Gastroduodenal Mucosal Damage Research Articles

Fixed dose combination of aspirin and pantoprazole: Results of a multicenter, comparative, randomized, double-blind, double dummy, phase III study in Indian patients

ObjectiveTo compare the efficacy and safety of a fixed-dose combination of aspirin and pantoprazole with that of aspirin alone for the prevention of gastro duodenal mucosal damage in patients taking aspirin for secondary prevention of cardiovascular disease or cerebrovascular disease. MethodsThis was a comparative, double-blind, double-dummy, randomized, multicenter, phase III study conducted in patients taking aspirin ≤150 mg daily for ≥3 to ≤6 months and expected to require daily aspirin therapy for at least 6 months for the secondary prevention of cardiovascular disease or cerebrovascular disease. ResultsA total of 240 patients were randomized to receive either a fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg or aspirin 150 mg alone in a 2:1 ratio. The proportion of non-responders (patients experiencing gastroduodenal events) was 9.7 % in the test group (fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg) compared to 19.7 % in the comparator group (aspirin 150 mg) at week 12, while the proportions were 11.0 % in the test group and 22.4 % in the comparator group at the end of 24 weeks of treatment (p-value was <0.05 at week 12 and 24). GI injuries were significantly less in test group as compared to comparator group. Both drugs were well tolerated by all patients. ConclusionThe fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg was found to be more efficacious and safer compared to aspirin 150 mg alone for the prevention of gastroduodenal mucosal damage in patients receiving aspirin.

Upper gastrointestinal endoscopic findings in celiac disease at diagnosis: A multicenter international retrospective study

Gastroduodenal endoscopy and biopsy following positive specific serology is considered the gold standard to diagnose celiac disease (CeD) in adults. Whether upper endoscopy helps detect comorbid conditions is unknown. To investigate the prevalence of non-celiac endoscopic findings in patients in whom endoscopy was performed to confirm CeD diagnosis. This is an observational, descriptive, multicenter, retrospective study that reports endoscopic findings obtained in adult patients enrolled in local registries from four tertiary centers. We collected data reported on first endoscopy, indicated for investigation of CeD. Diagnosis of CeD was performed by histology (≥ Marsh 2 type mucosal damage) and specific serology. Two European and one North American center included biopsy-confirmed CeD following positive serology. A fourth center (South America) included symptomatic patients undergoing endoscopy, irrespective of CeD serology. The latter cohort included a non-CeD control group. A total of 1328 patients (80% female; 35 years median age) were enrolled, of whom 95.6% had positive specific serology. In 135 patients, endoscopy revealed 163 abnormalities unrelated to CeD (prevalence: 10.1%). Erosive reflux esophagitis (6.4%), gastric erosions (2.0%), and suspicion of esophageal metaplasia (1.2%) were the most common findings. Biopsy-confirmed Barrett's esophagus was infrequent (0.2%). No endoscopic cancer was detected. Older patients (≥ 51 years of age) had a higher prevalence of endoscopic findings than those ≤ 50 (P < 0.01). Within the South American cohort, CeD was associated with a lower rate (8.2%) of comorbid endoscopic findings compared with controls (29.1%; P < 0.001). In the adjusted multivariate analysis of this cohort, having CeD was associated with a 72% reduction in the risk of any endoscopic abnormality (P < 0.0001), and having alarm symptoms was associated with a 37% reduction in the risk of finding at least one endoscopic lesion (P < 0.02). In this large multicenter study, young adults with positive CeD serology had few comorbid endoscopic findings. Although patients over 51 years had a high prevalence of non-CeD gastroduodenal mucosal damage, no malignancy or premalignant lesions were found.

EFFECT OF AMLODIPINE ON ENTEROPATHY INDUCED BY INDOMETHACIN IN RATS

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) have become well known for causing gastroduodenal mucosal damage. In addition, they are also known to affect the small intestine in humans. Amlodipine is a third-generation dihydropyridine-type calcium channel blocker; it can inhibit inflammatory cytokines and enhance antioxidant defenses. The aim of this study was to evaluate the effect of Amlodipine on indomethacin-induced enteropathy in rats.&#x0D; Methods: Enteropathy was induced by subcutaneous indomethacin (Indo) prepared in 5 % sodium bicarbonate administrated at a dose rate of 9 mg/kg for two days at 24h intervals. Amlodipine (10 mg/Kg body weight po) was administrated for seven consecutive days beginning 24 h after the first Indo injection. Rats were sacrificed under ether anesthesia on the 8th day. The small intestinal injury was assessed by body weight loss, small intestine weight/length ratio, macroscopic damage, histological study, as well as by biochemical measurement of reduced glutathione (GSH), lipid peroxides and superoxide dismutase (SOD) activity in the small intestine tissue.&#x0D; Results: The results showed that Amlodipine didn't decrease body weight loss, it decreased small intestine weight/length ratio, macroscopic and microscopic small intestinal damage scores caused by administration of Indo. It also increased SOD activity and decreased lipid peroxidation. The effect on the level of GSH wasn't observed. No statistical significance was observed when previous findings were compared to Indo induced enteropathy group (p&gt;0.05).&#x0D; Conclusion: Amlodipine didn't produce an obvious enhancement in enteropathy induced by Indo in rats.

Sucrose Permeability: A Simple Non-Invasive Marker of Gastro-Duodenal Damage in Dyspepsia

Introduction: Diagnosis of gastro-duodenal mucosal damage usually requires endoscopy, an invasive procedure. An attempt has been made to assess the clinical validity of sucrose permeability test as a non-invasive marker of gastro-duodenal damage.Methods: The test was carried out in 65 patients of dyspepsia evaluated by endoscopy and 21 healthy controls. On endoscopy, gastro-duodenal epithelial damage was assessed in all patients of dyspepsia and grouped as: group 1 (normal gastro-duodenal mucosa, n=18), group 2 (Gastric ulcer, n=15), group 3 (Duodenal ulcer, n=10), group 4 (Gastritis, n=12) and group 5 (Duodenitis, n=10).Results: The mean urinary sucrose excretions (mg) in 5 hours after 100g oral load was found to be significantly higher in patients of gastric ulcers (183.6 ±169.7, p value &lt; 0.001), duodenal ulcers (151.7± 79.2, p value &lt;0.001), gastritis (115.6±59.2, p value &lt;0.001) and duodenitis (105.2± 122.2, p value &lt;0.05) as compared to controls (35.2±17.2). However, the mean sucrose excretion in patients of dyspepsia with normal endoscopic findings (42.5±14.8 mg) was almost similar to the control group (p value &gt;0.05). A ROC curve analysis taking endoscopic findings as gold standard was undertaken to find the optimum cut-off to detect gastro-duodenal epithelial damage.Conclusions: The cut-off value of 64.5 mg/5h for urinary sucrose excretion provided the best sensitivity and specificity in the diagnosis of both surgical (gastric and duodenal ulcer) and non-surgical (gastritis and duodenitis) gastro-duodenal mucosal damage. At this cutoff sucrose permeability test provided a sensitivity of 72 % and specificity of 92%. Similarly, a cut-off value of 66.5 mg/5h of urinary sucrose excretion provided the best sensitivity and specificity in the diagnosis of surgical gastro-duodenal mucosal damage with sensitivity of 72% and specificity of 97%.

Sucrose permeability: A simple non-invasive marker of gastro-duodenal damage in patients of dyspepsia

&lt;p&gt;&lt;strong&gt;Introduction&lt;/strong&gt;: Diagnosis of gastro-duodenal mucosal damage usually requires endoscopy, an invasive procedure. An attempt has been made to assess the clinical validity of sucrose permeability test as a non-invasive marker of gastro-duodenal damage.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Materials and Methods&lt;/strong&gt;: The test was carried out in 65 patients of dyspepsia evaluated by endoscopy and 21 healthy controls. On endoscopy, gastro-duodenal epithelial damage was assessed in all patients of dyspepsia and grouped as: group 1 (normal gastro-duodenal mucosa, n=18), group 2 (Gastric ulcer, n=15), group 3 (Duodenal ulcer, n=10), group 4 (Gastritis, n=12) and group 5 (Duodenitis, n=10).&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Results&lt;/strong&gt;: The mean urinary sucrose excretions (mg) in 5 hours after 100g oral load was found to be significantly higher in patients of gastric ulcers (183.6 &amp;plusmn;169.7, p value &amp;lt; 0.001), duodenal ulcers (151.7&amp;plusmn; 79.2, p value &amp;lt;0.001), gastritis (115.6&amp;plusmn;59.2, p value &amp;lt;0.001) and duodenitis (105.2&amp;plusmn; 122.2, p value &amp;lt;0.05) as compared to controls (35.2&amp;plusmn;17.2). However, the mean sucrose excretion in patients of dyspepsia with normal endoscopic findings (42.5&amp;plusmn;14.8 mg) was almost similar to the control group (p value &amp;gt;0.05). A ROC curve analysis taking endoscopic findings as gold standard was undertaken to find the optimum cut-off to detect gastro-duodenal epithelial damage.&lt;/p&gt; &lt;strong&gt;Conclusion&lt;/strong&gt;: The cut-off value of 64.5 mg/5h for urinary sucrose excretion provided the best sensitivity and specificity in the diagnosis of both surgical (gastric and duodenal ulcer) and non-surgical (gastritis and duodenitis) gastro-duodenal mucosal damage. At this cutoff sucrose permeability test provided a sensitivity of 72 % and specificity of 92%. Similarly, a cut-off value of 66.5 mg/5h of urinary sucrose excretion provided the best sensitivity and specificity in the diagnosis of surgical gastro-duodenal mucosal damage with sensitivity of 72% and specificity of 97%.

The effect of low dose aspirin intake on gastro-duodenal mucosa, and protective effects of GSH-vitamin C-E

Objectives: Neutrophil-mediated inflammation and oxidative stress may be the important events that lead to gastroduodenal mucosal damage induced by aspirin. It is hypothesized that GSH-vitamin C-E may protect to the upper gastrointestinal mucosa against low dose aspirin’s (L-ASA) adverse effects. Material and methods: Male rats were fed regular diets and maintained for 40 days in the control group (n=8), the L-ASA group (n=8), which was given aspirin (1.44 mg/kg/ day) administered intragastrically by feeding tube to rats, or the L-ASA with antioxidant supplement group (n=8), to whom 1.44 mg of aspirin/kg/day + a solution that contained 50 mg vitamin C, 25 mg vitamin E and 25 mg GSH was administered intragastrically by feeding tube to rats every day. After the treatments, blood, stomach and duodenum were taken for pathological and myeloperoxidase (MPO) activity, heat shock protein (Hsp) 70, lipid and protein oxidation analyses. Results: The stomach and duodenum of the L-ASA group rats had higher scores of pathological findings compared with the control group, whereas the severity of the lesions was found low in the antioxidant-supplemented group according to the L-ASA group. In addition, the gastric mucosal MPO activity and Hsp 70 levels in the L-ASA group were significantly higher than control, but antioxidant supplementation lowered the values of MPO and Hsp 70 in the antioxidant supplemented group (P=0.009, P=0.04). Conclusion: A simultaneous intake of GSH-vitamin C-E along with aspirin attenuated the gastric injury. GSH-vitamin C and E could play a protective role in the stomach against gastric damage resulting from low dose daily long-term aspirin use.

Avances en patología gastrointestinal relacionada con el tratamiento con antiinflamatorios no esteroideos y antiagregantes plaquetarios

The most important and recent advance reported in the field of the non-steroidal antiinflammatory drug (NSAID)-associated gastrointestinal (GI) lesions is the CONDOR study. This study shows that treatment with celecoxib 200 mg/12 hours is associated with a lower frequency of clinically significant adverse effects throughout the GI tract when compared with treatment with diclofenac 75 mg/12 hours + omeprazole 20 mg/day in at-risk patients with osteoarthritis or rheumatoid arthritis. Other studies of interest report that most arthritis patients requiring NSAIDs are at increased GI and cardiovascular risk and that more than 50% do not receive appropriate therapy based on current recommendations. Recent epidemiological studies confirm that aspirin use, alone or associated with other antiplatelet agents, is associated with increased risk of GI bleeding from either the upper or the lower GI tract, and that proton pump inhibitors (PPIs) reduce the risk of upper GI bleeding. The most recent data also question the negative interaction between PPI and clopidogrel, but the data are still generally of low quality. A notable new compound is cobiprostone, a local chloride channel activator. When combined with NSAIDs, this agent reduces the occurrence of gastric lesions. Another new agent that combines aspirin with phosphatidylcholine is associated with a lower degree of gastroduodenal mucosal damage than aspirin and has identical antiplatelet effect to aspirin alone.

The principles of drug gastroduodenal bleeding prevention in critically ill condition patients and in postoperative period patients

The basic pathogenic mechanisms of ulcer formation in critically ill condition patients and in postoperative period patients are studied in the article. The role of central nervous system, humoral effects, drug aggression, system inflammatory response and also acid peptic factor as a key mechanism of damage is introduced. The basic reasons for preventive maintenance of the gastroduodenal bleedings is represented considering the character and degree of disease, time of hardwired vital functions replacement, presence of further diseases. The conception is developed, which assuming the proton pump inhibitors application for a long time (till one month) in two phases (intravenous and peroral) for prevention of stress relative gastroduodenal mucosal damage and its consequences.

Rapid protection of the gastroduodenal mucosa against aspirin‐induced damage by rabeprazole

The ability of a proton pump inhibitor to reduce or prevent NSAID-induced gastroduodenal damage during the first 24 h has not been tested. To determine, whether oral rabeprazole, administered 5 h before the initiation of therapeutic dosing of aspirin protects the gastroduodenal mucosa. Normal subjects were randomized into two groups - one received rabeprazole, 20 mg at 07:00 hours and the other placebo, before initiation of aspirin 650 mg at 12:00 hours, and then q4 h for 3 days. Upper endoscopic examinations were performed on all subjects at baseline, 24 and 72 h after initiation of aspirin. Gastroduodenal mucosal damage was scored. Thirty subjects were compliant with study medications and underwent three endoscopic examinations. Salicylate concentrations were similar for the placebo and the rabeprazole groups at all times. On rabeprazole, the Lanza scores were significantly lower compared with placebo at 24 h (1.3 +/- 0.26 vs. 2.1 +/- 0.26, P < 0.05) and at 72 h (1.3 +/- 0.29 vs. 2.3 +/- 0.28, P < 0.05). Gastric antral erosion counts were less with rabeprazole than placebo at 24 (4.1 +/- 1.3 vs. 7.6 +/- 2.0, P > 0.05) and 72 h (5.3 +/- 1.8 vs. 8.0 +/- 1.5; P > 0.05). Rabeprazole, initiated 5 h before the start of therapeutic dosing with aspirin, decreased Lanza scores and antral erosion counts at 24 h. These findings suggest that prophylaxis with rabeprazole could start concurrently with aspirin administration.

Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo

Data indicate that cyclooxygenase-2-specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n = 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n = 118), or placebo (n = 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were 2.99 +/- 0.51, 55% for naproxen/omeprazole compared to 0.32 +/- 0.10, 16% for celecoxib and 0.11 +/- 0.04, 7% for placebo (P < .001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P = .04). Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE.

Prise en charge de la dyspepsie chez les patients traités par AINS

NSAIDs-induced dyspepsia occurs in 10 to 30% of patients treated with NSAIDs, leading to discontinuation of treatment in 5 to 15%. Gastrointestinal tolerability of COX-2 selective inhibitors is better than for non-selective NSAIDs. Helicobacter pylori infection does not influence gastrointestinal tolerability of NSAIDs. Therefore, patients should not be tested and treated for H. pylori infection unless they have a history of peptic ulcer. Symptoms of NSAIDs-induced dyspepsia are poorly correlated with gastroduodenal mucosal damage. Therefore, upper gastrointestinal endoscopy should be performed only if symptom relief is not achieved with the first line empirical treatment and/or if symptoms suggestive of complications, such as bleeding, develop. Proton pump inhibitors appear to be the treatment of choice for NSAIDs-induced dyspepsia.

Upper endoscopic findings in children with active juvenile chronic arthritis

Aim: To investigate the association between gastroduodenal mucosal damage and symptoms of the digestive tract in children with juvenile chronic arthritis (JCA) Methods: This was a prospective, open, non‐randomized study. Gastroscopy was performed on 45 children with active JCA in 1996–2000. Gastrointestinal symptoms before and during the treatment were noted, as was the length of antirheumatic medication, for which the data were retrospectively assessed. Plasma haemoglobin (Hb) and mean corpuscular volume (MCV) levels and erythrocyte sedimentation rate (ESR) were analysed. Mucosal biopsies were obtained for histology and Helicobacter pylori culture. All patients were taking non‐steroidal anti‐inflammatory drugs (NSAIDs) and 11 (24.4%) were on peroral steroids; 16 (35.6%) were receiving hydorxychloroquine, 9 salazopyrine, 5 myocrisine and 14 methotrexate. Results: Seven children (15.6%) were found to have active inflammation in their gastric and/or duodenal mucosa, two having ulcers and two being infected with H. pylori. Abnormal endoscopic findings were more common in symptomatic children (n= 24) than in children without symptoms (n= 21) (75% vs 38%, p= 0.017). There was no clear association between the Hb or MCV level and the degree of gastroduodenal inflammation (p= 0.98 and 0.7, respectively). Significantly more children (66.6% vs 33.3%) experienced abdominal pain after beginning medical therapy than before therapy (p= 0.02). Conclusion: Endoscopic evaluation of patients with JCA and receiving NSAIDs should be considered at least in symptomatic cases.

Role of Helicobacter pylori infection in gastroduodenal injury and gastric prostaglandin synthesis during long term/low dose aspirin therapy: a prospective placebo-controlled, double-blind randomized trial

OBJECTIVES: Whether gastric infection with Helicobacter pylori increases the risk of gastric mucosal injury during long term/low dose aspirin therapy is unknown. We examined whether H. pylori infection enhances upper GI mucosal damage, assessed endoscopically, in volunteers given low dose aspirin. We studied 61 healthy men and women, 29 with and 32 without active H. pylori infection. METHODS: We treated volunteers for 45 days with a placebo or aspirin (either 81 mg every day or 325 mg every 3 days). Gastroduodenal mucosal damage was then assessed by endoscopy, as was gastric histology and ex vivo gastric mucosal prostaglandin E 2 and F 2α synthesis rates. RESULTS: Erosive disease from low dose aspirin (erosions and/or ulcers) occurred in 50% of H. pylori–infected volunteers and in 16% of their noninfected counterparts ( p = 0.02). Aspirin caused a significantly higher average mucosal injury score in the gastric antrum in H. pylori–infected participants than in noninfected subjects ( p = 0.03), and two H. pylori–infected subjects developed antral gastric ulcers. Subjects with H. pylori gastritis treated with the placebo had nearly 50% higher gastric mucosal prostaglandin (E 2 plus F 2α) synthesis rates than their noninfected counterparts (108 ± 6 ng/g/min versus 75 ± 6 ng/g/min, p < 0.001). Aspirin reduced mucosal prostaglandin synthesis to similar levels in infected and noninfected participants. CONCLUSIONS: Long term/low dose aspirin therapy led to more gastric mucosal damage when H. pylori gastritis was present than when it was absent, despite similar degrees of gastric mucosal prostaglandin depletion.

Current approaches to reducing gastrointestinal toxicity of low-dose aspirin

Use of low-dose aspirin is associated with gastroduodenal mucosal damage and increased risk of upper gastrointestinal (GI) bleeding. Many patients on low-dose aspirin should receive prophylactic treatment, because they often present several risk factors that may lead to upper GI complications in nonsteroidal anti-inflammatory drug (NSAID) users. It is reasonable to assume that effective therapy (e.g., omeprazole, misoprostol, and high-dose famotidine) in the prevention of NSAID-induced gastroduodenal ulcers will also be effective in this setting. However, the best therapeutic approach to reducing GI toxicity in low-dose aspirin users is not defined, because only a few studies have focused on this problem. Omeprazole seems very effective in reducing both acute gastroduodenal mucosal damage and upper GI bleeding in the high-risk patient taking low-dose aspirin, but data with other antiulcer agents are lacking (misoprostol) or inconsistent (ranitidine) at present. No data are available on the effect of these drugs on dyspepsia or chronic gastroduodenal ulcers in the long-term use of low-dose aspirin. The role of Helicobacter pylori is controversial, but it may increase mucosal damage and the risk of upper GI bleeding in these patients. More data are needed to define the best therapeutic regimen in patients taking low-dose aspirin.

Review article: non-steroidal anti-inflammatory drugs and Helicobacter pylori.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are well-recognized causes of gastroduodenal mucosal damage. This damage is mediated through the effects of both agents on acid secretion, neutrophil activity and function, and prosta- glandin metabolism. Clinical trials on the interrelation- ship between H. pylori, NSAIDs and gastroduodenal mucosal injury have yielded conflicting results. No consensus has been reached on what recommenda- tions should be implemented with regard to H. pylori eradication in patients on long-term NSAID therapy. At present, the presence of H. pylori is identified at endoscopy and eradication is carried out in symptomatic patients. Asymptomatic patients remain a dilemma that requires further investigation. Clinical practice will continue to be tailored to a patient's individual requirements. Therefore, in patients at risk of gastrointestinal haemorrhage, and on NSAID therapy, acid suppression therapy should be prescribed.

Endoscopic evaluation of aceclofenac-induced gastroduodenal mucosal damage: a double-blind comparison with sodium diclofenac and placebo

Gastroduodenal mucosal damage was endoscopically compared between aceclofenac, a non-steroidal anti-inflammatory drug, and sodium diclofenac or placebo in a double-blind clinical trial. Thirty healthy male volunteers received 150 mg/ day of aceclofenac, 75 mg/day of sodium diclofenac or placebo for 2 weeks. Aceclofenac caused significantly less gastropathy than sodium diclofenac, and placebo caused no gastropathy. Both the gastric mucosal hexosamine content and gastroduodenal blood flow were significantly reduced by sodium diclofenac, while gastric mucosal hexosamine was significantly increased and gastroduodenal blood flow was unchanged with aceclofenac. Aceclofenac appears to have a low potential for causing gastroduodenal mucosal damage in humans.

Endoscopic evaluation of aceclofenac-induced gastroduodenal mucosal damage: a double-blind comparison with sodium diclofenac and placebo

Gastroduodenal mucosal damage was endoscopically compared between aceclofenac, a non-steroidal anti-inflammatory drug, and sodium diclofenac or placebo in a double-blind clinical trial. Thirty healthy male volunteers received 150 mg/ day of aceclofenac, 75 mg/day of sodium diclofenac or placebo for 2 weeks. Aceclofenac caused significantly less gastropathy than sodium diclofenac, and placebo caused no gastropathy. Both the gastric mucosal hexosamine content and gastroduodenal blood flow were significantly reduced by sodium diclofenac, while gastric mucosal hexosamine was significantly increased and gastroduodenal blood flow was unchanged with aceclofenac. Aceclofenac appears to have a low potential for causing gastroduodenal mucosal damage in humans.

Role of endogenous endothelin-1 in stress-induced gastric mucosal damage and acid secretion in rats

In rats subjected to 8 h water-immersion stress, gastric and duodenal mucosal hemorrhage and erosions were detected by macroscopic and histopathological examination. Moreover, plasma and gastric mucosal endothelin-1 (ET-1) levels rose appreciably in a time-related manner during water immersion, with a higher concentration detected in gastric mucosa. Thus, the percentage increases in plasma (gastric mucosal) ET-1, relative to basal levels, after 1, 4 and 8 h of water immersion were 86(172), 169(322) and 210(391)%, respectively. Likewise, a marked increase of gastric acid output was demonstrated 30 min after water immersion and lasted for 3 h. Pretreatment with the endothelin ET A/ET B receptor blocker, bosentan (30 and 100 mg kg −1), orally, dose-dependently antagonized gastric and duodenal mucosal damage as indicated by reductions in lesion lengths of 67 and 80%, respectively. Similar protective effects on mucosa were observed when bosentan was given by the intramuscular route. On the other hand, bosentan suppressed the rate of acid output by 30.3±2.1% in the stressed rats, but had no such effect in non-stressed animals. Taken together, results from this study implicate the endogenous peptide, ET-1, as a powerful mediator of stress-evoked gastro-duodenal mucosal damage and, moreover, present bosentan as a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress.

Dopamine and the Brain-Gut Axis

Publisher Summary Some dopaminergic compounds are reported to be efficient in the treatment of duodenal ulcer disease in humans and prevent gastroduodenal mucosal damage in animal models of ulcer disease. These findings in humans and animals made it of interest to investigate the effects of dopamine and dopaminergic compounds on duodenal mucosal bicarbonate secretion. The secretion has been studied in anesthetized animals and in human volunteers. The results of these studies are summarized and some recent findings are reported in this chapter. Animal studies of effects of dopamine and dopaminergic compounds have to consider that well-documented sites of action are the central nervous system as well as some peripheral tissues, including the intestinal tract and the kidney. Dopamine may exert effects not only on dopamine receptors, but also on adrenoceptors. Dopamine D 1 -receptor stimulation by bromocriptine, in contrast, caused a decrease in secretion. Catecholamine O-methyl transferase (COMT) inhibitors decrease tissue degradation of catecholamines, including dopamine. Interestingly, the centrally acting D 1 /D 2 antagonist haloperidol does not decrease but stimulates the duodenal secretion. Studies of isolated duodenal enterocytes lend strong support to the suggestion that dopamine stimulates duodenal mucosal bicarbonate secretion by an action on the duodenal enterocytes and confirm that stimulation is D 1 -receptor-mediated. On the other hand peripheral COMT inhibition increases duodenal mucosal bicarbonate secretion in human volunteers as well as in animals. These results indicate that duodenal secretion is stimulated via peripheral dopamine D 1 receptors. The stimulation of the secretion by haloperidol may suggest the presence of central nervous as well as peripheral dopaminergic modulation of duodenal bicarbonate secretion and mucosal protection.

Helicobacter pylori factors involved in the development of gastroduodenal mucosal damage and ulceration.

Many putative virulence determinants of Helicobacter pylori are believed to trigger and worsen the gastroduodenal mucosa damage observed in infected patients. H. pylori urease reacts with the gastric urea and generates ammonia; ammonia combines with water and yields ammonium hydroxide, which is cytotoxic. Ammonia may also inhibit cell proliferation and cause indirect mucosal injury by stimulating neutrophils. Phospholipases may damage the gastric mucosa by degrading phospholipids and generating precursors of ulcerogenic components. Other enzymes, such as protease, neuraminidase, fucosidase, and alcohol dehydrogenase, can contribute to damage of the gastric epithelium by destroying the integrity of mucus or by inducing lipid peroxidation. Infection by vacuolating cytotoxic (VacA+) H. pylori strains is considered to constitute increased risk for development of peptic ulcer and gastric cancer. Exploration of the vacA gene structure has shown the existence of strongly toxigenic strains, and has confirmed at the molecular level the increased ulcerogenic potential of VacA+ H. pylori strains. A pathogenicity island called cag has been recently described in Type 1 H. pylori strains (VacA+/CagA+).cag contains the cagA gene (whose expression is associated with toxigenicity) and many genes, some of which are highly homologous to virulence genes of other virulent bacteria, that account for the enhanced pathogenic potential of CagA+ organisms.