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Gastric ulcer is a very common disease that represent an economic burden. Non-steroidal anti-inflammatory drugs induce ulcer in old patients and in patients with comorbidities. Indomethacin is widely used to induce gastric ulcer in animal models. Diabetic patients are highly susceptible to develop gastric ulcer. Metformin, the first line medication for the treatment of type II diabetes melilites that have many off label uses in non-diabetic patients, has been recently reported to have anti-inflammatory activities. Therefore, this research was conducted to assess the possible healing effects of metformin on gastric ulcers induced by indomethacin in rats. Indomethacin (48 mg/kg) single dose increased stomach acidity, ulcer index and induced histopathological changes. Indomethacin also decreased mucin levels and increased the activity of tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), Rho-associated protein kinas-1 (ROCK-1) and decreased the levels of the protective nitric oxide (NO). After the induction of ulcer, rats were treated by omeprazole (30 mg/kg) or metformin (50, 100 or 200 mg/kg). Omeprazole and metformin were found to decrease stomach acidity and ulcer index, restored the histological features and increased mucin levels. Both also decreased the levels of NF-κB, TNF-α, ROCK-1 and increased NO. Metformin exerted ulcer healing effects comparable to that of omeprazole. This can be attributed, at least partly, to its anti-inflammatory activity and increasing NO levels., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chrysin exhibits anti-inflammatory and antioxidant activities. Here, the gastroprotective effect of chrysin was investigated in mouse models of gastric ulcer induced by absolute ethanol, acetic acid, and ischemia-reperfusion injury. The gastric-healing effect was evaluated at 7 and 14 days after treatment; the mechanism of action was verified using the expression of metalloproteinase 2 ( MMP-2 ) and 9 ( MMP-9 ), caspase-3, cyclooxygenase 1 ( COX-1 ) and 2 ( COX-2 ), epidermal growth factor ( EGF ), and interleukin-10. Chrysin (10 mg/kg) inhibited macroscopic lesions and increased catalase activity in the mouse model established using absolute ethanol. It ameliorated the gastric ulcer caused by acetic acid by improving the expression of inflammatory genes such as COX-2 , inhibiting negative remodeling promoted by MMP-9, increasing cell proliferation effect via EGF , and reducing cellular apoptosis by modulating caspase-3. A faster healing effect was evident in the first 7 days of treatment compared to 14 days of treatment, indicating the pharmacological potential of chrysin. Overall, these results demonstrate the potent effect of chrysin in the gastrointestinal tract and elucidate the genes involved in the healing of gastric ulcers. Moreover, an increase in the levels of gastric mucosa defensive factors is involved in the activity of chrysin in the gastric mucosa., Competing Interests: The authors declare that they have no conflicts of interest.Abbreviations:

Objectives: The purpose of this study was to assess the gastroprotective properties of alpha-boswellic acid (α-BA), a pentacyclic triterpene compound from extracts of Frankincense., Methods: The gastroprotection of α-BA was assessed with ethanol-induced gastric lesions model, by histopathological assessment and measuring gastric juice acidity (pH), gastric wall mucus (GWM), prostaglandins E2 (PGE-2), membrane lipids peroxidation (MDA), superoxide dismutase (SOD) activity, catalase (CAT) activity and amount of nitric oxide (NO). The gastroprotective effects of α-BA through the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) anti-oxidative pathway were presented and measured by immunohistochemistry and Western blot., Key Findings: The results showed that α-BA reduced injuries associated with the administration of ethanol, gastric juice acidity and the formation of MDA and increased CAT activity and SOD activity and the level of NO and PGE-2 in a dose-depended manner. The expression of both Nrf2 and HO-1 was significantly increased in the group treated with 200 mg/kg α-BA, which suggested that activation of the Nrf2/HO-1 pathway might be critical in α-BA's prevention of gastric ulcers., Conclusions: These findings demonstrate that α-BA decreases oxidative stress and that the Nrf2/HO-1 pathway might play a role in the gastroprotective action of α-BA in ethanol-induced gastric injury in rats., (© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.)

Background: The current study was carried out to examine the gastroprotective effects of Parkia speciosa against ethanol-induced gastric mucosa injury in rats., Methodology/principal Findings: Sprague Dawley rats were separated into 7 groups. Groups 1-2 were orally challenged with carboxymethylcellulose (CMC); group 3 received 20 mg/kg omeprazole and groups 4-7 received 50, 100, 200 and 400 mg/kg of ethanolic leaf extract, respectively. After 1 h, CMC or absolute ethanol was given orally to groups 2-7. The rats were sacrificed after 1 h. Then, the injuries to the gastric mucosa were estimated through assessment of the gastric wall mucus, the gross appearance of ulcer areas, histology, immunohistochemistry and enzymatic assays. Group 2 exhibited significant mucosal injuries, with reduced gastric wall mucus and severe damage to the gastric mucosa, whereas reductions in mucosal injury were observed for groups 4-7. Groups 3-7 demonstrated a reversal in the decrease in Periodic acid-Schiff (PAS) staining induced by ethanol. No symptoms of toxicity or death were observed during the acute toxicity tests., Conclusion: Treatment with the extract led to the upregulation of heat-shock protein 70 (HSP70) and the downregulation of the pro-apoptotic protein BAX. Significant increases in the levels of the antioxidant defense enzymes glutathione (GSH) and superoxide dismutase (SOD) in the gastric mucosal homogenate were observed, whereas that of a lipid peroxidation marker (MDA) was significantly decreased. Significance was defined as p<0.05 compared to the ulcer control group (Group 2).

Ample of evidence proved the gastroprotective effect of thymoquinone (TQ), the main constituent of Nigella sativa oil; however, the full mechanistic cassette on the gastric ulcer etiopathogenesis is not fully elucidated. The aim of the present work is to unveil some of the possible mechanisms. Animals were injected with vehicle, TQ (10 & 20mg/kg), omeprazole (10 & 20mg/kg) or their combination (10mg/kg). Thirty minutes later, pyloric ligation was carried out and followed consequently with ischemia for another 30min, abided by reperfusion for 120min. The ischemia/reperfusion insult increased the gastric acid secretion, acid output, and pepsin, as well as the gastric mucosal content/activity of lipid peroxide, proton pump and myeloperoxidase, along with ulcer index. However, content/activity of gastric mucin, reduced glutathione, total nitric oxide, and superoxide dismutase were decreased. TQ, especially the high dose level, corrected the altered parameters in a comparable manner to that of the reference drug used, omeprazole. In addition, when the low doses were combined they add to each other to reach the effect of the high dose of either drug. These results showed that apart from its known antioxidant properties, TQ has novel gastroprotective mechanisms via inhibiting proton pump, acid secretion and neutrophil infiltration, while enhancing mucin secretion, and nitric oxide production., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Despite the widespread use of roots of Cassia sieberiana in managing several health conditions including gastric ulcer disease, there is little scientific data to support the rational phytotherapeutics as an anti-ulcer agent. This paper reports an evaluation of the in vivo anti-oxidant properties of an aqueous root bark extract of C. sieberiana in experimental gastric ulcer rats in a bid to elucidate its mechanism of action., Methods: Fisher 344 (F(344)) rats received pretreatment of C. sieberiana root bark extract (500, 750, and 1000 mg/kg body wt.) for 7 days after which there was induction of gastric injury with absolute ethanol. The mean ulcer index (MUI) was calculated and serum total anti-oxidant level determined. Gastric mucosal tissues were prepared and the activity level of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and myeloperoxidase (MPO) were measured together with the level of lipid hydroperoxides (LPO). Statistical difference between treatment groups was analysed using one-way analysis of variance (ANOVA) followed by Dunnett's post hoc t test. Statistical significance was calculated at P< 0.05., Results: The administration of ethanol triggered severe acute gastric ulcer and pretreatment with C. sieberiana root bark extract significantly and dose dependently protected against this effect. The root bark extract also dose dependently and significantly inhibited the ethanol induced decrease in activity levels of the enzymes SOD, CAT and GPx. The extract also inhibited the ethanol-induced decrease in level of serum total anti-oxidant capacity. The increase in ethanol-induced LPO level and MPO activity were also significantly and dose-dependently inhibited by the root bark extract., Conclusions: The gastro-cytoprotective effect, inhibition of decrease in activity of gastric anti-oxidant enzymes and MPO as well as the inhibition of gastric LPO level suggests that one of the anti-ulcer mechanisms of C. sieberiana is the anti-oxidant property.

Current anti-gastric ulcer agents have side effects, despite the progression and expansion of advances in treatment. This study aimed to investigate the gastroprotective mechanisms of Pithecellobium jiringa ethanol extract against ethanol-induced gastric mucosal ulcers in rats. For this purpose, Sprague Dawley rats were randomly divided into five groups: Group 1 (normal control) rats were orally administered with vehicle (carboxymethyl cellulose), Group 2 (ulcer control) rats were also orally administered with vehicle. Group 3 (positive control) rats were orally administered with 20 mg/kg omeprazole, Groups 4 and 5 (experimental groups) received ethanol extract of Pithecellobium jiringa ethanol extract at a concentration of 250 and 500 mg/kg, respectively. Sixty minutes later, vehicle was given orally to the normal control group, and absolute ethanol was given orally to the ulcer control, positive control and experimental groups to generate gastric mucosal injury. The rats were sacrificed an hour later. The effect of oral administration of plant extract on ethanol-induced gastric mucosal injury was studied grossly and histology. The level of lipid peroxidation (malondialdehyde-MDA), superoxide dismutase (SOD) and gastric wall mucus were measured from gastric mucosal homogenate. The ulcer control group exhibited severe gastric mucosal injury, and this finding was also confirmed by histology of gastric mucosa which showed severe damage to the gastric mucosa with edema and leucocyte infiltration of the submucosal layer. Pre-treatment with plant extract significantly reduced the formation of ethanol-induced gastric lesions, and gastric wall mucus was significantly preserved. The study also indicated a significant increase in SOD activity in gastric mucosal homogenate, whereas a significant decrease in MDA was observed. Acute toxicity tests did not show any signs of toxicity and mortality up to 5 g/kg. The ulcer protective effect of this plant may possibly be due to its preservation of gastric wall mucus along with increased SOD activity and reduction of oxidative stress (MDA). The extract is non-toxic, even at relatively high concentrations.

Relevance: Simaba ferruginea A. St-Hil. (Simaroubaceae) is a subshrub typical of the Brazilian Cerrado, whose rhizomes are popularly used as infusion or decoction for the treatment of gastric ulcers, diarrhea and fever., Aim of the Study: To evaluate the pharmacological mechanism(s) of action of the antiulcer effects of the methanol extract of Simaba ferruginea and its alkaloid canthin-6-one., Materials and Methods: Rhizome of Simaba ferruginea was macerated with methanol to obtain the methanol extract (MESf) from which was obtained, the chloroform fraction. Canthin-6-one alkaloid (Cant) was purified and then isolated from the chloroform fraction (CFSf). The isolated Cant was identified by HPLC. Anti-ulcer assays were determined using ethanol and indomethacin-induced ulcer models in mice and rats respectively. In order to determine the probable mechanisms of actions of MESf and Cant animals were pretreated with l-NAME prior to anti-ulcer agent treatments and ulcer induction and nitric oxide (NO) level determined in order to assess NO involvement in the gastroprotective effects. Assays of malondialdehyde (MDA), myeloperoxidase (MPO), pro-inflammatory cytokines: interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-α) and prostaglandin E(2) (PGE(2)) were also carried out according to previously described methods., Results: The results indicate that the antiulcerogenic effects of MESf and Cant in ethanol-induced ulcer is mediated in part through increase in the production of protective endogenous NO as the antiulcerogenic activity of MESf and Cant was reduced in animals pre-treated with l-NAME. In indomethacin-induced ulcer pre-treatment with MESf and Cant showed reduction in the levels of MPO and MDA in the gastric tissue, thus indicating the participation of the antioxidant mechanisms on the gastroprotective effects. The plasma levels of IL-8 in ulcerated rats with indomethacin were also reduced by Cant, but not by MESf, indicating that inhibition of this cytokine contributes to the gastroprotective effect of Cant. However MESf and Cant had no effect on the mucosal membrane levels of PGE(2), indicating that the gastroprotective effects of these agents is independent of PGE(2) modulation., Conclusion: The results obtained in this study with MESf and Cant added insights into the pharmacological mechanisms involved in their mode of antiulcer action. The results indicate that Cant is one of the compounds responsible for these effects. Such findings are of extreme importance in the strive for future development of potent, safer and effective antiulcer agent. The efficacy of MESf and Cant in gastroprotection shows that Simaba ferruginea might be a promising antiulcer herbal medicine, in addition to confirming the popular use of this plant against gastric ulcer models utilised in this study., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A recent study showed that resveratrol, a polyphenol found in many plant species, exerts dual effects on gastric mucosal injury. By using the model of ethanol-induced gastric mucosal injury in the present study, we explored the effect of trans-3,5,4'-trimethoxystilbene (BTM-0512), a novel analog of resveratrol, on gastric mucosal injury and the possible underlying mechanisms. Gastric mucosal injury in the rat was induced by oral administration of acidified ethanol. The gastric tissues were collected for determination of the gastric ulcer index, asymmetric dimethylarginine (ADMA) and nitric oxide (NO) contents, the activity of dimethylarginine dimethylaminohydrolase (DDAH) and superoxide anion (O2(-)) or hydroxyl radical (OH*) formation. The results showed that acute administration of ethanol significantly increased the gastric ulcer index concomitantly with the decrease in DDAH activity and NO content as well as the increase in ADMA content, effects that were reversed by pretreatment with BTM-0512 (100 mg/kg) or L-arginine (300 mg/kg). Administration of BTM-0512 did not show a significant effect on O2(-) or OH. formation. The results suggest that BTM-0512 could protect the gastric mucosa against ethanol-induced injury, which is mainly related to an increase in DDAH activity and subsequent decrease in ADMA content.

We demonstrated the development of antral ulcers induced in rats by alendronate and investigated the pathogenic factors involved in this model. Animals fasted for 18 h were given alendronate p.o., and then re-fed normally and killed on various days up to 7 days later. Alendronate caused non-hemorrhagic damage in both the corpus and antrum of fasted rats, but after refeeding for 3 days the lesions in the corpus healed completely, while those in the antrum developed into large ulcers with increased vascular permeability. The development of antral ulcers was accompanied by an increase in MPO activity and lipid peroxidation as well as a decrease in SOD activity and GSH content in the mucosa. Histologically, the damage did not penetrate the muscularis mucosa, yet severe edema and neutrophil infiltration were observed in the submucosa. Neither omeprazole nor indomethacin had any effect, while allopurinol and SOD reduced the severity of these ulcers. Rebamipide dose-dependently suppressed the ulcerogenic response to alendronate, with a concomitant reversal of the increased vascular permeability, MPO activity and lipid peroxidation as well as the reduced SOD activity and GSH content. These results suggest that alendronate did not cause gross damage in the stomach of fasted rats, yet produced large ulcers in the antrum with severe edema after refeeding. The pathogenesis of these ulcers may be explained by impairment of the mucosal antioxidative system and does not involve acid/peptic digestion and deficiency of prostaglandins. Rebamipide prevents the antral ulcers, probably due to its anti-oxidative as well as anti-inflammatory actions.

The influence of components and some schemata of antiulcerous therapy on content and activity of monooxigenase system's enzymes in mucous membrane of stomach are studied on the model of experimental stomach ulcer in rats. It is established, that among components of antiulcerous therapy such as omeprazole, clarithromycin and metronidazole inhibit content and activity of MOS enzymes. Tinidazol, amoxicillin and azithromycin do not affect the function of MOS. Rifampicin and pantoprazole induce enzyme system of monooxigenase. In triple therapy with omeprazole, clarithromycin and metronidazole the inhibit effect of preparations to system of MOS is exponentiated and it leads to suppression of mucous cytoprotaction of gastro duodenal zone. Triple therapy of ulcerous disease with pantoprazole, rifampicin and azithromycin is effective planning to stimulate defense mechanisms of the organism.

Gastric ulcer is a multifaceted process including acid secretion, reactive oxygen species generation, prostaglandin inhibition, and extracellular matrix (ECM) degradation. Matrix metalloproteinases (MMPs) have the ability to cleave and remodel the ECM. We investigated the activity and expression of MMP-9 and -2 in ethanol-induced acute gastric ulceration in rats. We found that severity of gastric ulcer was strongly correlated with increasing doses of ethanol and increased secretion of proMMP-9. ProMMP-9 was upregulated approximately 25-fold at maximum ulcer index. Increased secretion of proMMP-9 was associated with increased expression of tumor necrosis factor-alpha and interleukin-6. We examined the effect of H(2)-receptor antagonists and antioxidants on proMMP-9 secretion and synthesis during prevention of ethanol-induced gastric ulcer. Our data reveal that famotidine dose dependently blocked increased secretion and synthesis of proMMP-9 during gastroprotection and arrested infiltration of inflammatory cells as well as oxidative stress in rat gastric tissues. Similar to H(2)-receptor antagonists, N-acetylcysteine and dimethyl sulfoxide, well-known antioxidants, inhibited proMMP-9 upregulation to the control level. In conclusion, ethanol-induced gastric ulceration is associated with increased expression of proMMP-9 that can be attenuated by H(2)-receptor antagonists and antioxidants. These findings furnish a novel MMP-9-mediated pathway and its inhibition via proinflammatory cytokines by famotidine in ethanol-induced gastric ulceration.

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.

The ethanol extract of Pterocarpus santalinus (PS) was evaluated for gastroprotection in rats using ibuprofen as the induction model. Rats treated with PS (100-400 mg/kg) showed a significant reduction in gastric lesions. PS at a dose of 200 mg/kg was found to be the minimum effective dose and hence further studies with that dose were carried out. PS treatment increased the LDH activity and decreased the lipid peroxidation levels. The extract had the ability to increase the antioxidant enzymes SOD, CAT and GPx when compared with the untreated but induced rats. The membrane bound ATPases - H(+)K(+)ATPase, Na(+)K(+)ATPase and Ca(2+)ATPases were increased upon the induction with ulcerogen. The treated group showed a decrease in the activities of these enzymes and also had the ability to restore the sodium and potassium ion concentrations to near normal levels, which were altered by ibuprofen mediated acid stimulation. The results suggest that the antiulcer properties of PS could traced to its acid inhibiting potential, antioxidant activity and the ability to maintain functional integrity of the cell membranes.

In this study, the effects of Centella asiatica water extract (CE) and its active constituent, asiaticoside (AC), on the expression and activity of inducible nitric oxide synthase (iNOS) during gastric ulcer healing in rats were investigated. CE was prepared from Centella asiatica dry plant and the concentration of AC in CE was quantitatively determined with the use of high performance liquid chromatography analysis. Different concentrations of CE (0.10 g/kg and 0.25 g/kg) and AC (5 mg/kg and 10 mg/kg) were orally administered to rats with acetic acid-induced gastric ulcers. They were found to reduce the size of the ulcers at days 1, 3 and 7 after ulcer induction in a dose-dependent manner, with a concomitant attenuation of iNOS activity and protein expression at the ulcer tissues. The levels of nitrite and nitrate (NO(X)-), the stable end-products of nitric oxide (NO), in the gastric ulcer tissues were also decreased. N-[3-(aminomethyl)benzyl]acetamidine (1400W), a highly selective inhibitor of iNOS, was found to produce similar but more potent inhibition on iNOS activity at a dose of 0.1 mg/kg. These findings indicate that CE and AC have an anti-inflammatory property that is brought about by inhibition of NO synthesis and thus facilitates ulcer healing.

The mechanism of the antiulcer effect of Neem leaf aqueous extract to block gastric lesions in rat has been studied with emphasis on acid secretion, oxidative damage and apoptosis. The extract dose-dependently inhibits gastric lesions induced by restraint-cold stress, indomethacin and ethanol. In stress ulcer model, it is more effective than ranitidine but less effective than omeprazole. It also dose-dependently blocks pylorus ligation and mercaptomethylimidazole-induced acid secretion. In the pylorus-ligation model, it is less effective than omeprazole but as effective as ranitidine. It inhibits H+-K+-ATPase activity in vitro in concentration-dependent manner to inhibit acid secretion. Oxidative membrane damage by hydroxyl radical (*OH) as measured by lipid peroxidation in stress ulcer is significantly blocked by leaf extract. Stress-induced apoptotic DNA fragmentation is also protected. The extract also prevents *OH-mediated mucosal DNA damage in vitro by scavenging the *OH. Neem leaf extract, thus, offers antiulcer activity by blocking acid secretion through inhibition of H+-K+-ATPase and by preventing oxidative damage and apoptosis.

Many studies have shown that a variety of strategies, including the use of cyclooxygenase-2 (COX-2) inhibitors, or co-prescription of misoprostol or proton pump inhibitors, result in reduced endoscopic damage and ulceration compared with non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Questions have been raised as to whether this would translate into improved clinical outcomes. Consequently, several studies have investigated whether use of COX-2 inhibitors (Vioxx Gastrointestinal Outcomes Research [VIGOR] and the Celecoxib Long-Term Arthritis Safety Assessment Study [CLASS] studies) or co-prescription with misoprostol (MUCOSA) would reduce the event rate of clinically significant ulcers. These studies have shown an approximate halving of such events. They have raised the possibility that use of low dose aspirin may compromise these benefits and appear to have shown differences between (at least some) COX-2 inhibitors and (at least some) NSAIDs with regard to myocardial infarction. Among the lessons learned from this experience are the need to define closely the outcomes of interest and possibly to concentrate on ulcer complications, the need for adequately powered studies, and the fact that endoscopic studies broadly predict outcomes. However, there are differences in the estimated rates of reduction. It is not self evident whether outcomes studies or endoscopic studies give a truer estimate of risk. A helpful development would be more standardized gastrointestinal assessment at the time of ulcer complications and this could be achieved if studies were done in countries with well-developed primary care systems.

Helicobacter pylori can colonize the stomachs of Mongolian gerbils and subsequently induce penetrating ulcers five months later. Using this gerbil model, the effects of both combined treatment with omeprazole and clarithromycin, as well as treatment with each drug separately, on the healing of H. pylori-induced gastric ulcers, and the effects of the cessation of the drug treatment on healed ulcers were examined. Beginning five months after H. pylori (NCTC11637) inoculation, omeprazole (four weeks), clarithromycin (two weeks), their combination, or the vehicle was orally administered once daily. These drugs, in combination or separately, markedly enhanced ulcer healing and lowered the increased myeloperoxidase (MPO) activity. While omeprazole had no effect on viable H. pylori, clarithromycin and the drug combination significantly reduced viable H. pylori. The degree of bacterial eradication was much higher in the case of the drug combination compared to clarithromycin alone. Four months after cessation of the treatment, visible ulcers, hypertrophic gastritis and increased MPO activity were found in the control animals (all H. pylori-positive). Nonetheless, only one of the eight gerbils subjected to the drug combination developed a small ulcer, although no hypertrophic gastritis was exhibited. It is concluded that: (1) the gerbil model of H. pylori infection is useful for the study of ulcer healing; (2) combined treatment with omeprazole and clarithromycin enhances the ulcer healing in infected gerbils; and (3) healed ulcers do not relapse, despite cessation of the drug treatment.

Aim: To assess activity of superoxide dismutase and catalase in acute ulcer and in the end of its treatment with antisecretory (omeprasole and zaran), anti-Helicobacter (metronidasole) and antioxidant (alpha-tocopherol) drugs in patients with duodenal ulcer., Materials and Methods: 126 patients with duodenal ulcer were divided into 6 groups: group 1 patients had Helicobacter pylori (HP+) and were given omeprasole; group 2 patients had HP and were given omeprasole + metronizarole; group 3 patients were free of HP and received metronidasole + alpha-tocopherol; group 4 HP+ patients received zaran; group 5 HP+ patients got zaran = metronidasole; group 6 free of HP received zaran + alpha-tocopherol. The patients were examined using esophagogastroduodenoscopy, roentgenoscopy of the stomach, tests of the gastric juice., Results: An acute phase of ulcer was accompanied with enhanced activity of superoxide dismutase and low activity of catalase in mucosal biopsies from ulcer lesion and periulcer zone. In remission, antioxidant system resumed normal activity depending on the kind of the combined therapy. The combination omeprasole + metronidasole was more effective in HP eradication than zaran + metronidasole. Effect of alpha-tocopherol was poor., Conclusion: It is suggested that HP stimulates lipid peroxidation and thus maintains inflammation in gastric and duodenal mucosa.

Regulation of lipid peroxidation is realized not only by antioxidant enzymes but by natural antioxidants as well. We have lately succeeded, together with the students, in identifying antioxidant properties of quaternary ammonium compounds, which fact makes it possible for the above properties to gain extensive applicability in a setting where there is this variety of disbolism. One of such drug preparations is ethonium. The article contains information about uses of ethonium in the tablet dose form. The tablets are of little toxicity, they stimulate the oxidation-reduction processes and proved to be effective in experimental gastric and duodenal ulcers.

Eradication therapy for Helicobacter pylori (H. pylori) has been established. However, the physiological factors influencing the success of treatment remain unclear. The aim of this study was to analyze these factors and to evaluate the efficacy of sofalcone on H. pylori eradication therapy. Forty-four H. pylori-infected and peptic ulcer patients were enrolled in this study. Twenty-seven patients were treated with lansoprazole (LPZ, 30 mg o.d. for 1-8 weeks) and amoxicillin (AMPC, 500 mg q.i.d, 1-2 weeks), followed by 8 weeks of treatment with famotidine (FAM, 20 mg o.d.). Moreover, sofalcone (SOF, 100 mg t.i.d) was administered to 17 patients throughout the therapeutic period. Endoscopic and serologic evaluations and the urea breath test (UBT) were performed before therapy. At the endoscopic examination, mucosal samples were biopsied and then tissue myeloperoxidase (MPO) content, an index of neutrophil infiltration was measured. Cure of H. pylori infection was determined 8 weeks after the cessation of LPZ. This eradication regimen afforded an overall cure rate of 63.0% (17/27) without SOF and 76.5% (13/17) with SOF. In the control group, treatment success was inversely associated with pre-UBT value (gastric urease activity), whereas this association was not observed in the SOF group. Furthermore, in the patients exhibiting a high preUBT value (>40%), a twofold higher eradication rate was obtained by the administration of SOF. In patients who were successfully eradicated, mucosal MPO level was slightly higher than those of unsuccessful cases, whereas there was no significant association with serum pepsinogen (PG I, PG II) concentration and its ratio (PG I/PG II). These results suggest that a low UBT value is a factor predicting treatment success. SOF administration may improve the eradication rate, especially in the high-UBT subgroup.

The role of chloroform fraction of Calotropis procera root extract on different experimental ulcer models in rats was investigated. The extract demonstrated significant anti-ulcer activity against aspirin, indomethacin, ethanol, indomethacin + ethanol, or stress-induced ulcerations. Significant inhibition of gastric secretory volume and total acidity in pylorus ligated rats were observed to occur with the extract. It was also observed that the root extract significantly inhibited arachidonic acid metabolism induced by soyabean lipoxygenase. The results suggest that the anti-ulcer activity of the extract might be attributable to the inhibition of 5-lipoxygenase (5-LO).

1. The effect of antiulcer agents, ebrotidine and sucralfate, on the expression of gastric mucosal proliferating cell nuclear antigen (PCNA) and cyclin-dependent kinase (p34Cdk2) during chronic ulcer healing was examined. 2. Rats with experimentally induced gastric ulcers were treated twice daily for 14 days with either ebrotidine at 100 mg/kg, sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for quantitization of gastric mucosal PCNA and Cdk2 expression. 3. The assays revealed that the ulcer healing was accompanied by a marked elevation in mucosal expression of PCNA and Cdk2. The maximum increase in PCNA (4.7-fold) occurred by the second day of healing, and the expression of Cdk2 reached a maximum increase (2.3-fold) by the fourth day. 4. Accelerated ulcer healing with ebrotidine (7 days) and sucralfate (8 days) treatments was reflected in a significant enhancement of PCNA and Cdk2 expression. By the second day of treatment, ebrotidine evoked a 15-fold increase in PCNA expression, and sucralfate produced an 11.8-fold enhancement. The mucosal expression of Cdk2 attained a maximum of 4.3-fold increase over that of the controls by the sixth day of healing with ebrotidine, and a fivefold increase in Cdk2 expression occurred by the fourth day of ulcer treatment with sucralfate. 5. The findings implicate cell cycle regulatory proteins in the processes to leading to mucosal repair and suggest that the two drugs exert a similar effect on the expression of proteins that control cell cycle progression.

Background: Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti-gastric ulcer effects equivalent to famotidine, an H2 blocker, in rats. This study was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity., Methods: Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatment, and effects of FK506 on NO synthase activity were determined enzymatically. Gastric mucosal interleukin (IL)-1 beta and IL-2 were measured by immunoradiometric assay. Gastric mucosal blood flow was measured by hydrogen gas clearance technique., Results: FK506 mitigated gastric lesions developed by water immersion stress. Stress-induced lesions were exacerbated by NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, while sodium nitroprusside, a NO donor, mitigated the lesions. Water immersion stress increased NO synthase activity in the early phase (0.5 h after stress treatment) and decreased it in the late phase (6 h after). Decrease in NO synthase activity in the late phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion stress increased gastric mucosal IL-1 beta and IL-2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 itself did not affect gastric mucosal blood flow. L-NMMA treatment significantly decreased gastric mucosal blood flow. In contrast, gastric mucosal blood flow was significantly increased by sodium nitroprusside., Conclusions: Increase in NO synthase activity might contribute to cytoprotection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might be involved in FK506's protective effects on the gastric mucosa.

Background: Gastric mucosal microcirculation is an important factor in the protection of gastric mucosa, and nitric oxide (NO) plays a crucial role in the regulation of regional blood flow. This study was designed to evaluate the effect of cetraxate, an anti-ulcer drug, on water immersion stress-induced gastric lesions in relation to the changes in NO synthase activity., Methods: Gastric lesions were induced in rats by water immersion stress. The effects of cetraxate on NO synthase activity with or without stress was determined enzymatically. Changes in gastric mucosal prostaglandin (PG) contents with or without stress were also determined using high-performance liquid chromatography. Gastric mucosal blood flow was measured by hydrogen gas clearance technique., Results: Water immersion stress-induced gastric lesions. Cetraxate significantly mitigated the lesions but N(G)-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, exacerbated the lesions. The favourable effect of cetraxate was remarkably diminished by administration of L-NMMA. NO synthase activity decreased significantly by 6 h after stress. Cetraxate treatment increased NO synthase activity throughout the experiment in rats with or without stress treatment. Water immersion stress decreased all PGs detected, i.e. 6-keto-PGF1alpha, PGF2alpha, PGE2 and PGD2. Cetraxate prevented stress-induced decreases in PG contents. L-NMMA showed no significant effect on PG contents. Cetraxate increased gastric mucosal blood flow significantly and L-NMMA cancelled out cetraxate-induced increase in blood flow., Conclusions: The pharmacological efficacy of anti-ulcer drugs such as cetraxate might be attributable to the enhancement of NO synthase activity resulting in an increase in gastric mucosal blood flow.

Rebamipide, a novel antipeptic ulcer drug, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinone-4-yl]-propionic acid, was studied for its inhibitory effect on gastric xanthine oxidase activity and type conversion of the enzyme that has a profound role in free radical generation. Intraperitoneal administration of rebamipide at 60 mg/kg body weight reduced gastric mucosal hemorrhagic lesions and lipid peroxidation, which was proportional to the inhibitory effect of rebamipide on alcohol-induced xanthine oxidase-type conversion and enzyme activity. It was also observed that the activity of xanthine oxidase was significantly inhibited by administration of rebamipide at 60 mg/kg body weight, leading to a significant reduction of lipid peroxide content in alcohol-treated rats. The results suggest that alcohol-induced gastric mucosal lesions might be, in part, due to the increased activity of xanthine oxidase and type conversion rate of the enzyme and the protective effect of rebamipide on gastric mucosal lesions would result from its ability to protect against oxidative stress on gastric mucosal lesions of alcohol-treated rats.

The relationship of Wiener's topological index and molecular connectivity index with antiulcer activity of a series of 4-substituted-2-guanidino thiazole analogs has been investigated. The values of Wiener's topological index and molecular connectivity index of 128 compounds were computed and active ranges were identified. The activity assigned to each analog using these topological descriptors was subsequently compared with the reported in vitro and in vivo activities against gastric hydrogen-potassium stimulated adenosine triphosphatase (H+K(+)-ATPase) enzyme. Predictions with an accuracy of the order of approximately 89% were observed with regard to in vivo activity using these topological indices.

Anti-ulcer effects of cetraxate, a new compound possessing anti-plasmin, anti-casein and anti-trypsin actions were investigated by using experimental gastric ulcer models in rats. Cetraxate, 300 mg/kg p.o. showed significant inhibitory effects of 65.3%, 70.0%, 30.2%, and 67.1% against aucte types of ulcers producing by aspirin, phenylbutazone, indomethacin, and pyloric ligature (Shay's ulcer), respectively. These effects were greater than those obtained by gefarnate and aluminum sucrose sulfate may be mainly attributed to the protecting action of this drug on gastric mucosa. Ctraxate further revealed remarkable inhibitory effects on chronic types of ulcers produced by acetic acid, clamping, and clamping-cortisone. In acetic acid ulcer in particular, cetraxate was found to have a dose-dependent inhibitory effect at doses over 50 mg/kg. Of test drugs including L-glutamine and methylmethionine sulfonium chloride, cetraxate showed the most remarkable inhibitory effect on beta-glucuronidase activity in ulcer tissue of these three types of ulcers. These findings suggest that cetraxate may prevent the connective tissue in the ulcer location from decomposition due to lysosomal enzymes such as beta-glucuronidase, thereby accelerating the recovery from ulcer.

The antiulcer effect of two medicinal forms (oil solution, liniment) of dibunol in rats with different models of the stomach and duodenum ulcers was studied. The therapeutic activity of dibunol was evaluated by determining the index of ulcer formation as well as during the morphological and histochemical studies. The two medicinal forms of dibunol possessed equal antiulcer activity by all studied criteria. One should note a characteristic property of dibunol--its ability to produce pronounced epithelialization of ulceroerosive and ulceronecrotic lesions of the mucosa without rough scarring.