Attenuation of stress-induced gastric lesions by lansoprazole, PD-136450 and ranitidine in rats

Combining restraint with cold temperature (4°C) consistently induces gastric ulceration in rats after 3.5 h. The cold restraint-stress (CRS) method provides a suitable model for acute ulcer investigations. This study compares the antiulcer activities of lansoprazole (a proton pump inhibitor), PD-136450 (CCK(2)/gastrin receptor antagonist) and ranitidine (histamine H(2) receptor antagonist) on CRS-induced gastric ulcers in rats. The results have shown that lansoprazole, which is a potent anti-secretory agent, provides complete protection in this model of ulcer formation. The use of indomethacin pretreatment to inhibit the prostaglandin (PG) synthesis and N(G)-nitro L-arginine methyl ester (L-NAME) pretreatment to inhibit nitric oxide synthase did not alter the lansoprazole-induced inhibition of ulcer index obtained in the untreated Wistar rats indicating that these two systems were not involved in the activation of lansoprazole. PD-136450, an effective anti-secretory agent against gastrin- but not dimaprit-induced stimulation, evoked a dose-dependent inhibition of CRS-induced gastric ulcers. The results show that both PG and nitric oxide pathways can influence the inhibitory effect of PD-136450 against CRS-induced gastric ulcer. The antiulcer activities of both lansoprazole and PD-136450 were compared to that of ranitidine. The results showed that ranitidine was more potent than lansoprazole and PD-136450 in inhibiting CRS-induced gastric ulcers and its effect was shown to be influenced by PG as well as nitric oxide synthase. The results of this study have demonstrated that although lansoprazole, PD-136450 and ranitidine were protective against CRS-induced gastric ulcers, the antiulcer activities of PD-136450 and ranitidine involved both PG and nitric oxide pathways, while lansoprazole acted independently of these two systems during CRS.     

Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer

Matrix metalloproteinases (MMPs) are suggested to play a critical role in extracellular matrix degradation and remodeling during inflammation and wound healing processes. However, the role of MMPs in indomethacin-induced gastric ulcer and its healing process are not clearly understood. This study is aimed at determining the regulation of MMP-9 and -2 activities in indomethacin-induced acute gastric ulceration and healing. Indomethacin-ulcerated stomach extracts exhibit significant up-regulation of pro-MMP-9 (92 kDa) activity and moderate reduction of MMP-2 activity, which strongly correlate with indomethacin dose and severity of ulcer. The anti-inflammatory and antioxidant properties of curcumin, an active component of turmeric, suggest that curcumin may exert antiulcer activity through scavenging reactive oxygen species, by regulating MMP activity, or both. To test these possibilities, the effect of curcumin in indomethacin-induced gastric ulcer is examined by biochemical and histological methods. The results show that curcumin exhibits potent antiulcer activity in acute ulcer in rat model by preventing glutathione depletion, lipid peroxidation, and protein oxidation. Denudation of epithelial cells during damage of gastric lumen is reversed by curcumin through re-epithelialization. Furthermore, both oral and intraperitoneal administration of curcumin blocks gastric ulceration in a dose-dependent manner. It accelerates the healing process and protects gastric ulcer through attenuation of MMP-9 activity and amelioration of MMP-2 activity. Omeprazole, an established antiulcer drug does not inhibit MMP-9 while protecting indomethacin-induced gastric ulcer. We conclude that antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing.     

Participation of cyclic nucleotides and phospholipidis in signal transduction of histamin receptor H3 of the gastric mucosa parietal cells in rats with experimental ulcer

The goal of the work was to evaluate plasma membrane phospholipid composition in rat gastric parietal cells under the histamine H3 receptor activation. The content of cyclic nucleotides was also studied. It was shown that H3-receptor agonist (R)-alpha-methylhistamine increases the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) level and decreases the phoshatidylinositole level in plasma membrane of rat gastric parietal cells and leads to attenuation of the cGMP production and enhancement of the cAMP production under the experimental stress--the induced stomach ulcer formation. The histamine H3-receptor antagonist, thioperamide, insignificantly increases the PC and PE level and increases the phoshatidylinositole level in the plasma membrane of rat gastric parietal cells and leads to cAMP production attenuation, and cGMP contents decreases in the above-stated cells. Thus it was shown that histamine H3 receptor activation causes different effects on polyphosphoinositide and adenylatcyclase cascades in parietal cells under stomach ulcer conditions.     

Gastroprotective effects of ‘Amla’ Emblica officinalis on in vivo test models in rats

An ethanol extract of 'Amla' Emblica officinalis Gaertn. was examined for its antisecretory and antiulcer activities employing different experimental models in rats, including pylorus ligation Shay rats, indomethacin, hypothermic restraint stress-induced gastric ulcer and necrotizing agents (80% ethanol, 0.2 M NaOH and 25% NaCl). Oral administration of Amla extract at doses 250 mg/kg and 500 mg/kg significantly inhibited the development of gastric lesions in all test models used. It also caused significant decrease of the pyloric-ligation induced basal gastric secretion, titratable acidity and gastric mucosal injury. Besides, Amla extract offered protection against ethanol-induced depletion of stomach wall mucus and reduction in nonprotein sulfhydryl concentration. Histopathological analyses are in good agreement with pharmacological and biochemical findings. The results indicate that Amla extract possesses antisecretory, antiulcer, and cytoprotective properties.     

Gastric toxicity and mucosal ulceration induced by oxygen-derived reactive species: protection by melatonin

Uncontrolled hydrochloric acid secretion and ulceration of the stomach mucosa due to various factors are serious global problems. Although the mechanism of acid secretion from the parietal cell is now well understood, the processes involved in gastric ulceration are still not clear. Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection and due to use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs have proven useful in controlling hyperacidity and ulceration but their long-term use is associated with disturbing side-effects. Hence, the search is still on to find a compound possessing antisecretory, antiulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, drugs controlling them with their merits and demerits and, the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a gastroprotective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view of eventually using this indole as a therapeutic agent to control gastric ulceration in humans.     

Plausible Novel Ribose Metabolism Catalyzed by Enzymes of the Methionine Salvage Pathway in Bacillus subtilis

Although several studies have shown that milk protein components have a wide range of biological activities, the potential role of these proteins in the gastrointestinal mucosal defense system is less well elucidated. In this study, we investigated the effect of the major proteins in cow’s milk on gastric mucosal injury by using two acute ulcer models in Wistar rats. Gastric mucosal injury was induced by either intragastric 60% ethanol-HCl or water-immersion restraint stress (23°C, 7 h). Each test milk protein was orally administered 30 min before the induction of gastric injury. Among the major milk proteins, α-lactalbumin (α-LA) is demonstrated to have a marked protective effect against ethanol-induced gastric injury, with the same potency as that of the typical antiulcer agent, Selbex. Whey protein isolate (WPI), which contained 25% α-LA, also protected against gastric injury, while casein showed no effect. Comparative studies on the protective effect of the four major components of WPI, β-lactoglobulin, α-LA, bovine serum albumin and γ-globulins (immunoglobulins), on the basis of their contents in WPI revealed that α-LA was responsible for the protective effect of WPI, being about 4-fold more effective than WPI itself. α-LA showed dose-dependent protection against gastric injury induced by stress as well as ethanol. Pretreatment with indomethacin (10 mg/kg body weight, s.c.), which is a potent inhibitor of endogenous prostaglandin synthesis, resulted in a significant reduction in the protective effect of α-LA. These results indicate that α-LA has marked antiulcer activity as an active component of cow’s milk protein, and suggest that α-LA intake may serve to protect against gastric mucosal injury, in part through endogenous prostaglandin synthesis.     

New biological function of bovine alpha-lactalbumin: protective effect against ethanol- and stress-induced gastric mucosal injury in rats.

Although several studies have shown that milk protein components have a wide range of biological activities, the potential role of these proteins in the gastrointestinal mucosal defense system is less well elucidated. In this study, we investigated the effect of the major proteins in cow's milk on gastric mucosal injury by using two acute ulcer models in Wistar rats. Gastric mucosal injury was induced by either intragastric 60% ethanol-HCl or water-immersion restraint stress (23 degrees C, 7 h). Each test milk protein was orally administered 30 min before the induction of gastric injury. Among the major milk proteins, alpha-lactalbumin (alpha-LA) is demonstrated to have a marked protective effect against ethanol-induced gastric injury, with the same potency as that of the typical antiulcer agent, Selbex. Whey protein isolate (WPI), which contained 25% alpha-LA, also protected against gastric injury, while casein showed no effect. Comparative studies on the protective effect of the four major components of WPI, beta-lactoglobulin, alpha-LA, bovine serum albumin and gamma-globulins (immunoglobulins), on the basis of their contents in WPI revealed that alpha-LA was responsible for the protective effect of WPI, being about 4-fold more effective than WPI itself. Alpha-LA showed dose-dependent protection against gastric injury induced by stress as well as ethanol. Pretreatment with indomethacin (10 mg/kg body weight, s.c.), which is a potent inhibitor of endogenous prostaglandin synthesis, resulted in a significant reduction in the protective effect of alpha-LA. These results indicate that alpha-LA has marked antiulcer activity as an active component of cow's milk protein, and suggest that alpha-LA intake may serve to protect against gastric mucosal injury, in part through endogenous prostaglandin synthesis.     

Gastric antisecretory and antiulcer activity of oxytocin in rats and guinea pigs.

The effect of oxytocin (1 mg/kg s.c) on gastric acid secretion and on different experimentally induced gastric and duodenal ulcers was studied. The acute gastric ulcer models used were pylorus ligation, indomethacin, ethanol and histamine induced acute gastric ulcers. Chronic gastric ulcers were induced using acetic acid and duodenal ulcers by cysteamine hydrochloride. Oxytocin showed significant antisecretory and antiulcer activity in pylorus ligated rats. Similarly oxytocin reduced the ulcer index in histamine induced gastric ulcers in guinea pigs and cysteamine induced duodenal ulcers in rats. The antiulcer and antisecretory effect was comparable to that of ranitidine (50mg/kg, i.p) though less in intensity. However, it did not show any gastric cytoprotective effect in ethanol and indomethacin induced ulcer models but ranitidine showed protection (p<0.05) in later model. Oxytocin enhanced gastric ulcer healing in acetic acid induced chronic gastric ulcer model. The reversal of oxytocin effect by atosiban, an oxytocin receptor antagonist indicates a role for oxytocin receptors. The antiulcer activity of oxytocin can be attributed to its antisecretory effect.     

Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats

Clinical studies have shown that anxiolytic and antidepressant drug therapy benefits patients with ulcers. Many antidepressant drugs have been shown experimentally to produce antiulcer activity in various ulcer models. This study investigated the antiulcer activities of tianeptine, trazodone, and venlafaxine on indomethacin-induced ulcers in rats; and evaluated tianeptine's effects on oxidant and antioxidant parameters in rat stomach tissue. The results show that trazodone and venlafaxine did not prevent indomethacin-induced ulcers. Tianeptine, however, decreased indomethacin-induced ulcers significantly at all doses used (6, 12, and 25 mg/kg). Famotidine, an H₂ receptor blocker, showed the highest antiulcer activity. Tianeptine significantly prevented the decrease in glutathione (GSH) content that occurred in the indomethacin-only group's damaged stomach tissues. All doses of tianeptine, but especially the 25 mg/kg dose, significantly decreased catalase (CAT) activity in stomach tissue, compared to the control. All doses of tianeptine eliminated the decrease in superoxide dismutase (SOD) activity in the stomach tissue of rats given indomethacin. Although all doses of tianeptine significantly decreased the malondialdehyde (MDA) content, all doses of tianeptine, except 6 mg/kg, decreased myeloperoxidase (MPO) activities significantly compared to the control. Our results indicate that activating enzymatic and non-enzymatic antioxidant mechanisms and inhibiting some toxic oxidant mechanisms play a role in tianeptine's antiulcer effect mechanism.     

Protective and therapeutic effects of Argyreia speciosa against ethanol-induced gastric ulcer in rats

The protective and therapeutic effects of Argyreia speciosa Sweet (Convolvulaceae) against ethanol-induced gastric ulcer in rats were evaluated. Ethanolic and water extracts of the aerial plant parts (200 mg/kg body weight) were orally administered daily for seven days prior to or after ulceration with one oral dose of 1 mL absolute ethanol on 24-h empty stomachs. Rats were divided into eleven groups. Group 1 served as control. To groups 2 and 3 each extract was administered. Groups 4 to 6 received each extract or ranitidine (100 mg/kg body weight) prior to ulcer induction. Groups 7 to 9 received each extract or ranitidine post ulcer induction. Groups 10 and 11 were gastric ulcerative rats after one hour and one week of ethanol induction. The evaluation was done through measuring ulcer indices: stomach acidity and volume, lesion counts, mucus, and prostaglandin E2 contents. Oxidative stress marker, i. e. malondialdehyde, glutathione, and superoxide dismutase, were estimated. Certain marker enzymes for different cell organelles, i. e. succinate and lactate dehydrogenases, glucose-6-phosphatase, acid phosphatase, and 5'-nucleotidase, were evaluated. The work was extended to determine the collagen content and the histopathological assessment of the stomach. Gastric ulcer exhibited a significant elevation of the ulcer index, antioxidant levels, collagen content, and the marker enzymes. The water extract attenuated these increments and was more potent as a protective agent, while the ethanol extract exhibited stronger therapeutic potency. In conclusion, A. speciosa acted as antiulcer agent. More detailed studies are required to identify the compounds responsible for the pharmacological effect.     

Effect of Convolvulus pluricaulis Chois on gastric ulceration and secretion in rats

Convolvulus pluricaulis is an indigenous plant commonly mentioned in Ayurveda, an ancient system of Indian medicine, as a rasayana which is mainly advocated for use in rejuvenation therapy. The present study was conducted to evaluate the potential anti-ulcerogenic effect of juice of fresh whole plants of C. pluricaulis (CPJ) against various experimental gastric ulcer models induced by ethanol, aspirin, 2 hr cold restraint stress and 4 hr pyloric ligation in rats. The drug was given orally twice daily for five days in the doses of 375 and 750 mg/kg body weight. CPJ showed anti-ulcerogenic effect at both doses in all the experimental gastric ulcer models and was comparable to the reference drug sucralfate (250 mg/kg). Gastric juice secretion and mucosal studies were undertaken to find out the possible mechanism of action of antiulcer effect by studying its effects both on offensive and defensive mucosal factors. The antiulcerogenic effect of CPJ was found to be due to augmentation of mucosal defensive factors like mucin secretion, lifespan of mucosal cells and glycoprotiens rather than on the offensive factors like acid-pepsin.     

Involvement of reactive oxygen species in gastric ulceration: protection by melatonin

Uncontrolled hydrochloric acid secretion and ulceration in the stomach due to various factors are serious global problems today. Although the mechanism of acid secretion from the parietal cell is now fairly known, the mechanism of gastric ulceration is still not clear today. Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection and use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species especially hydroxyl radical (*OH). A number of excellent drugs have been proved useful in controlling hyperacidity and ulceration but their long term uses are not devoid of disturbing side-effects. Hence, the search is still on to find out a compound possessing antisecretory, antiulcer and antioxidant properties which will serve as a powerful therapeutic agent to cure gastric hyperacidity and ulcer. This article describes the role of reactive oxygen species in gastric ulceration, drugs controlling them with their merits and demerits and, the role of melatonin, a pineal hormone in protecting the gastric lesions with a final commentary on how melatonin research with respect to gastric pathophysiology can be taken forward with a view to projecting this indole as a promising therapeutic agent to control gastric ulceration in humans.     

胃溃疡对大鼠胃中HAP1表达的影响

建立冰乙酸性大鼠胃溃疡模型,采用ABC法进行免疫组织化学染色,观察并探讨胃溃疡对胃壁中HAP1(huntingtin as-soc iated protein 1,HAP1)表达的影响。结果溃疡组大鼠胃壁中HAP1阳性细胞数目及光密度与正常进食的大鼠相比显著增多。     

The pharmacological differences and similarities between stress- and ethanol-induced gastric mucosal damage.

Stress- and ethanol-induced gastric mucosal damage are the two commonly used ulcer models in animals. They share some of the similarities but also have differences in the etiology of gastric ulceration. This article reviews the influences of various protective drugs on these two types of gastric damage in rats. Verapamil (a calcium antagonist) or N-ethylmaleimide (a sulfhydryl depletor) prevents cold restraint-, but potentiates ethanol-provoked gastric lesion formation. N-Acetylcysteine (a mucolytic agent) and acetaminophen (an antipyretic analgesic) have the opposite actions. Prostaglandins provide a much better antiulcer effect on ethanol-induced lesions. Cimetidine (a histamine H2-receptor antagonist) prevents only stress-induced mucosal damage. These differences in drug actions indicate that stress and ethanol may have dissimilar ulcerogenic mechanisms in rats. On the other hand, carbenoxolone (a mucus inducer), histamine H1-receptor antagonists, leukotriene inhibitors (FPL 55712 and nordihydroguaiaretic acid) and mast cell stabilizers (like zinc compounds, sodium cromoglycate, FPL 52694 and ketotifen), all protect against gastric mucosal damage by stress or ethanol in rats. However, the role of gastric sulfhydryls in both types of gastric lesions is still controversial. These findings imply that the two types of lesion formation share some of the ulcerogenic mechanisms. This communication attempts to analyze the various findings and to relate them to the etiology of stress and ethanol-induced gastric lesions. It also summarizes the uses, and the antiulcer mechanisms, of the drugs that have been studied utilizing these two animal ulcer models, and suggests their possible implications in man.     

Effect of cytoprotective and antiulcer drugs on the healing process of subacute gastric ulcer in rat (a new model)

It has been developed by us a simple new method for producing subacute gastric ulcer in rats, combined with a novel method for the quantitative evaluation of the healing process. Fasted rats with 120-150 g were used. The animals were anaesthesized by ether and than a polyethylene chateter was orally inserted into the stomach with a fine needle inside. After the cannule reached the gastric wall, the needle was pressed gently so as to punch the gastric wall. Drugs under study were administered orally 30 min and 24 h after the puncture. Food and water were given ad libitum from 2 h after the intervention until the end (96 h) of experiments. In order to follow the healing process of subacute ulcer, the so-called tensile strength of the ulcer was determined by inflating and expressed in mmHg. The healing rate was calculated. The antiulcer drugs: Cimetidine, Famotidin, Pirenzepine and sucralfate dose dependently and significantly increased the healing rate of ulcer. Non steroidal antiinflammatory drugs: naproxen, piroxicam, indomethacin and ibuprofen significantly delayed the healing of ulcer. ASA showed tendency to delay the healing. Strong HCl (0.5 molar) significantly delayed the healing of ulcer. N-EM given subcutaneously dose dependently delayed the healing of subacute ulcer.     

Comparative morphology of the stomach of some laboratory mammals

Histomorphology of the stomach of mouse, rat, hamster, guineapig, gerbil, and rabbit was studied. Although a common structural basis existed in the stomach between these species, the occurrence and distribution of various cells in gastric glands differed considerably between them. In mice, rats, hamsters and gerbils, the lower one-third of the glandular lamina propria was seemingly occupied by a varying proportion of parietal and chief cells. In rabbits, the predominantly occurring chief cells were distributed in the lower three-quarters of the glands intermingling with parietal cells, but in guinea-pigs the chief cells were not discernible. In hamsters, there was, however, a gradual increase of chief cells from the junction between nonglandular-glandular stomach toward the pyloric region. In all these species, parietal cells were the predominant cell type in the upper half to upper one-third of the gastric glands, often extending up to the neck of the glands interspersing between mucus neck cells and occasionally between chief cells.     

Contribution of carbon monoxide-producing cells in the gastric mucosa of rat and monkey

 Recent studies have shown that carbon monoxide (CO) may function as a gaseous signaling molecule in a similar way to nitric oxide. In the gastrointestinal tract, immunoreactivity against a CO-producing enzyme, heme oxygenase-2 (HO-2), was reported in epithelial cells and neurons of submucosal and myenteric plexus. However, details of the epithelial cells in the gastric mucosa remain unknown. The aim of this study was to clarify if mRNA for HO-2 is expressed in the rat stomach, if HO-2 protein is present in the mucosa, and to define the cell types of the HO-2-immunoreactive cells. HO-2 mRNA and protein were detected in fundic and pyloric mucosa of rat stomach using an RNA protection assay and western blot analysis. Immunohistochemical study showed that HO-2 was localized in parietal cells of the fundic glands and gastrin cells of the pyloric glands of both rat and monkey. The results suggest that HO-2 enzyme is produced in the gastric mucosa, and that CO is released from parietal cells and gastrin cells. Accepted: 12 November 1997     

Rhamnogalacturonan from Acmella oleracea (L.) R.K. Jansen: Gastroprotective and Ulcer Healing Properties in Rats

A rhamnogalacturonan (RGal) isolated from Acmella oleracea (L.) R.K. Jansen administered by oral route showed gastroprotective activity against acute lesions induced by ethanol. In this study, we investigated the gastric ulcer healing effect of RGal and its mechanisms of action. Intraperitoneal treatment of animals with RGal protected the gastric mucosa against acute lesions induced by ethanol, with participation of gastric mucus. Furthermore, in the chronic ulcer model, oral administration of RGal accelerates the gastric ulcer healing, accompanied by increasing of cellular proliferation and gastric mucus content, reducing inflammatory parameters and oxidative stress. In addition, the repeated 7 days-treatment of animals with RGal did not show alterations of clinical and behavioral symptoms, body and organs weights or plasmatic biochemical parameters. Collectively, these results showed that RGal has an interesting antiulcerogenic activity and could constitute an attractive molecule of interest for the development of new antiulcer agents.     

应激状态下NO的胃粘膜保护作用及其与壁细胞泌酸的关系

目的:探讨应激状态下一氧化氮(NO)的胃粘膜保护作用及其与壁细胞泌酸的关系.方法:采用水浸-束缚应激(WRS)方法制备应激性溃疡(SU)动物模型,检测胃粘膜溃疡指数(UI)、胃粘膜NO含量和壁细胞H ,K -ATPase活性,观察L-硝基精氨酸甲酯(L-NAME)和L-精氨酸(L-Arg)对应激后大鼠壁细胞H ,K -ATPase活性及胃粘膜损伤的影响.结果:L-NAME(20 mg·kg-1)可使胃粘膜NO含量减少(P＜0.01),壁细胞H ,K -AT-Pase活性增加(P＜0.05),并加重应激所致的胃粘膜损伤;L-Arg(300 mg·kg-1)则使胃粘膜NO含量增加(P＜0.01),壁细胞H ,K -ATPase活性下降(P＜0.05),减轻应激所致胃粘膜损伤.结论:NO对应激状态下大鼠胃粘膜具有保护作用,其机制与抑制壁细胞H ,K -ATPase活性有关.     

Short peptide fragments with antiulcer activity from a collagen hydrolysate

A peptide acidic hydrolysate of collagen (PHC) was obtained under conditions (4 N HCl) ensuring the predominant formation of short peptides, glyprolines. They were separated and their antiulcer activity was studied. Thirty individual peptides with molecular masses of 174–420 amu were isolated from the PHC by HPLC. The PHC was shown to predominantly contain 2-to 4-aa peptides, including PG, GP, and PGP. Experiments on rats demonstrated that, on intragastric administration at a dose of 1 mg/kg, PHC enhances the stability of the gastric mucosa to the action of ulcerogenic factors, such as ethanol and stress, and exhibits a protecting antiulcer effect. Even a lesser dose (0.1 mg/kg), which reduced ulcer area twofold, was effective in the stress model of ulcer formation. The intraperitoneal and intragastric administration of PHC at a dose of 1 mg/kg was found to exhibit a therapeutic effect in the acetate model of ulcer formation.