Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.     

Protective effect of teprenone against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats

The protective effect of teprenone, an anti-ulcer drug, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Teprenone (50, 100, or 200 mg/kg) was orally administered 0.5 h before compound 48/80 treatment. Administered teprenone prevented gastric mucosal lesion development found at 3 h after compound 48/80 treatment dose-dependently, although no dose of teprenone affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. Increases in the activities of myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase and the content of thiobarbituric acid reactive substances (an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus occurred in gastric mucosal tissues at 3 h after compound 48/80 treatment. Administered teprenone dose-dependently attenuated all these changes found at 3 h after compound 48/80 treatment. These results indicate that orally administered teprenone protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its stimulatory action on gastric mucus synthesis and secretion and its inhibitory action on neutrophil infiltration and enhanced lipid peroxidation in the gastric mucosal tissue.     

Role of endogenous serotonin and histamine in the pathogenesis of gastric mucosal lesions in unanaesthetised rats with a single treatment of compound 48/80, a mast cell degranulator.

In unanaethetised rats with a single injection of compound 48/80, a mast cell degranulator (0.75 mg kg-1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented the formation of gastric mucosal lesions with attenuation of reduced gastric mucosal blood flow at 0.5 h after compound 48/80 injection, while pretreatment with either amitriptyline (a selective inhibitor of histamine release from mast cells), tripelennamine (a histamine H1-receptor antagonist), famotidine (a histamine H2-receptor antagonist) or cimetidine (a histamine H2-receptor antagonist) had no effect. Pretreatment with either cyproheptadine, methysergide, amitriptyline or tripelennamine prevented the development of gastric mucosal lesions at 3 h after compound 48/80 injection, while pretreatment with either famotidine or cimetidine had no effect. These results indicate that in unanaesthetised rats with a single compound 48/80 treatment, acutely released endogenous serotonin causes gastric mucosal lesions, while released endogenous histamine mainly contributes to the lesion development and that gastric acid plays little role in the pathogenesis of the compound 48/80-induced acute gastric lesions.     

Effect of oral vitamin E administration on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator

The effect of oral vitamin E administration on acute gastric mucosal lesion progression was examined in rats treated once with compound 48/80 (C48/80) (0.75 mg/kg, i.p.) in comparison with that of subcutaneously administered superoxide dismutase (SOD) plus catalase (CAT). Vitamin E (50, 100 or 250 mg/kg) administered at 0.5 h after C48/80 treatment reduced progressive gastric mucosal lesions at 3 h after the treatment dose-dependently, like SOD plus CAT administered at the same time point. The gastric mucosa of C48/80-treated rats had decreased Se-glutathione peroxidase activity and vitamin E, ascorbic acid, and hexosamine contents and increased myeloperoxidase and xanthine oxidase activities and thiobarbituric acid reactive substances content at 3 h after the treatment. Administered vitamin E attenuated all these changes found at 3 h after C48/80 treatment dose-dependently, like administered SOD plus CAT. C48/80-treated rats administered with vitamin E (100 or 250 mg/kg) had higher gastric mucosal vitamin E content than C48/80-untreated rats. Neither administered vitamin E nor SOD plus CAT had any effect on the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow found at 3 h after C48/80 treatment. In the gastric mucosa of C48/80-untreated rats administered with vitamin E, thiobarbituric acid reactive substances content decreased with an increase in vitamin E content. These results indicate that orally administered vitamin E prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing oxidative stress, neutrophil infiltration, and mucus depletion in the gastric mucosa like administered SOD plus CAT.     

Protective effect of ebselen,a seleno-organic compound,against the progression of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator,in rats

The protective effect of ebselen, which possesses glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, against the progression of acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Ebselen (50, 100 or 200 mg/kg) was orally administered 0.5 h after compound 48/80 treatment, at which time gastric mucosal lesions appeared. Post-administered ebselen suppressed gastric mucosal lesion progression at 3 h after compound 48/80 treatment dose-dependently, although no dose of ebselen affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. A decrease in Se-glutathione peroxidase activity and increases in myeloperoxidase and xanthine oxidase activities and the concentration of thiobarbituric acid reactive substances were found in gastric mucosal tissues at 0.5 h after compound 48/80 treatment, and these changes were further enhanced at 3 h. Post-administered ebselen attenuated all these changes found at 3 h after compound 48/80 treatment dose-dependently. The present results indicate that ebselen exerts a protective effect against the progression of compound 48/80-induced acute gastric mucosal lesions in rats, and they suggest that this protective effect of ebselen could be due to its glutathione peroxidase-like activity and its antioxidative and anti-inflammatory properties.     

Effects of sucralfate, cimetidine and rabeprazole on mucosal hydroxyproline content in healing of ethanol-hcl-induced gastric lesions

1. No general consensus has been reached on the treatment of acute gastric lesions. The aims of the present study were to clarify the effects of sucralfate, cimetidine and rabeprazole monotherapies and combination therapies on acute gastric lesions from the viewpoint of connective tissue regeneration. 2. Gastric lesions were experimentally created by the oral administration of 50% ethanol-0.15 mol/L HCl to rats. After 30 min, the anti-ulcer agents sucralfate (100 mg/kg), cimetidine (20 mg/kg) and rabeprazole (2 mg/kg) were administered separately or in combination and the stomach was excised at different times to measure the level of hydroxyproline in the gastric mucosa and determine lesion index. Immunostaining against prolylhydroxylase was performed on some specimens. 3. In the control group, lesion index decreased linearly from 30 min after ethanol-HCl administration and the level of mucosal hydroxyproline peaked between 2 and 4 h later. Although sucralfate significantly promoted lesion healing, it had no effect on mucosal hydroxyproline level. Cimetidine suppressed increases in mucosal hydroxyproline and prolonged lesion healing, but these findings were reversed by combining cimetidine and sucralfate. Rabeprazole had no significant effect on lesion healing, but promoted lesion healing in combination with sucralfate. Immunohistochemical analysis showed that prolylhydroxylase was expressed in spindle cells that lined the glandular cells in a boundary area between normal and injured tissues. 4. Under conditions in which the effects of intragastric pH are minimal, sucralfate is superior to antisecretory agents in promoting the healing of acute gastric lesions.     

Protective effect of omeprazole against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats.

Omeprazole, a proton pump inhibitor is known to function not only as a proton pump inhibitor but also as an anti-inflammatory agent, an antioxidant or a stimulator of gastric mucus secretion. We have shown that the pathogenesis of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats involves neutrophil infiltration, lipid peroxidation, and mucin depletion, but not acid secretion, in the gastric mucosal tissue. Therefore, we examined whether omeprazole protects against acute gastric mucosal lesions induced by compound 48/80 in rats. Rats were injected with omeprazole (10 or 50 mgkg(-1), i.p.) at 0.5h before injection of compound 48/80 (0.75 mgkg(-1), i.p.). Omeprazole prevented gastric mucosal lesion development at 0.5 and 3h after compound 48/80 injection. Omeprazole attenuated decreased nonprotein sulfhydryl content and increased myeloperoxidase and xanthine oxidase (XO) activities and lipid peroxide (LPO) content in the gastric mucosa at 0.5h after compound 48/80 injection and increased myeloperoxidase and XO activities and LPO content, but not decreased hexosamine and adherent mucus contents, in the gastric mucosa at 3h. These results indicate that omeprazole protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its anti-inflammatory and antioxidant actions.     

Plaunotol prevents the progression of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats

We examined the preventive effect of plaunotol, an antiulcer drug, on acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80). Rats treated with C48/80 (0.75 mg/kg BW, i.p.) received plaunotol (10, 25 or 50 mg/kg BW, p.o.) 0.5 h after the treatment at which time gastric mucosal lesions appeared. The gastric mucosa of C48/80-treated rats showed progressed lesions and had increased myeloperoxidase (an index of neutrophil infiltration) activity and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreased ascorbic acid and adherent mucus contents and Se-glutathione peroxidase activity at 3 h after C48/80 treatment. Postadministered plaunotol attenuated all these changes dose-dependently. These attenuating effects of plaunotol were not counteracted by pretreatment with indomethacin (5 mg/kg BW, i.p.), a prostaglandin synthesis inhibitor. These results indicate that plaunotol prevents the progression of C48/80-induced acute gastric mucosal lesions in rats possibly by its anti-inflammatory and antioxidant actions, but not by affecting gastric mucosal prostaglandin levels.     

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5–20 mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20–80 mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10–80 mg/kg, twice daily for 10 days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.     

Role of gastric acid and bile acids in the pathogenesis of compound 48/80-induced gastric lesions in rats

We studied the effects of various agents, which influence gastric acidity and bile acids, on compound 48/80 (48/80)-induced gastric lesions in rats. 48/80-Induced gastric lesions were produced by repeated intraperitoneal administration of 48/80 at 0.75 mg/kg once daily for 4 days. Test agents were given orally twice daily (30 min before and 9 hr after 48/80 administration) for 4 days. AI(OH)3 and sucralfate at 2000 mg/kg/day, a weak antacid dose, significantly inhibited (about 50-60%) the development of 48/80-induced lesions. Propantheline at 60 mg/kg/day and omeprazole at 60 or 200 mg/kg/day, which reduced gastric secretion for more than 12 hr, also significantly inhibited (about 30-40%) these lesions. Cimetidine at 200 mg/kg/day, which reduced gastric secretion for only 5 hr, had little effect on the lesion formation. Cholestyramine, which is a potent bile acids binding agent, had no effect on 48/80-induced lesions in doses of 600 or 2000 mg/kg/day. These results suggest that gastric acid, but not bile acids, is partly involved in the pathogenesis of 48/80-induced gastric lesions.     

Effects of the new anti-ulcer agent KB-5492 on experimental gastric mucosal lesions and gastric mucosal defensive factors, as compared to those of teprenone and cimetidine.

Effects of KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5-200 mg/kg inhibited water-immersion stress- and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicating that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5-100 mg/kg, also inhibited ethanol-induced gastric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB-5492 was 3 times more potent than teprenone, whereas cimetidine produced no obvious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-induced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti-ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.     

Preventive effect of teprenone on acute gastric mucosal lesion progression in compound 48/80-treated rats

The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.     

Effects of prolonged treatment with compound 48/80 on the gastric mucosa and mast cells in the rat

Effects of prolonged administration of compound 48/80 (48/80) on the gastric mucosa, serotonin and histamine levels in serum, and mast cells of rats were studied. Daily administration of 48/80 (0.75 mg/kg, i.p.) for 2 or 4 days produced widespread gastric lesions. Further administration of the agent for up to 12 days did not aggravate the lesions which had developed in the early period of administration of the drug. There were only a few visible lesions and numerous healed ones. Almost the same phenomenon was observed with the daily administration of serotonin plus histamine (10 mg/kg each, i.p.) for 2 to 12 days. While 48/80 given for 2 or 4 days increased serotonin and histamine levels in serum, it induced no appreciable increase of these amines after 8 or 12 days of treatment. Serotonin and histamine levels in peritoneal mast cells significantly decreased after the treatment with 48/80 over a 4 day period. The decrease in gastric lesions after prolonged treatment with 48/80 is due to both the depletion of serotonin and histamine from mast cells and an increased resistance of the gastric mucosa with healed lesions.     

Effects of the anti-ulcer agents ecabet sodium,cimetidine and sucralfate on acetylsalicylic acid-induced gastric mucosal damage deteriorated by renal failure in rats

Renal failure including post-renal transplantation increases the susceptibility of the upper gastrointestinal mucosa to injury. The aim of this study was to confirm the influence of renal failure on gastric mucosal barrier and the protective effect of various anti-ulcer agents in rats. Renal failure (RF) was induced by 45-min left renal artery clamping and right-uninephrectomy. Four days after surgery, gastric mucosal lesions were induced by intragastric administration of acetylsalicylic acid (ASA, CAS 50-78-2) (100 mg/kg). Anti-ulcer agents were given orally 30 min before ASA administration. RF induced moderate gastric mucosal damages, but significantly worsened the ASA-induced gastric lesions. Ecabet sodium (CAS 86408-72-2) and cimetidine (CAS 51481-61-9) significantly inhibited ASA-induced gastric lesions in RF rats, whereas sucralfate (CAS 54182-58-0) tended to inhibit it. ASA and all of these anti-ulcer agents had no effect on the serum creatinine and blood urea nitrogen levels increased by RF. The gastric mucosa of RF rats is more susceptible to damage induced by ASA. Ecabet and cimetidine potently inhibited gastric lesions in RF rats suggesting its utility for the gastric mucosal damage in patients with RF including post-renal transplant.     

Effects of anti-ulcer agents on ethanol-induced gastric mucosal lesions in D-galactosamine-induced hepatitis rats

Patients with hepatic injury have an increased incidence of gastric ulcers and erosions. In this study, the effect of D-galactosamine(GalN)-induced hepatitis on ethanol-induced gastric mucosal lesions and the protective effect of anti-ulcer agents in rats were examined. Subcutaneous injection of GalN (1 g/kg) remarkably increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities suggesting induction of hepatic injury. Gastric mucosal lesions induced by ethanol were significantly aggravated in GalN-induced hepatitis rats. Orally administered ecabet (CAS 86408-72-2; 20-200 mg/kg) dose dependently inhibited ethanol-induced gastric mucosal lesions in GalN-induced hepatitis rats. Sucralfate (CAS 54182-58-0) tended to inhibit the gastric mucosal lesions at a dose of 200 mg/kg but teprenone (CAS 6809-52-5), cimetidine (CAS 51481-61-9) and rebamipide (CAS 90098-04-7) had little effect. All anti-ulcer agents had no effect on the serum ALT and AST activities increased by GalN pretreatment. These results indicate that the gastric mucosa of GalN-induced hepatitis rats is more susceptible to injury induced by luminal irritants such as ethanol. Ecabet potently inhibited gastric mucosal lesions suggesting its clinical utility for the gastric mucosal damage in patients with hepatic injury.     

Effects of the anti-ulcer agents on the amine contents and regulating enzyme activity of gastric mucosa during the healing process of acetic acid induced gastric ulcer in rats

In order to elucidate the action of an H2 blocker (cimetidine) and gastric mucosal protection agents (sucralfate and sofalcone) on the relapse and recurrence of gastric ulcer, the effects of cimetidine, sucralfate and sofalcone on the contents of histamine and serotonin and histidine decarboxylase (HDC) activity in the gastric mucosa were examined in the ulcer region and the intact region at the 10th day after the operation to produce acetic acid-induced gastric ulcer in rats. The following results were obtained: 1) HDC activity in the gastric mucosa of rats treated with cimetidine (100 mg/kg twice daily) tended to increase in the intact region, and it was significantly increased in the ulcer region. 2) Increased HDC activity due to cimetidine treatment was observed at the 10th day after interruption of cimetidine administration. 3) The HDC activity in the gastric mucosa was not changed by the treatment with sucralfate (500 mg/kg/day) and sofalcone (200 mg/kg/day). The results suggest that the increased HDC activity in the gastric mucosa might participate in the relapse and recurrence of gastric ulcer after discontinuation of cimetidine administration.     

The effect of long-term treatment with antisecretory and antiulcer drugs on gastric secretory and motor responsiveness to caerulein in rats with chronic ulcers

In the present paper the gastric secretory and motor responsiveness to a gastrin-like peptide, caerulein, was assessed in rats with a chronic gastric ulcer induced by 'isolation', 48 h after completing prolonged treatments (30 and 60 days) with cimetidine (80 and 160 mg/kg), pirenzepine (8 and 16 mg/kg) and sulglycotide (160 mg/kg) administered orally as a single daily dose. After a 30 day pretreatment with both doses of cimetidine, gastric acid secretion was inhibited and the pylorus spasmogenic activity induced by caerulein was enhanced. The gastric effects of the peptide were not modified by pirenzepine pretreatment while an antisecretory action was shown by sulglycotide after the completion of prolonged treatment (60 days). The ulcers were significantly reduced by cimetidine (low dose) and sulglycotide after 30 day pretreatment. The effects are more likely to be related to the treatment than to the presence of the drugs on gastric receptors.     

Anti-ulcer effect of tea catechin in rats

Oral administration of tea catechin dose-dependently prevented absolute ethanol-induced (50, 100, 200 mg/kg) or restraint plus water immersion stress-induced acute gastric mucosal injury (300, 400 mg/kg) in rats. When the effect of test compound was evaluated on the 15th day after acetic acid injection to rats, repeated oral administration of tea catechin (25, 50, 100 mg/kg twice daily) dose-dependently accelerated the healing of acetic acid-induced chronic gastric ulcers. Tea catechin (10(-5)-10(-1) g/100 ml) concentration-dependently scavenged superoxide anions in vitro. Tea catechin (100, 200 mg/kg orally) markedly inhibited the increase in thiobarbituric acid-reactive substances in the injured mucosa of rats treated with 50% ethanol. Tea catechin (50, 100 mg/kg twice orally, daily) markedly inhibited the increase in content of thiobarbituric acid-reactive substances in the ulcerated region of acetic acid-induced gastric ulcers on the 7th and 15th days. In addition, at 50, 100 and 200 mg/kg orally, it dose-dependently prevented the decrease in gastric mucosal hexosamine content induced by absolute ethanol, although it failed to inhibit the basal gastric acid secretion. These results suggest that tea catechin may primarily protect gastric mucosa from acute gastric mucosal injury and promote the healing of chronic gastric ulcers by its antioxidant activity and gastric mucus-increasing actions.     

Effects of FRG-8813, a new-type histamine H2-receptor antagonist, on the healing of gastric and duodenal ulcer in rats and spontaneously ulcerative mice]

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.     

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.