamine, was observed within 30 min after intraduodenal administration (40 mg/kg). The plasma concentrations of histamine determined 30 min after intraduodenal, subcutaneous, and intravenous administration of histamine were nearly the same. Pretreatment with aminoguanidine sulfate (diamine oxidase inhibitor) at 30 mg/kg significantly increased the gastric acid secretion caused by intraduodenal histamine. The gastric acid secretion stimulated by intraduodenal histamine was significantly inhibited by cimetidine, pirenzepine, and omeprazole, but remained unchanged with tripelennamine. Intraduodenal histamine (20 mg/kg) also maximally stimulated the gastric acid secretion in guinea pigs. The response was comparable to that with subcutaneous histamine (1 mg/kg). We conclude that intraduodenal histamine has the ability to stimulate gastric acid secretion in both rats and guinea pigs.     

Gastric motility is an important factor in the pathogenesis of indomethacin-induced gastric mucosal lesions in rats

Effects of atropine, cimetidine, and 16,16-dimethyl prostaglandin E₂ (16,16-dmPGE₂) on indomethacin-induced gastric lesions were investigated in rats by correlating their effects on gastric acid and HCO^}-₃ secretion and motility. Subcutaneously administered indomethacin (25 mg/kg) produced gastric mucosal lesions within 4 hr. In parallel studies, an equivalent dose of indomethacin inhibited gastric HCO^}-₃ secretion, and stimulated gastric motor activity measured as intraluminal pressure recordings, whereas acid secretion was unaffected. The lesions induced by indomethacin were significantly prevented by three agents: cimetidine (100 mg/kg), which reduced acid secretion; atropine (1 mg/kg), which reduced acid secretion and gastric motility; and 16,16-dmPGE₂ (10 g/kg), which reduced acid secretion and motility and increased gastric HCO^– ₃ secretion. If acid (150 mM HCl) was infused into the stomach (1.2 ml/hr) during indomethacin treatment, only the latter two agents significantly prevented the formation of gastric lesions in response to indomethacin. Since only the effect on gastric motility was common to these two agents (atropine and 16,16-dmPGE₂), the increased gastric motility may be an important pathogenetic factor in indomethacin-induced gastric lesions. The presence of acid as well as a deficiency of endogenous PGs may be prerequisite for later extension of the lesions but cannot account for the induction of mucosal lesions in rats following administration of indomethacin.     

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

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

The gastric antisecretory activity of pyridyl-2-thioacetamide (CMN 131)

A thiocarboxamide derivative, pyridyl-2-thioacetamide, referred to as CMN 131, was characterized for its gastric antisecretory properties in rats and dogs. Its activity was first determined in 4-hr pylorus-ligated rats and in gastric fistula rats under basal and carbachol-stimulated (18 μg/kg/hr s.c.) conditions. ED₅₀ of acid output inhibition was 1.46 (0.92–2.31) mg/kg by intraduodenal route and 3.85 (2.65–5.59) mg/kg s.c. respectively. The activity was further confirmed in Heidenhain-pouch dogs whose gastric secretion was stimulated by pentagastrin (3.20 μg/kg/hr i.v.) and histamine (160 μg/kg/hr i.v.). Under all these conditions, CMN 131 in doses ranging from 1 to 10 mg/kg, whatever the drug administration route, possesses a long-acting antisecretory property characterized first by an activity on acid concentration and second by an equal inhibitory potency on histamine and pentagastrin stimulation.     

CP-66,948: An antisecretory histamine H2-receptor antagonist with mucosal protective properties

CP-66,948 is a histamine H₂-receptor antagonist with gastric antisecretory activity and mucosal protective properties. The affinity of CP-66,948 for the guinea pig atria histamine H₂-receptor is 15 times greater than that of cimetidine and seven times greater than that of ranitidine.In vivo, the ED₅₀ value for inhibition of gastric acid secretion in pylorusligated rats is 2 mg/kg intraduodenally, and in histamine or pentagastrin-stimulated Heidenhain pouch dogs the antisecretory ED₅₀ values are 0.3 mg/kgper os and 1.0 mg/kgper os, respectively. CP-66,948 also inhibits ethanol-induced gastric hemorrhagic lesions in rats following either oral or systemic administration (ED₅₀ values of 12 mg/kgper os and 6 mg/kg subcutaneously). In addition, the mucosal protective activity is independent of prostaglandin synthesis. CP-66,948 inhibits gastric acid secretion in man, and its mucosal protective activity may provide additional benefits in peptic ulcer therapy.     

Validity of kissing gastric ulcers induced in rats for screening of antiulcer drugs

Abstract We examined the validity of kissing gastric ulcers induced in rats by determining the effects of conventional antiulcer drugs. Gastric ulcers were produced by luminal application of 60% acetic acid (0.2 mL, 45 s) to an area clamped with a pair of forceps. The ulcers were evaluated as to either the ulcerated area (mm²) or ulcer index (ulcerated area x depth). The healing of kissing ulcers was significantly enhanced by 2 week treatment with oral omeprazole (10, 30 mg/kg per day), leminoprazole (30, 60 mg/kg per day) or cimetidine (300, 450 mg/kg per day). The rate of healing was > 50% to both the ulcerated area and ulcer index. Aluminium hydroxide (up to 1800 mg/kg per day) had no effect on ulcer healing on the ulcerated area, but it caused a significant reduction in the ulcer index. Gastric acid secretion was significantly inhibited by repeated administration of omeprazole, leminoprazole and cimetidine in a dose-dependent manner. Aluminium hydroxide significantly increased the pH of the gastric contents. The mechanism of action of these drugs appears to involve partly the inhibition of gastric acid secretion and neutralization of secreted acid. We conclude that kissing gastric ulcers are a sensitive ulcer model for the screening of antiulcer drugs.     

Inhibition of Pentagastrin-Stimulated Gastric Acid Secretion by Pantoprazole and Omeprazole in Healthy Adults

Our objective was to compare the onset and duration of a single dose of pantoprazole or omeprazole on maximally stimulated gastric acid secretion. This double-blind, randomized, placebo-controlled study involved 36 healthy adults and utilized continuous pentagastrin infusion to stimulate acid secretion after administration of pantoprazole, 40 mg, omeprazole, 20 mg, or placebo. Gastric aspirates were collected over 24 hr and analyzed for volume, pH, and hydrogen ion concentration, and gastric acid outputs (GAO) were calculated. Comparison between GAO and intragastric pH was performed. Pantoprazole resulted in significantly greater inhibition of GAO than omeprazole. Mean cumulative 24-hr GAO was 164 ± 130 mEq for pantoprazole versus 283 ± 159 mEq for omeprazole (P = 0.031). Pantoprazole patients reached and maintained GAO levels below the 10-mEq/hr threshold at 5.7 hr, whereas omeprazole patients never reached this threshold. We conclude that pantoprazole significantly suppressed gastric acid secretion compared to omeprazole. Comparisons between pH and GAO showed that GAO was a more appropriate measure of gastric acid secretion than intragastric pH. This work received financial support from Wyeth Pharmaceuticals.     

Effects of histamine H2-receptor antagonists and a proton pump inhibitor on the mucosal hydroxyproline content of ethanol-HCl-induced gastric lesions in rats.

We evaluated the effects of different antisecretory agents (H2-receptor antagonists and a proton pump inhibitor) on collagen regeneration in rat gastric lesions induced by intragastric administration of 50% ethanol +0.15 N HCl (EtOH-HCl). The lesion indices showed the highest value 30 min after administration of EtOH-HCl and a significantly decreased value 15 h later. The mucosal hydroxyproline concentration was significantly increased 30 min after EtOH-HCl administration, reached a maximum 6 h later and subsequently decreased as time passed. Intraperitoneal administration of cimetidine at a dose of 100 mg/kg or famotidine at a dose of 5 mg/kg 30 min after EtOH-HCl administration could not reduce the lesion indices in less than 24 h and suppressed the increase in mucosal hydroxyproline concentrations significantly compared with the control group. On the other hand, treatment with 10 mg/kg of E-3810, a proton pump inhibitor, had no effects on the lesion healing nor on the fluctuation of mucosal hydroxyproline concentrations. These facts suggest that H2-receptor antagonists might delay the healing of EtOH-HCl-induced gastric lesions through the suppression of collagen regeneration under the condition of exclusion of gastric acid secretion.     

Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats

Effects of indomethacin on gastric motility and secretion, and levels of endogenous prostaglandins (PGs) were investigated in rats, in attempts to elucidate the factors involved in the pathogenesis of indomethacin-induced macroscopic gastric lesions. Subcutaneous administration of indomethacin had no effect on the gastric mucosa at doses of 1 and 5 mg/kg, but induced visible lesions dose dependently at over 10 mg/kg within 4 hr. At 25 mg/kg, there were apparent nonhemorrhagic lesions within 1 hr, and these lesions became hemorrhagic with time. Acid secretion was not affected by this agent at either dose level, but pepsin or acid-induced HCO₃ ^– secretion was significantly increased or decreased, respectively, at a dose less than 5 mg/kg, which did not induce any lesion. Gastric motility, however, was dose dependently increased after administration of indomethacin, and its effect was significant at 10 mg/kg or greater. Time-course changes in the motility were in parallel with those of the lesion formation. PGE₂ and 6-keto PGF₁ levels in the corpus mucosa were reduced around 80–90% for more than 4 hr from 30 min after administration of 5 mg/kg or more of indomethacin. When all the above changes caused by indomethacin were plotted for the various doses, a significant correlation (r=0.958, P<0.01) was found between the lesion index and the changes in motility, but not in other factors, including PG levels. These results indicate that gastric motility may be an important factor in the pathogenetic mechanism of indomethacin-induced gastric lesions in rats. A deficiency of endogenous PGs may be a prerequisite for later extension of the lesions.     

Modulatory action of adenosine on gastric function and ethanol-induced mucosal damage in rats

This study examines the gastric effects of adenosine and its antagonist, theophylline, on secretory function, mucosal blood flow, and on ethanol-induced glandular mucosal damage in rats that were fasted for 24 hr before experimentation. The animals were anesthetized with sodium pentobarbitone (50 mg/kg intraperitoneal) and their tracheae cannulated. An ex vivo stomach chamber then was prepared. The luminal bathing solution was collected every 15 min and the concentrations of H⁺ and Na⁺ were determined by a pH autotitrator and an ionmeter, respectively. The glandular mucosal blood flow was measured by a laser Doppler flowmeter and the severity of lesions was determined by measuring the hemorrhagic areas. Adenosine administration (2.5 or 7.5 mg/kg, subcutaneous) markedly lowered the H⁺ and Na⁺ output but increased the secretory volume and mucosal blood flow in a dose-dependent manner. The same doses of the nucleoside also prevented ethanol-induced mucosal damage. These effects were prevented by pretreatment with theophylline (30 or 60 mg/kg, subcutaneous). Ethanol given alone significantly depressed the H⁺ and Na⁺ secretion. Both effects were not modified by adenosine treatment. However, the depressive action of ethanol on mucosal blood flow was prevented by adenosine. These findings indicate that adenosine modulates the physiological function of the stomach. It also directly activates the defensive mechanism of the stomach, which is partially mediated by the improvement of the gastric mucosal blood flow and an increase in the nonacid component of gastric secretion.     

Role of endogenous secretin and cholecystokinin in intraduodenal oleic acid-induced inhibition of gastric acid secretion in rats

We investigated a possible role of endogenous secretin and cholecystokinin (CCK) in inhibition of gastric acid secretion induced by intraduodenal administration of oleic acid in rats. Intraduodenal administration of oleic acid emulsion in a dose of 1 mmol/hr resulted in significant inhibition of gastric acid secretion stimulated by intravenous infusion of pentagastrin (0.3 g/kg/hr), and this was accompanied by an increase in the plasma concentration of both secretin and CCK, from 1.2±0.08 pM and 20.6±1.2 pM to 4.3±0.18 pM and 31.6±0.9 pM, respectively (P<0.001). Intravenous infusion of secretin (0.05 CU/kg/hr) inhibited pentagastrin-stimulated gastric acid secretion, but CCK-8 (0.03 /kg/hr) failed, although intravenous infusion of secretin, and CCK in those doses produced plasma levels comparable to the levels achieved in response to oleic acid administration. Furthermore, the oleic acid-induced suppression of gastic acid secretion was blocked significantly by intravenous injection of rabbit anti-secretin serum (0.1 ml), but not by intravenous infusion of a CCK-receptor antagonist, CR 1409 (5 mg/kg/hr). Thus, the results of this study indicate that endogenous secretin rather than CCK is involved in the hormonal mechanism regulating the inhibition of gastric acid secretion by intestinal fat in rats.This work was supported in part by a grant from the Japanese Ministry of Education. Part of this work was presented at the Annual Meeting of the American Gastroenterological Association, May 12–18, 1990, San Antonio, and appeared in abstract form inGastroenterology 98:A124, 1990     

Effects of route of administration on the production of gastric hemorrhage in the rat by aspirin and sodium salicylate

Dose response curves were obtained in food-deprived rats for aspirin-induced incidence of gastric hemorrhage by four routes of administration: oral (ED₅₀=18 mg/kg); intravenous (ED₅₀=36 mg/kg); small intestinal (ED₅₀=34 mg/kg); and colonic (ED₅₀=12 mg/kg). A similar study with sodium salicylate gave a dose response curve after oral administration (ED₅₀=33 mg/kg), but no incidence of gastric hemorrhage was produced when sodium salicylate was given by the other three routes, even at toxic dose levels. The data indicate that aspirin can produce gastric hemorrhage in the rat by parenteral as well as by oral route, but that sodium salicylate causes gastric hemorrhage in the rat only on direct contact with the gastric mucosa.     

Control of Nocturnal Gastric Acidity: A Role for Low Dose Bedtime Ranitidine to Supplement Daily Omeprazole

In some patients, proton pump inhibitors do not abolish nocturnal gastric acidity and additional evening antisecretory medication may be required. In 16 subjects with chronic heartburn, 24-hr gastric and esophageal pH were measured at baseline and again after six days of 20 mg omeprazole alone at 08:00 hr followed by placebo, 75 mg ranitidine, or 20 mg omeprazole at 22:00 hr. Integrated acidity was calculated from the cumulative, time-weighted mean acid concentrations (derived from pH values for each second). Baseline integrated gastric acidity increased progressively over 24 hr, whereas integrated esophageal acidity increased only until 22:00 hr. Morning omeprazole nearly abolished 24-hr esophageal acidity and significantly decreased overall gastric acidity but did not abolish nocturnal gastric acidity. Adding evening ranitidine or omeprazole nearly eliminated the nocturnal increase in gastric acidity. Integrated acidity was more sensitive than time pH < 4 in assessing gastric and esophageal acidity as well as their inhibition by omeprazole and ranitidine. In conclusion, integrated acidity provides novel information regarding the synergy of omeprazole plus ranitidine. Adding low-dose ranitidine helps control nocturnal gastric acidity that can occur with conventional omeprazole administration. Although the heartburn patients in the present study had nocturnal gastric acidity without accompanying nocturnal esophageal acid reflux, other patients who do have nocturnal esophageal reflux might profit from addition of bedtime ranitidine or another gastric antisecretory agent.     

Importance of gastric acid in gastric ulcer formation in rabbits with antibody-induced prostaglandin deficiency.

The role of gastric acid in the development of gastroduodenal ulcers in prostaglandin-deficient conditions is unclear. In the current study, the effect of the proton pump inhibitor omeprazole on the formation of gastric ulcers was examined in a previously validated rabbit model of antibody-induced prostaglandin deficiency. Intragastric administration of 20 mg/kg omeprazole every 12 hours caused a profound suppression of gastric acidity (i.e., pH above 5 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by passive immunization with 6-keto-prostaglandin F1 alpha antibodies. It is concluded from these observations that gastric acid plays a critical role in the formation of gastric ulcers in rabbits with antibody-induced prostaglandin deficiency.     

The effects of rabeprazole on parietal cells and enterochromaffin-like cells in rats: a comparison with omeprazole

Background. We investigated the effects of rabe-prazole compared with those of omeprazole on enterochromaffin-like cells and parietal cells in rats. Methods. Rabeprazole or omeprazole was administered for 7 days by intraperitoneal injection (100 mg/kg or 20 mg/kg once a day) and the serum gastrin concentration, the antral density of G cells and D cells, fundic histamine content, fundic H⁺, K⁺-ATPase mRNA level, and parietal cell morphology were determined. Results. Both rabeprazole and omeprazole inhibited gastric acid secretion and increased the intragastric pH to over 6.5, as well as causing a marked increase in the serum gastrin concentration. The serum gastrin level was lower with rabeprazole treatment than with omeprazole treatment at both doses. Also, the antral G-cell density was higher with omeprazole than with rabeprazole, while the increase in both the histamine content and the H⁺, K⁺-ATPase mRNA level in the fundic mucosa was higher with omeprazole treatment at both doses, with the difference being significant at 100 mg/kg. Ultrastructural examination indicated that the stimulation of parietal cells by omeprazole was stronger than that by rabeprazole. Conclusions. Rabeprazole treatment does not drive enterochromaffin-like cells and parietal cells as strongly as omeprazole treatment despite its potent acid suppressive effect, suggesting that it represents a new generation of proton pump inhibitors. Received: March 16, 2001 / Accepted: August 10, 2001     

Effect of omeprazole on gastric acid secretion in rat: evaluation of dose, duration of effect, and route of administration

The effect of omeprazole on gastric acid output was studied in rats before and during stimulation by continuous administration of tetragastrin at 50 micrograms/kg-hour. From 5 to 20 mg/kg of omeprazole was given to animals intraperitoneally, perorally and intravenously from 2 to 24 hours before the gastric secretory study was started, and the respective effects on acid secretion were compared. In each administration group, 20 mg/kg of omeprazole was the most potent among the groups receiving 5, 10 or 20 mg/kg, when the drug was given 2 hours before the study. There were statistically significant differences between the control group given tetragastrin only and each of the groups given 20 mg/kg of omeprazole perorally, intraperitoneally and intravenously. There was no significant difference among the groups given 20 mg/kg of omeprazole intraperitoneally, intravenously and perorally. The effect of 20 mg/kg of omeprazole continued at least 24 hours after the agent was administered perorally.