bluuebunny/crossref_metadata_2025 huggingface dataset:
Otilonium bromide in irritable bowel syndrome: a double‐blind, placebo‐controlled, 15‐week study
Authors: Battaglia  , Morselli‐Labate  , Camarri  , Francavilla  , Marco  , Mastropaolo  , Naccarato
Published: March 2003

Aim:

To evaluate the efficacy of otilonium bromide, a spasmolytic agent, in the treatment of irritable bowel syndrome using modern and validated diagnostic criteria.

Methods:

Three hundred and seventy‐eight patients with irritable bowel syndrome were enrolled in the study. At entry, endoscopy/barium enema, clinical examination and laboratory tests were used to rule out organic diseases. After a 2‐week placebo run‐in, 325 patients were randomly assigned to receive either otilonium bromide 40 mg t.d.s. or placebo for 15 weeks. Abdominal pain, abdominal distension and disturbed defecation were scored at the beginning of the study and every 5 weeks. A global determination of well‐being by visual analogue scale and the tenderness of the sigmoid colon were also scored.

Results:

The reduction in the number of abdominal pain episodes was significantly higher (P < 0.01) in otilonium bromide patients (55.3%) than in those taking placebo (39.9%) as was the severity of abdominal distension (42.0% vs. 30.2%; P < 0.05). Bowel disturbance improved in both groups, but without any statistically significant difference. The visual analogue scale of well‐being revealed a significant improvement (P < 0.05) in patients taking otilonium bromide. The investigators’ global positive assessment was in favour of otilonium bromide (65.2%) compared with placebo (49.6%) (P < 0.01).

Conclusions:

Otilonium bromide may represent an effective treatment for irritable bowel syndrome because it reduces its predominant symptom (abdominal pain/discomfort) more than placebo does.
Randomized controlled trial of omeprazole or endoscopy in patients with persistent dyspepsia: a cost‐effectiveness analysis
Authors: Laheij  , Severens  , Lisdonk  , Verbeek  , Jansen
Published: March 2003

Background

Cost‐effectiveness analysis, Helicobacter pylori research and the development of proton pump inhibitors are having an increasing impact on the management of dyspepsia. However, clinical trials have not always included both H. pylori diagnosis and proton pump inhibitors in their protocols.

Methods

Patients who were referred for upper gastrointestinal endoscopy by their general practitioner were randomized to either prompt endoscopy followed by directed medical treatment (conventional group, n = 38), or to empirical treatment with omeprazole and, in the case of symptom relapse, serological screening for H. pylori infection followed by eradication therapy in seropositive patients (empirical group, n = 42). The study lasted for up to 1 year.

Results

In the empirical group, only 13 patients (31%) underwent endoscopy. The average number of days for which the patients kept records of their dyspeptic symptoms was 266 (95% CI: 226–307) in the empirical group, of which 166 (95% CI: 128–204) were symptom‐free. In the conventional group, 159 (95% CI: 119–198) out of 255 days (95% CI: 209–302) were recorded as symptom‐free. The average medical cost in the empirical group was 284 (95% CI: 218–350) and in the conventional group 491 (95% CI: 383–600). In the empirical group, two malignancies were found, whereas in the conventional group one malignancy was found.

Conclusions

The empirical drug treatment strategy in patients with persistent dyspeptic symptoms resulted in 69% fewer diagnostic endoscopies with lower medical costs and equal effectiveness in the first year, compared to prompt endoscopy followed by directed medical treatment.
Does eradication of Helicobacter pylori impair healing of nonsteroidal anti‐inflammatory drug associated bleeding peptic ulcers? A prospective randomized study
Authors: Chan  , Sung  , Suen  , Lee  , Wu  , Leung  , Chan  , Lai  , Lau  , Ng  , Chung
Published: March 2003

Background:

Despite the widely accepted view that Helicobacter pylori is the most important cause of peptic ulcer disease, recent studies have suggested that the microbe protects against nonsteroidal anti‐inflammatory drug (NSAID)‐associated gastroduodenal lesions and promotes ulcer healing. We investigated the effects of H. pylori eradication on the healing of NSAID‐associated bleeding peptic ulcers.

Methods:

Chronic NSAID users presenting with peptic ulcer haemorrhage underwent endoscopy to secure haemostasis and to document H. pylori infection by rapid urease test and culture. They were prospectively randomized to receive either omeprazole (20 mg once daily) for 8 weeks or a 1‐week course of triple therapy (bismuth subcitrate 120 mg, tetracycline 500 mg, metronidazole 400 mg, all given four times daily) plus omeprazole (20 mg once daily) for 8 weeks. Endoscopy was repeated after 8 weeks. Final H. pylori status was determined by a 13C‐urea breath test that was performed at least 4 weeks after discontinuation of omeprazole.

Results:

195 H. pylori‐infected NSAID users, complicated by bleeding ulcers, were randomized to receive omeprazole alone (102) or triple therapy plus omeprazole (93). 174 patients returned for second endoscopy at 8 weeks (91 in the omeprazole group, 83 in the triple therapy group). Urea breath test was negative in 14% in the omeprazole group vs. 92% in the triple therapy group (P < 0.001). Complete ulcer healing was achieved in 88 (97%) patients in the omeprazole group and 77 (93%) in the triple therapy group (P = 0.31). On intention‐to‐treat analysis, ulcers were healed in 86% of the omeprazole group and 83% of the triple therapy group (P = 0.50). There was no significant difference in the healing rates of gastric or duodenal ulcers between the two groups.

Conclusion:

Eradication of H. pylori did not impair the healing of NSAID‐associated bleeding peptic ulcers.
Review article: efficacy of infliximab in Crohn’s disease — induction and maintenance of remission
Authors: Rutgeerts P.J.
Published: March 2003

The primary goals of treating patients with Crohn’s disease are to induce a clinical remission, maintain the remission, and prevent associated complications. Various treatment regimens for patients with Crohn’s disease induce a response and remission; however, most prove ineffective for maintenance of the clinical effect. A therapeutic agent that can induce and maintain remission, while promoting the restoration of intestinal mucosa, would prove to be most beneficial in such a patient population.

Several studies with infliximab have clinically demonstrated that the antitumour necrosis factor‐alpha therapy rapidly reduced the signs and symptoms in patients with moderate‐to‐severe Crohn’s disease. In acute studies with the chimeric monoclonal antibody, clinical benefit was associated with healing and reduction of inflammation in the bowel mucosal tissue. In a maintenance study, retreatment with infliximab maintained remission of the active disease. Additionally, treatment with the lowest infusion dose of infliximab (5 mg/kg) provided a high degree of clinical benefit with a long‐term outcome.
Novel therapies for Helicobacter pylori infection
Authors: OPEKUN  , EL‐ZAIMAITY  , OSATO  , GILGER  , MALATY  , TERRY  , HEADON  , GRAHAM
Published: March 2003

Background:

Increasing antibiotic resistance has begun to impair our ability to cure Helicobacter pylori infection.

Aim:

To evaluate orally administered novel therapies for the treatment of H. pylori infection.

Methods:

Healthy H. pylori infected volunteers received: (a) hyperimmune bovine colostral immune globulins, (b) an oligosaccharide containing an H. pylori adhesion target, Neu5Aca2‐3Galb1–4Glc‐(3′‐sialyllactose), or (c) recombinant human lactoferrin. Outcome was assessed by urea breath test or histological assessment of the number of H. pylori present.

Results:

None of the novel therapies appeared effective and no adverse events occurred.

Conclusion:

Although in vitro data appeared promising, in vivo results were disappointing. Higher doses, longer duration of therapy, adjunctive acid suppression, or a combination could possibly yield better results.
Effect of vitamin E in gastric mucosal injury induced by ischaemia‐reperfusion in nitric oxide‐depleted rats
Authors: NAITO  , YOSHIKAWA  , MATSUYAMA  , YAGI  , KASAI  , SUGIMOTO  , MASUI  , YOSHIDA  , KONDO
Published: March 2003

Background

: Neutrophil infiltration and lipid peroxide accumulation are involved in reperfusion‐induced gastric mucosal injury in nitric oxide‐depleted rats.

Aim

: To assess the effect of vitamin E on this injury.

Methods

: After ischaemia‐reperfusion, the total area of erosions, lipid peroxide contents in gastric mucosa, and gastric neutrophil accumulation were compared between nitric oxide‐depleted rats with deficient, normal, and increased vitamin E intake over 8 weeks. Thiobarbituric acid‐reactive substances and tissue‐associated myeloperoxidase activity were measured in gastric mucosa as indices of lipid peroxidation and neutrophil infiltration.

Results

: The total area of erosions was significantly increased in the vitamin E‐deficient group compared with the sufficient‐intake and vitamin‐supplemented groups. Both thiobarbituric acid‐reactive substances and myeloperoxidase activity also were significantly increased in the vitamin E‐deficient group compared with others. The total area of erosions closely paralleled the increases in both thiobarbituric acid‐reactive substances and myeloperoxidase activity.

Conclusion

: These results indicate that the inhibition of lipid peroxidation and interference with neutrophil infiltration by vitamin E may be responsible for its cytoprotective effect in ischaemia‐reperfusion.
A double‐blind, placebo‐controlled study of the efficacy and safety of non‐prescription ranitidine 75 mg in the prevention of meal‐induced heartburn
Authors: PAPPA  , WILLIAMS  , PAYNE  , BUARON  , MUSSARI  , CIOCIOLA
Published: March 2003

Background

: Ranitidine 75 mg (Zantac 75) has been shown to be effective for the treatment of pre‐existing heartburn symptoms.

Aim

: To compare the efficacy of dosing ranitidine 75 mg or placebo 30 min prior to a proven heartburn‐provoking meal in completely preventing or reducing subsequent heartburn symptoms.

Methods

: A randomized, double‐blind, parallel methodology was used at nine investigative centres. Following a screening visit, patients ate a standard test meal consisting of chilli, chips and a soft drink on two occasions. On the first occasion, patients received single‐blind placebo 30 min before the meal. This meal was used to qualify patients and to ensure the onset of a minimum level of heartburn. Patients who qualified were randomized (n = 284) to receive double‐blind ranitidine 75 mg or placebo 30 min before a second test meal administered 4–14 days later at the treatment visit. Patients recorded whether heartburn was present and rated heartburn severity by completing visual analogue scales at 15‐min intervals over the 4.5 h meal evaluation periods.

Results

: Statistically significant differences favouring ranitidine 75 mg were determined for complete prevention of heartburn (P < 0.006), heartburn severity area under the curve (P < 0.001), a clinical success end‐point (P < 0.001), and all other end‐points (P < 0.001).

Conclusions

: These data clearly demonstrate that ranitidine 75 mg is effective in completely preventing or decreasing heartburn when administered 30 min prior to a provocative meal.
Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans
Authors: HOND E. DEN , PEETERS  , HIELE  , BULTEEL  , GHOOS  , RUTGEERTS
Published: March 2003

Background

: Long‐term non‐steroidal anti‐inflammatory drug (NSAID) intake may induce increased intestinal permeability, eventually resulting in enteropathy. Because increased permeability might be related to cell damage resulting from energy depletion, it was hypothesized that glutamine—the major energy source of the intestinal mucosal cell—might prevent permeability changes.

Methods

: The 6‐h urinary excretion of 51Cr‐EDTA after an oral load of 51Cr‐EDTA was used in this study as a measure for intestinal permeability. Healthy volunteers underwent a series of permeability tests: (i) basal test; (ii) test following NSAID (indomethacin); (iii) test following NSAID in combination with glutamine and/or misoprostol.

Results

: The NSAID induced increased permeability in all volunteers. Pre‐treatment with glutamine (3 × 7 g daily, 1 week before NSAID‐dosing) did not prevent the NSAID‐induced increase in permeability. Multiple doses of glutamine close in time to NSAID‐dosing resulted in significantly lower permeability compared to the NSAID without glutamine. Co‐administration of misoprostol with the multiple‐dose scheme of glutamine resulted in a further reduction in the NSAID‐induced increase in permeability.

Conclusions

: Glutamine decreases the permeability changes caused by NSAID‐dosing when it is administered close in time, and misoprostol has a synergistic effect.
Changes in gastric mucosal ulcerogenic responses in rats with adjuvant arthritis: role of nitric oxide
Authors: Kato S. , Tanaka A. , Kunikata T. , Nishijima M. , Takeuchi K.
Published: March 2003

Aim

: To examine gastric mucosal ulcerogenic responses to indomethacin and HCl/ethanol in adjuvant arthritic (AA) rats.

Methods and Results

: Arthritis was induced in male Dark Agouti (DA) rats by injection of Freund's complete adjuvant (FCA) into the right hind paw. The gastric ulcerogenic response to indomethacin was markedly worsened in AA rats, depending on the degree of arthritic change. This aggravation of indomethacin‐induced gastric lesions in AA rats was significantly prevented by NG‐nitro‐L‐arginine methyl ester (L‐NAME) and amino‐guanidine as well as dexamethasone. In contrast, the mucosal ulcerogenic response to HCl/ethanol was inhibited in AA rats. The suppression of HCl/ethanol‐induced gastric lesions in AA rats was reversed almost totally by L‐NAME and aminoguanidine as well as dexamethasone and partly by indomethacin. The expression of inducible nitric oxide synthase (iNOS) mRNA was observed in the stomach of AA rats but not of normal rats. Moreover, the luminal releases of nitric oxide (NO) metabolites as well as prostaglandin (PG) E2 were significantly increased in AA rats.

Conclusions

: The gastric mucosal ulcerogenic responses were modified in AA rats, in different manners depending on the irritants; an increase in response to indomethacin and a decrease in response to HCl/ethanol. These changes may both be accounted for by increased production of NO by iNOS, and the latter is also partly related to increased production of PGs.
Helicobacter pylori, NSAIDs and cognitive dissonance
Authors: Hawkey C. J.
Published: March 2003

Helicobacter pylori and non‐steroidal anti‐inflammatory drugs (NSAIDs) each cause peptic ulcers but by different mechanisms. As a result, the effect of both of these risk factors together is not a synergistic enhancement of injury, ulceration or rates of complications. Indeed, there are circumstances under which patients infected with H. pylori are less prone to NSAID‐induced ulcers than those who are not infected or who have undergone eradication treatment. This may be because of opposite effects on gastric mucosal prostaglandin synthesis or for other reasons. Reluctance to accept that there may be specific circumstances where H. pylori is beneficial may arise because of the psychological process of cognitive dissonance.
The influence of Helicobacter pylori on oesophageal acid exposure in GERD during acid suppressive therapy
Authors: Peters  , Kuipers  , Ganesh  , Sluiter  , Klinkenberg‐Knol  , Lamers  , Kleibeuker
Published: March 2003

Background

: Helicobacter pylori exaggerates the effect of acid suppressive drugs on intragastric pH. It is unknown whether this is relevant for the treatment of GERD.

Aim

: To compare oesophageal acid exposure and symptoms in H. pylori‐negative and H. pylori‐positive GERD patients during low and profound acid suppression.

Methods

: Barrett’s oesophagus patients with gastro‐ oesophageal acid reflux were studied by 24‐h oesophageal pH‐metry at baseline and during randomized treatment with omeprazole 40 mg b.d. or ranitidine 150 mg b.d. H. pylori status was determined by a serum IgG ELISA. Symptoms were scored on a four‐graded scale.

Results

: Of 58 patients, 26 (14 H. pylori‐negative, 12 H. pylori‐positive) were randomized to omeprazole, 32 (16 H. pylori‐negative, 16 H. pylori‐positive) to ranitidine. At baseline, oesophageal acid exposure and symptoms did not differ between H. pylori‐negative and H. pylori‐positive: mean time proportion pH < 4 per 24 h was 16.1% (95% CI 11.5–23.2) in H. pylori‐negative, and 15.8% (11.3–21.4) in H. pylori‐positive patients. Omeprazole treatment resulted in a decrease of acid reflux per 24 h from 23.4% (7.9–39.3) to 0.0% (0.0–2.9) in H. pylori‐negative, and from 17.3% (8.9–38.8) to 0.1% (0.0–1.7) in H. pylori‐positive patients; ranitidine resulted in a decrease from 14.4% (10.5–18.5) to 9.3% (5.6–12.8) in H. pylori‐negative, and from 15.1% (9.8–21.0) to 9.0% (3.1–20.1) in H. pylori‐positive patients, the difference between H. pylori‐negative and H. pylori‐positive patients being N.S. There was no significant difference between H. pylori‐negative and H. pylori‐positive patients with respect to erect and supine acid reflux, or symptom scores in both treatment groups.

Conclusions

: H. pylori infection does not influence oesophageal acid reflux and symptoms in patients with Barrett’s oesophagus, either at baseline or during low as well as profound acid suppressive therapy. We conclude that the dose of acid suppression does not have to be titrated upon H. pylori status in GERD.
Low‐dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease
Authors: Casson  , Davies  , Thomson  , Lewis  , Walker‐Smith  , Murch
Published: March 2003

Background

: The management of acute fulminant colitis unresponsive to intravenous steroids is usually surgical. However, recent evidence suggests that intravenous administration of azathioprine at very high doses may allow more rapid onset of clinical efficacy, although its use has not previously been reported in the emergency situation.

Aim

: To report the successful use of intravenous azathioprine in the management of acute fulminant colitis complicating both Crohn’s disease and ulcerative colitis.

Method

: We initially used intravenous azathioprine because of the refusal of the family of the first patient to accept surgery following failure of conventional medical management. Importantly the azathioprine was successful at the low dose of 3 mg/kg.day, equivalent to standard oral doses. Two subsequent patients demonstrated a similar resolution. All were weaned successfully to oral azathioprine and have remained in long‐term endoscopic and histological remission.

Conclusion

: These preliminary data suggest that low‐dose intravenous azathioprine may be helpful adjunct therapy in selected cases of severe fulminant colitis. However, the need for close monitoring and daily surgical assessment remains paramount, and a formal trial of low‐dose intravenous azathioprine is required before it may be more widely recommended.
Effect of ranitidine bismuth citrate on the phospholipase A2 activity of Naja naja venom and Helicobacter pylori: a biochemical analysis
Authors: Ottlecz  , Romero  , Lichtenberger
Published: March 2003

Background

: Helicobacter pylori has become recognized as a fundamental pathogen in the development of gastritis and peptic ulcer disease. Bismuth compounds in combination with antibiotics are widely used to treat H. pylori associated peptic ulcer disease.

Methods

: In this study we measured and analysed the inhibitory effect of ranitidine bismuth citrate (RBC, Pylorid, Tritec) on the activity and kinetics of phospholipase A2 (PLA2) (E.C.3.1.1.4) of commercial cobra (Naja naja) venom and H. pylori (French press lysates) using
L‐α‐dipalmitoyl‐(2[1–14C]palmitoyl)‐phosphatidylcholine as substrate.

Results

: Our data suggest that RBC might exert a dose‐dependent uncompetitive inhibition on PLA2 activity of both H. pylori and Naja naja venom. the inhibitory effect of RBC on the PLA2 activity cannot be abolished by the optimal concentration of calcium (10 m
M), indicating its mechanism to be unrelated to the displacement of calcium from the activation site of the enzyme.

Conclusion

: Our results suggest that one of the mechanisms by which bismuth compounds are therapeutically effective in the treatment of H. pylori associated gastritis is by inhibiting the activity of the degradative PLA2 enzyme secreted by H. pylori. As a consequence of the inhibitory action of RBC on PLA2 of the bacteria, the extracellular and/or intracellular phospholipid components of the gastric mucosal barrier are preserved.
Review article: liver support systems in acute hepatic failure
Authors: Rahman  , Hodgson
Published: March 2003

The treatment of acute hepatic failure has developed rapidly over the last 40 years, reducing morbidity and mortality from this syndrome. Whilst this has been partly attributed to significant improvements in the specialist medical management of these patients, advances in surgical techniques and pharmaceutical developments have led to the establishment of successful liver transplantation programmes, which have improved mortality significantly.

This review will examine the clinical impact of alternative methods that have been used to provide extra‐corporeal hepatic support. Non‐biological, bio‐ logical and hybrid hepatic extra‐corporeal support will be explored, offering a comprehensive historical overview and an appraisal of present and future advances.
Helicobacter pylori treatment instead of maintenance therapy for peptic ulcer disease: the effectiveness of case‐finding in general practice
Authors: De Wit  , Quartero A. O. Puartero , Numans
Published: March 2003

Background

: Maintenance therapy with acid‐inhibiting medication is common in general practice. Since the eradication of Helicobacter pylori has become the treatment of choice for peptic ulcer disease, H. pylori treatment could replace maintenance therapy in patients with an ulcer history.

Aim

: To determine the effectiveness of a full peptic ulcer disease history case‐finding strategy, together with subsequent H. pylori testing and treatment, in discontinuing maintenance therapy.

Method

: Patients were included from seven general practices, who had been using acid‐inhibiting medication for more than 3 months in the period May 1996–May 1997. Patients with a history of proven peptic ulcer disease were tested, and treated with proton pump inhibitor‐triple therapy if positive. Maintenance therapy was discontinued and restart within 12 months was monitored.

Results

: Long‐term acid suppression was used by 2.8% of the practice‐populations. A peptic ulcer disease history was found in 18% of the patients, 73% of whom were offered the ‘H. pylori test and treat’ alternative. The majority responded: 92% of the H. pylori‐infected patients were treated, 78% of whom successfully discontinued long‐term medication.

Conclusion

: Implementing an ‘H. pylori test and treat’ strategy enabled one‐third of the patients with a peptic ulcer disease history to stop maintenance therapy successfully. The strategy contributes to reduction of long‐term drug use, but compliance needs improvement.
Nα‐methyl histamine and histamine stimulate gastrin release from rabbit G‐cells via histamine H2‐receptors
Authors: Bliss  , Healey  , Arebi  , Calam
Published: March 2003

Background:

Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3‐receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nα‐methyl histamine (NαMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine.

Aim:

To determine the direct effects of histamine receptor agonists on isolated gastrin cells.

Methods:

Rabbit G‐cells were prepared by countercurrent elutriation and cultured on 24‐well plates.

Results:

NαMH (10–6–10–4 M) caused a dose‐dependent increase in gastrin release from a basal level of 2.3 ± 0.2% total cell content (TCC; mean ± S.E.M.) to a maximum of 5.1 ± 0.7%, an increase of 117% (P < 0.005) above basal. This was abolished by the H2‐antagonist ranitidine (10–5 M), but not by immunoblockade with anti‐somatostatin antibody, the H1‐antagonist chlorpheniramine (10–5 M) or the H3‐antagonist thioperamide (10–4 M). The histamine H2‐receptor agonist dimaprit (10–6–10–4 M) increased gastrin release from 2.4 ± 0.2% to 3.6 ± 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10–7–10–4 M) from a basal value of 3.0 ± 0.3% to 5.4 ± 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10–5 M) (P < 0.01).

Conclusion:

NαMH and histamine release gastrin from G‐cells via H2‐receptors; this might contribute to H. pylori‐associated hypergastrinaemia.
N‐bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation
Authors: Wallace  , Dicay  , Mcknight  , Bastaki  , Blank
Published: March 2003

Background:

Nitrogen‐containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget’s disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations.

Methods:

An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N‐bisphosphonates.

Results:

Alendronate and pamidronate caused a concentration‐dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow.

Conclusions:

These results suggest that these N‐bis‐ phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.
Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients
Authors: Jones  , Holtmann  , Rodrigo  , Ehsanullah  , Crompton  , Jacques  , Mills
Published: March 2003

Background

: Irritable bowel syndrome is one of the most common gastrointestinal disorders, yet no therapy convincingly controls the multiple symptoms of this syndrome.

Aim

: To compare the efficacy and tolerability of the new 5‐HT3‐receptor antagonist alosetron and the smooth muscle relaxant mebeverine in a double‐blind, multicentre, randomized trial.

Methods

: Six hundred and twenty‐three nonconstipated females with irritable bowel syndrome were randomized to receive alosetron 1 mg twice daily (n=319) or mebeverine 135 mg three times daily (n=304) for 12 weeks, followed by a 4‐week post‐treatment period. The primary efficacy end‐point was monthly responders for adequate relief of irritable bowel syndrome related abdominal pain and discomfort (defined as patients reporting adequate relief on at least 2 out of 4 weeks). Secondary end‐points included assessments of bowel function, including urgency, stool frequency and stool consistency.

Results

: There were significantly more responders in the alosetron group compared with mebeverine at months 2 and 3 (P < 0.01). Compared with mebeverine, the alosetron group experienced significant decreases in proportion of days with urgency and mean stool frequency, and had firmer stools within 1 week of starting treatment. A similar proportion of patients reported adverse events in the two treatment groups.

Conclusions

: In nonconstipated female irritable bowel syndrome patients, alosetron is significantly more effective than mebeverine in improving symptoms.
Nasogastric lansoprazole is effective in suppressing gastric acid secretion in critically ill patients
Authors: Tsai  , Poon  , Yu  , Chang  , Yeh  , Ko  , Chen
Published: March 2003

Aim:

To evaluate the effect of nasogastric lansoprazole on acid suppression in critically ill patients.

Methods:

Patients were eligible for the study if they had a nasogastric tube in place and had not received acid‐suppressive agents for 3 days prior to enrolment into the study. Patients with active gastrointestinal bleeding or a baseline gastric pH > 4.0 were excluded. Patients served as their own controls during a 24 h lead‐in period. Lansoprazole 30 mg was administered once daily with water through a nasogastric tube for 2 days. Intragastric pH was measured by continuous 24 h pH‐metry for 3 days.

Results:

Fifteen patients were enrolled into the study. The baseline median 24 h intragastric pH was 2.25 ± 1.01, and increased to 6.70 ± 0.82 (P= 0.001) after 2 days of lansoprazole. Mean percentage of time intragastric pH was ≥ 4.0 was 25 ± 13% at baseline, and increased to 84 ± 14% (P=0.001) after 2 days of lansoprazole.

Conclusions:

Nasogastric lansoprazole 30 mg daily is effective in suppressing gastric acid secretion in critically ill patients.
The effects of capsaicin on reflux, gastric emptying and dyspepsia
Authors: Rodriguez‐Stanley  , Collings  , Robinson  , Owen  , Miner
Published: March 2003

Aims:

To evaluate capsaicin’s effects on heartburn, dyspepsia, gastric acidity and emptying, and gastro‐oesophageal reflux, and to test the hypothesis that capsaicin induces heartburn and exacerbates symptoms by sensitizing the oesophagus.

Methods:

Eleven heartburn sufferers underwent two separate pH monitoring sessions and assessments of gastric emptying (13C‐octanoic acid breath test), heartburn and dyspepsia (100 mm VAS) after a non‐irritant meal. The meal consisted of a sausage biscuit with egg, cheese and 30 g raw onion, 8 oz chocolate milk and a peppermint patty. Thirty minutes prior to meal consumption, subjects were administered a placebo capsule. On visit 1, subjects consumed the meal containing 100 μl 13C‐octanoic acid cooked in the egg, over 15 min. On visit 2, subjects consumed the meal plus 5 mg capsaicin in gelatin capsules.

Results:

Oesophageal and gastric pH profiles and gastric emptying were not different between meals. Capsaicin did not alter mean heartburn and dyspepsia scores (P > 0.05), but significantly decreased time to peak heartburn (120 min vs. 247 min; P < 0.003). Time to peak dyspepsia was not altered by capsaicin (P > 0.05).

Conclusion:

Capsaicin enhances noxious postprandial heartburn, presumably by direct effects on sensory neurons.
Endothelial changes precede mucosal ulceration induced by indomethacin: an experimental study in the rat
Authors: Kelly  , Anthony  , Piasecki  , Lewin  , Pounder  , Wakefield
Published: March 2003

Background

: Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat.

Aim

: To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium.

Methods

: In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 μg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion‐fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy.

Results

: All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger‐like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger‐like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration.

Conclusion

: This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.
The effect of motilin agonist ABT‐229 on gastro‐oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients
Authors: Van Herwaarden  , Samsom  , Van Nispen  , Verlinden  , Smout
Published: March 2003

Background:

ABT‐229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans.

Aim:

To investigate the effect of oral treatment with ABT‐229 10 mg b.d., ABT‐229 5 mg b.d. and cisapride 10 mg q.d.s. on gastro‐oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients.

Methods:

Twenty‐four GERD patients completed the study. A randomized, double‐blind, placebo‐controlled, three‐period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT‐229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT‐229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water‐perfused manometric system.

Results:

Oesophageal acid exposure was not affected by ABT‐229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT‐229 10 mg b.d. and cisapride reduced the severity of daytime heartburn.

Conclusion:

The value of ABT‐229 in the treatment of GERD appears to be limited.
Beta(β)3‐adrenergic receptors in human pancreatic islet and duodenal somatostatin neuroendocrine cells
Authors: Anthony  , Sim  , Guillaume  , Strosberg  , Dhillon  , Pounder  , Wakefield
Published: March 2003

Background:

We previously localized β3‐adrenergic receptors immunohistochemically in human gastrointestinal smooth muscle and incidently found a population of human pancreatic islet cells and duodenal epithelial neuroendocrine cells that also expressed β3‐adrenergic receptors.

Aim:

To identify the nature of the islet and duodenal cells that stained positive for β3‐adrenergic receptors.

Methods:

Paraffin sections of human pancreas and duodenum and Chinese hamster ovary cells transfected with the human β3‐adrenergic receptor were immuno‐stained for β3‐adrenergic receptors using an affinity‐purified rabbit polyclonal antibody (anti‐P12) raised against a 15 amino acid sequence (P12) of the human receptor. Immunohistochemical staining for the receptor was carried out in the presence and absence of P12 peptide and both somatostatin 14 and 18 peptides. β3‐adrenergic receptor‐stained sections were also double‐immunostained with anti‐insulin, ‐glucagon, ‐somatostatin and ‐pancreatic polypeptide antibodies.

Results:

A subpopulation of human pancreatic islet cells and duodenal epithelial cells expressed positive cytoplasmic β3‐adrenergic receptor immunostaining. Using distribution and double‐staining techniques, these cells were found to be somatostatin‐positive D cells but not A or B cells. The positive staining of D cells with anti‐P12 antibody was inhibited by prior incubation of the antibody with P12 peptide but not somatostatin‐14 or ‐28 peptides. Pancreatic vascular smooth muscle and duodenal vascular and non‐vascular smooth muscle also stained with anti‐P12 antibody. Transfected Chinese hamster ovary cells showed positive membrane staining.

Conclusion:

We have identified a population of neuroendocrine cells in the human pancreas and duodenum that express β3‐adrenergic receptors. These cells appear to be somatostatin D cells.
The control of gastric acid and Helicobacter pylori eradication
Authors: Sachs G. , Shin J. M. , Munson K. , Vagin O. , Lambrecht N. , Scott D. R. , Weeks D. L. , Melchers K.
Published: March 2003

This review focuses on the gastric acid pump as a therapeutic target for the control of acid secretion in peptic ulcer and gastro‐oesophageal reflux disease. The mechanism of the proton pump inhibitors is discussed as well as their clinical use. The biology of Helicobacter pylori as a gastric denizen is then discussed, with special regard to its mechanisms of acid resistance. Here the properties of the products of the urease gene clusters, ureA, B and ureI, E, F, G and H are explored in order to explain the unique location of this pathogen. The dominant requirement for acid resistance is the presence of a proton gated urea transporter, UreI, which increases access of gastric juice urea to the intrabacterial urease 300‐fold. This enables rapid and continuous buffering of the bacterial periplasm to ≈ pH 6.0, allowing acid resistance and growth at acidic pH in the presence of 1 m
M urea. A hypothesis for the basis of combination therapy for eradication is also presented.
Gastrin and Colorectal Cancer
Authors: Smith A. M. , Watson S. A.
Published: March 2003

The polypeptide hormone gastrin was identified nearly a hundred years ago and its role in the regulation of acid secretion is well established. Gastrin also acts as a growth factor and is trophic for the normal gastric oxyntic mucosa. This growth promoting action has led to the extensive investigation of its role in carcinogenesis, in particular colorectal neoplasia. The relationship between gastrin and colorectal adenocarcinoma has been subject to controversy, however the findings from several recent studies have resulted in a clearer understanding of the mechanism of action of gastrin in this is common cancer.

The majority of colorectal cancers produce their own gastrin, which may act in an autocrine manner. The tumour cells also express gastrin/CCKB receptors (and/or a combination of isoforms) which mediate the proliferative action. This locally produced gastrin gives rise to a small increase in systemic gastrin levels. Autocrine gastrin may also have a role in tumour development, as expression occurs early in the adenoma–carcinoma sequence. In addition, several studies using animal models have shown that systemic hypergastrinaemia promotes the proliferation of both normal and neoplastic colonic epithelium. Hyperproliferative colonic epithelium in the presence of hypergastrinaemia has been recorded in humans and a well‐designed epidemiological study has demonstrated an increased incidence of colorectal cancer.

Gastrin is a potential therapeutic target in the treatment of colorectal cancer and several approaches have been assessed. Receptor antagonists and antisecretory agents have been demonstrated to be ineffectual. Novel methods of inhibition, including the use of anti‐gastrin antibodies, are currently being evaluated.
Gastric acid secretion in dogs in response to combinations of beer, ethanol and peptone meal – the role of endogenous gastrin
Authors: Matsuno K. , Sasaki N. , Okabe S.
Published: March 2003

Aim: To examine the effects of beer, ethanol, peptone meal and combinations of either peptone meal and beer or peptone meal and ethanol on gastric acid secretion in vagally denervated pouch dogs.

Methods and Results: The oral administration of either 200 mL of beer, 5% ethanol or 10% peptone meal significantly stimulated gastric acid secretion for 60–90 min in these dogs. With 5% ethanol the plasma gastrin concentration was not affected for 90 min. Combinations of 10% peptone and beer (peptone–beer) or 10% peptone and 5% ethanol (peptone–ethanol) potentiated the acid secretion and increased the plasma gastrin level. While a selective cholecystokinin‐B/gastrin receptor antagonist, S‐0509, had no effect on ethanol‐stimulated acid secretion, the compound markedly inhibited both peptone–beer‐stimulated and peptone–ethanol‐stimulated gastric acid secretion. Famotidine and atropine significantly inhibited gastric acid secretion stimulated by 5% ethanol, peptone–beer and peptone–ethanol.

Conclusions: The mechanisms by which peptone–beer and peptone–ethanol stimulate gastric acid secretion may be mediated not only by increased plasma gastrin, but also by the action of histamine and acetylcholine coupled with the increased plasma gastrin. Ethanol‐stimulated secretion appears to be unrelated to circulating gastrin, yet may be related to the acid regulatory mechanism involving histamine and acetylcholine.
Protective role of intracellular glutathione against nitric oxide‐induced necrosis in rat gastric mucosal cells
Authors: Naito Y. , Yoshikawa T. , Boku Y. , Fujii T. , Masui Y. , Tanaka Y. , Fujita N. , Yoshida N. , Kondo M.
Published: March 2003

Background: Nitric oxide synthase activity is increased in the stomach in association with Helicobacter pylori infection and portal hypertension, but the mechanism by which nitric oxide contributes to mucosal damage remains unclear.

Aim: To examine whether nitric oxide injures gastric mucosal cells and whether cellular glutathione affects nitric oxide‐induced cytotoxicity.

Methods: A confluent monolayer of RGM‐1 gastric mucosal cells was exposed to nitric oxide donors (NOC5 or NOC12). Cell viability was determined by trypan blue dye exclusion, lactate dehydrogenase release and supravital staining with Hoechst 33342 and propidium iodide. The kinetics of the reduced/oxidized forms of glutathione were also measured, as well as the effect of glutathione‐depletion or glutathione‐precursor treatment on nitric oxide‐induced cytotoxicity.

Results: Excess exogenous nitric oxide produced by NOC5 or NOC12 induced necrosis in RGM‐1 cells in a time‐ and concentration‐dependent manner. The level of reduced glutathione drastically decreased prior to the loss of cell viability and remained low, but oxidized glutathione was not affected. Glutathione depletion increased necrosis of both NOCs in an NOC‐concentration‐related fashion, while pre‐treatment with γ‐glutamylcysteine ethyl ester reduced their necrotic susceptibility.

Conclusion: Exogenous nitric oxide induced necrosis in gastric mucosal cells, and intracellular reduced glutathione protects gastric mucosal cells from damage by nitric oxide.
Effects of growth factors on aspirin‐induced inhibition of wound repair in a rabbit gastric epithelial cell model
Authors: Yoshizawa T. , Watanabe S. , Hirose M. , Yamamoto J. , Osada T. , Sato K. , Oide H. , Kitamura T. , Takei Y. , Ogihara T. , Miwa H. , Miyazaki A. , Sato N.
Published: March 2003

Background: Aspirin is known to cause adverse effects, including gastric mucosal injury, and to retard gastric wound healing. Growth factors including hepatocyte growth factor (HGF), epidermal growth factor (EGF) and insulin‐like growth factor‐I (IGF‐I) have been shown to play an important role in the repair of gastric mucosal injury.

Aim: To employ the cultured gastric epithelial cell model to elucidate the effects of aspirin, as well as several growth factors (HGF, EGF and IGF‐I), on gastric wound repair.

Methods: Isolated rabbit gastric epithelial cells (92% mucous cells) were cultured in F‐12 medium and formed a complete monolayer cell sheet in 48 h. A wound with a cell‐free area of constant size (2 mm
2) was then created and the wound repair process was monitored by measuring wound size every 12 h. Proliferating cells were detected by BrdU staining. Effects of aspirin (8 m
m), HGF (10 ng/mL), EGF (10 ng/mL) and IGF‐I (30 ng/mL) were assessed.

Results: Aspirin significantly retarded wound healing, but simultaneous addition of growth factors significantly accelerated wound repair compared with aspirin alone. Growth factors reversed the aspirin‐induced inhibition of cell proliferation.

Conclusion: Growth factors, including HGF, EGF and IGF‐I, reversed the aspirin‐induced inhibition of wound repair through their cytoprotective effects on gastric epithelial cells.
Comparison between in vivo and in vitro chemokine production in Helicobacter pylori infection
Authors: Ohsuga M. , Kusugami K. , Ina K. , Ando T. , Yamaguchi H. , Imada A. , Nishio Y. , Shimada M. , Tsuzuki T. , Noshiro M. , Konagaya T. , Kaneko H.
Published: March 2003

Background: Enhanced gastric mucosal chemokine activity has been demonstrated in patients with Helicobacter pylori infection. However, little is known about the mechanisms involved in this phenomenon.

Aim: To examine whether in vivo chemokine activity is similar to in vitro response of gastric epithelial cells infected by H. pylori.

Patients and Methods: Antral biopsy specimens were obtained from patients with H. pylori infection for organ culture, isolation of H. pylori and histological examination.

Results: In organ cultures of mucosal tissues, the levels of interleukin‐8 and growth‐related gene product α were elevated in patients with peptic ulcer disease compared with those with erosive gastritis or endoscopically normal mucosa. However, there were no significant differences in in vitro cultures of MKN45 or KATO III cells that were infected with H. pylori isolated from these same patients. These in vivo and in vitroα‐chemokine levels showed no significant association with the presence of cagA gene and CagA protein, ureB genotype, or binding capacity to MKN45 or KATO III cells in individual H. pylori isolates. In contrast, in vivo mucosal α‐chemokine activity correlated with H. pylori colonization density.

Conclusion: Mucosal chemokine profiles and inflammatory responses in H. pylori infection may be associated more closely with host factors, including those determining bacterial adhesiveness, than with differences in H. pylori strains.
Review article: in vitro studies of gall‐bladder smooth muscle function. Relevance in cholesterol gallstone disease
Authors: Portincasa P. , Minerva F. , Moschetta A. , Venneman N. , Vanberge‐Henegouwen G. P. , Palasciano G.
Published: March 2003

The interplay between contraction and relaxation in the gall‐bladder muscularis leads to appropriate gall‐bladder emptying and refilling during fasting and in the postprandial state in vivo. Several studies in both human and animal models have focused on cellular and molecular events in the gall‐bladder wall in health and disease in vitro. Principal methods to study gall‐bladder smooth muscle function include receptor binding studies (at the level of plasmamembranes or histological sections), phase contrast microscopy (at the level of isolated smooth muscle cells), and tensiometry (at the level of smooth muscle strips or the whole gall‐bladder). At a very early stage, cholesterol gallstone disease is characterized by exposure of the gall‐bladder wall to excess of biliary cholesterol and the cytotoxic effect of the bile salt deoxycholate. On a long‐term basis, a form of gall‐bladder leiomyopathy develops with defects involving the mechanisms of signal transduction at the level of plasmamembranes. The end‐stage result is pathological contraction and/or relaxation of smooth musculature, impaired gall‐bladder motility and gall‐bladder stasis, all key factors in the pathogenesis of biliary cholesterol crystallization and gallstones.