Showing papers in "Alimentary Pharmacology & Therapeutics in 1998"

Review article: short chain fatty acids in health and disease

Abstract: Short chain fatty acids (SCFAs) have been the subject of much research over the past few decades. They play a vital role in maintenance of colonic integrity and metabolism. They are produced when dietary fibre is fermented by colonic bacteria. SCFAs are avidly absorbed in the colon, at the same time as sodium and water absorption and bicarbonate secretion. Once absorbed, SCFAs are used preferentially as fuel for colonic epithelial cells and have trophic effects on the epithelium. Clinically, SCFAs have been studied as possible therapeutic agents in diversion colitis, ulcerative colitis, radiation proctitis, pouchitis and antibiotic-associated diarrhoea. Although some promising effects have been observed in uncontrolled studies, a specific therapeutic role for SCFAs remains to be defined. SCFAs may be the effector of the beneficial role of fibre in prevention of colon cancer.

Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies)

Abstract: Background: The efficacy of H2-receptor antagonists in functional dyspepsia is equivocal and the therapeutic place of proton pump inhibitors in functional dyspepsia is unknown. Aim: To evaluate the efficacy of proton pump inhibitor therapy in functional dyspepsia. Methods: Patients (n = 1262) with a clinical diagnosis of functional dyspepsia (persistent or recurrent epigastric pain or discomfort for at least 1 month and a normal upper gastrointestinal endoscopy) were randomized to receive omeprazole 20 mg, 10 mg or identical placebo, for 4 weeks. Symptoms were assessed using validated measures. Helicobacter pylori status was determined pre-entry by a 13C-urea breath test. Results: On an intention-to-treat analysis (n=1248), complete symptom relief was observed in 38% on omeprazole 20 mg, compared with 36% on omeprazole 10 mg and 28% on placebo (P = 0.002 and 0.02, respectively). Among those with ulcer-like and reflux-like dyspepsia, complete symptom relief was achieved in 40% and 54% on omeprazole 20 mg, and 35% and 45% on omeprazole 10 mg, respectively, compared with 27% and 23% on placebo (all P < 0.05, except omeprazole 10 mg in ulcer-like dyspepsia, P = 0.08). There was no significant benefit of omeprazole over placebo in dysmotility-like dyspepsia. Symptom relief was similar in H. pylori-positive and negative cases. Conclusions: Omeprazole is modestly superior to placebo in functional dyspepsia at standard (20 mg) and low doses (10 mg) but not in patients with dysmotility-like dyspepsia.

Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome

Abstract: Background: Visceral hypersensitivity plays a major role in the pathophysiology of irritable bowel syndrome, as shown by balloon distension studies. 5-HT3 receptors on afferent nerves may modulate visceral sensitivity and be the target of new treatments for irritable bowel syndrome. Aim: To evaluate the effects of alosetron, a potent and selective 5-HT3 antagonist, on the perception of colonic distension by patients with irritable bowel syndrome, and on the colonic compliance to distension with a barostat. Methods: Twenty-five irritable bowel syndrome patients were included in a randomized double-blind parallel group trial; data were available for 22 (Rome criteria; 48 ± 11 years; 13 men and nine women). Patients were treated for 7 days with placebo (n = 6), alosetron 0.25 mg b.d. (n = 8) or alosetron 4 mg b.d. (n = 8). On day 6, a barostat bag was placed in the left colon. On day 7, after an overnight fast, isobaric phasic distensions were performed (4 mmHg steps, 5 min) up to the step triggering a sensation of abdominal pain. Results: Groups were comparable at inclusion (age, sex, symptoms, bowel habits). There were no differences between treatment groups in pressure recorded within the bag at the time of first sensation of abdominal pain. However, bag volumes were significantly increased. At the first sensation threshold, median volume differences of 61 mL and 90 mL (P = 0.028) were recorded with alosetron 0.25 mg b.d. and 4 mg b.d., respectively. At the threshold of abdominal pain, these differences were 71 mL (P = 0.039) and 84 mL (P = 0.017). Colonic compliance increased from 5.9 mL/mmHg on placebo to 7.6 mL/mmHg on alosetron 0.25 mg b.d. and to 9.8 mL/mmHg (P = 0.034) on alosetron 4 mg b.d. Conclusion: Alosetron increases the compliance of the colon to distension, and could thereby contribute to changes in perception of colonic distension and improvement in the symptoms of irritable bowel syndrome.

glycyrrhizin as a potential treatment for chronic hepatitis C

Abstract: Chronic hepatitis C is a slowly progressive liver disease that may evolve into cirrhosis with its potential complications of liver failure or hepatocellular carcinoma. Current therapy with α-interferon is directed at viral clearance, but sustained response is only achieved in 20–40% of patients without cirrhosis, and less than 20% in patients with cirrhosis who have the greatest need for therapy. Treatment for those who do not respond to anti-viral therapy is highly desirable. In Japan glycyrrhizin has been used for more than 20 years as treatment for chronic hepatitis. In randomized controlled trials, glycyrrhizin induced a significant reduction of serum aminotransferases and an improvement in liver histology compared to placebo. Recently, these short-term effects have been amplified by a well-conducted retrospective study suggesting that long-term usage of glycyrrhizin prevents development of hepatocellular carcinoma in chronic hepatitis C. The mechanism by which glycyrrhizin improves liver biochemistry and histology are undefined. Metabolism, pharmacokinetics, side-effects, and anti-viral and hepatoprotective effects of glycyrrhizin are discussed.

Gastrointestinal pH profiles in patients with inflammatory bowel disease

Abstract: Background: 5-Amino salicylic acid preparations are used in therapy for patients with inflammatory bowel diseases. The bioavailability of these drugs depends on their coating. Aim: To determine whether intraluminal pH is decreased by the presence of inflammation, thereby altering the release of 5-amino salicylic acid in the intestinal lumen. Methods: Intraluminal gastrointestinal pH was measured by means of a radiotelemetry capsule in 12 healthy controls, in 12 patients with Crohn’s disease (five with active disease), and in 11 patients with ulcerative colitis (seven with active disease). Results: The median gastric pH values in the patient groups (Crohn’s disease 2.4, range 1.5–4.1; ulcerative colitis 1.95, range 1.55–4.4) were significantly higher than those observed in the controls (1.55, range 0.95–2.6). In the small bowel and colonic segments, all the pH values of Crohn’s disease patients were comparable to those of the controls, as were the pH values in the proximal small intestine and in the left colon in patients with ulcerative colitis. However, the latter group had higher pH values in the terminal ileum, the caecum and the right colon. Patients with active disease had comparable median gastrointestinal pH values to patients in remission. Conclusions: The luminal release of 5-amino salicylic acid might not be inhibited by low pH in patients with active inflammatory bowel diseases. This supports a safe disintegration of the slow release mesalazine preparations even in the presence of severe disease.

Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors.

Abstract: Background Nocturnal gastric acid breakthrough, defined as intragastric pH < 4 for more than 1 h in the overnight period, is observed in up to 70% of normal subjects on proton pump inhibitors taken twice daily. The frequency of this breakthrough in patients with gastro-oesophageal reflux and accompanying oesophageal reflux during this period has not been studied. Aim To examine the frequency of nocturnal breakthrough and accompanying oesophageal acid exposure in patients with gastro-oesophageal reflux treated with proton pump inhibitors twice daily. Methods Prolonged ambulatory pH records from 76 patients on twice daily proton pump inhibitors between January 1991 and July 1997 were analysed for the presence of nocturnal gastric acid breakthrough and accompanying oesophageal pH < 4. Studies from 31 normal subjects on twice daily proton pump inhibitors constituted the control group. Results Nocturnal gastric acid breakthrough was seen in 70% of 61 patients with gastro-oesophageal reflux, 80% of 15 patients with Barrett’s oesophagus and 67% of normal controls (P = N.S.). Oesophageal acid exposure was seen in 33% of gastro-oesophageal reflux patients, 50% of Barrett’s oesophagus patients and 8% of normal controls (P < 0.03). No difference was found between patients taking omeprazole or lansoprazole. Conclusion Nocturnal acid breakthrough is frequently seen on proton pump inhibitors twice daily and is often accompanied by oesophageal reflux. This has important implications for medical therapy in patients with severe gastro-oesophageal reflux and Barrett’s oesophagus.

Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily

Abstract: Background On chronic intake of omeprazole, most healthy volunteers and patients still have nocturnal acid breakthrough (NAB), defined as night-time periods with gastric pH < 4.0 lasting for longer than 1 h. Gastro-oesophageal reflux during NAB may be particularly injurious to the oesophageal mucosa, contributing to the chronic lesions complicating the condition. Aim To compare the effect of three different dosing regimens of omeprazole 40 mg daily with regard to suppressing nocturnal gastric acidity and avoiding NAB. Methods Eighteen healthy volunteers were given three different regimens of omeprazole for 7 days each in randomized order: 40 mg before breakfast (qAM), 40 mg before dinner (qPM) and 20 mg before breakfast and dinner (b.d.). On day 7, 24-h intragastric and intra-oesophageal pH-metry was performed. Tracings were analysed for the period from 22.00 h until 06.00 h with regard to the percentage of time at which gastric pH was below 4.0, 3.0 and 2.0, and also the occurrence and duration of NAB. Results Nocturnal acid breakthrough was significantly more common on qAM than on qPM and b.d. (P < 0.05) dosing. The percentage of time gastric pH was less than 4.0 overnight was significantly lower on qPM (median 31.3) and b.d. (median 20.5) than on qAM (median 66.3) dosing (P = 0.01 and P < 0.02, respectively). A pH threshold of 3 and 4 showed the same differences, as did median 24-h gastric pH. Daytime acidity was not significantly different. Conclusions In healthy volunteers, dinner time or split dosing of omeprazole 40 mg daily is significantly more effective than dosing before breakfast in preventing NAB and controlling gastric acidity. These regimens should be preferred in patients in whom suppression of nocturnal gastric acidity is desirable.

A placebo‐controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24‐h intragastric acidity and plasma gastrin concentrations in young healthy male subjects

Abstract: Background: Rabeprazole (LY307640, E3810) is a new, potent, proton pump inhibitor. A single daily 20 mg dose significantly decreases 24-h intragastric acidity. There are no data currently available directly comparing the effect of rabeprazole on 24-h acidity with established proton pump inhibitors. Aim: To compare the effects of rabeprazole 20 mg o.m. and omeprazole 20 mg o.m. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind, placebo-controlled trial, in healthy H. pylori-negative subjects. Methods: Twenty-four healthy male volunteers, negative for H. pylori infection by serology and 13C-urea breath test, were studied on the 1st and 8th day of dosing with either placebo, rabeprazole 20 mg or omeprazole 20 mg, once each morning, in a crossover fashion. On days 1 and 8, hourly intragastric acidity was measured by gastric aspiration for 24 h from 08.00 hours. On day 8, plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, then every 2 h thereafter. Results: A single dose of both rabeprazole and omeprazole significantly decreased 24-h intragastric acidity compared with placebo. The 24-h acidity on day 1 was significantly decreased for rabeprazole compared with omeprazole (331 vs. 640 mmol.h/L, P 3 and> 4. On day 8 of dosing, the decrease in 24-h intragastric acidity was greater with rabeprazole than with omeprazole, but the difference was not statistically significant (160 vs. 218 mmol.h/L, P = 0.1). However, 24-h plasma gastrin concentration (1687 vs. 1085 pmol.h/L, P 3 (69 vs. 59%, P = 0.008) and> 4 (60 vs. 51%, P = 0.03) were significantly greater. Conclusions: Rabeprazole 20 mg once daily has a significantly faster onset of antisecretory activity than omeprazole 20 mg once daily. After 8 days the differences in intragastric pH > 3 and> 4 holding times persisted, but there was no significant difference in 24-h acidity.

Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users.

Abstract: Aim: To investigate the efficacy of omeprazole 20 mg o.m. as primary prophylaxis against non-steroidal anti-inflammatory drug (NSAID)-associated ulcer disease or dyspeptic symptoms. Methods: A parallel group study compared patients randomized to receive omeprazole 20 mg o.m. or placebo as co-therapy with on-going NSAID treatment, over 6 months, in 19 specialist centres in Ireland, Hungary, France, the UK and the USA. One hundred and sixty-nine patients taking NSAIDs regularly, chronically and above defined minimum doses entered the trial. The main outcome measure was the development of gastric or duodenal ulcers detected endoscopically, the development of multiple erosions in the stomach or duodenum, or the onset of moderate or severe dyspeptic symptoms. Results: The estimated probability of remaining free of these end-points for 6 months for patients taking omeprazole was 0.78 compared to 0.53 for placebo (P = 0.004). Fourteen patients receiving placebo (16.5%) developed 15 ulcers, comprising nine gastric and six duodenal ulcers, compared to three patients (3.6%) receiving omeprazole (all gastric ulcers). Logistic regression analysis showed that older patients were less likely, whilst those with rheumatoid arthritis were more likely, to remain free of NSAID-associated problems. Conclusions: Omeprazole is an effective agent for gastroduodenal prophylaxis in patients taking NSAIDs. Its main effect is to reduce the rate of development of gastric and duodenal ulcers.

Psyllium is superior to docusate sodium for treatment of chronic constipation.

Abstract: Background: Stool softening is a physician’s first step in the management of chronic constipation. Aim: To compare stool softening (stool water content) and laxative efficacy of psyllium hydrophilic mucilloid vs. docusate sodium. Methods: The multi-site, randomized, double-blind, parallel-design study of 170 subjects with chronic idiopathic constipation involved a 2-week baseline (placebo) phase followed by 2 weeks of treatment. The treatment phase compared psyllium (5.1 g b.d.) plus docusate placebo to docusate sodium (100 mg b.d.) plus psyllium placebo. Stools were collected and assessed. Results: Compared to baseline, psyllium increased stool water content vs. docusate (psyllium 2.33% vs. docusate 0.01%, P = 0.007). Psyllium also increased stool water weight (psyllium 84.0 g/BM; docusate 71.4 g/BM; P = 0.04), total stool output (psyllium 359.9 g/week; docusate 271.9 g/week; P = 0.005), and O’Brien rank-type score combining objective measures of constipation (psyllium 475.1; docusate 403.9; P = 0.002). Bowel movement (BM) frequency was significantly greater for psyllium (3.5 BM/week) vs. docusate (2.9 BM/week) in treatment week 2 (P = 0.02), with no significant difference (P > 0.05) between treatment groups in treatment week 1 (3.3 vs. 3.1 BM/week). Conclusion: Psyllium is superior to docusate sodium for softening stools by increasing stool water content, and has greater overall laxative efficacy in subjects with chronic idiopathic constipation.

Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta‐analysis?

Abstract: Background: Controversies surrounding medical treatment in patients with unresectable hepatocellular carcinoma continue to persist. Aim: To perform a meta-analysis of therapeutic modalities which had been evaluated in two or more randomized trials. Methods: Fifty-two randomized trials were studied; only 30 were included. This overview identified seven therapeutic modalities which had been evaluated in two or more trials: adriamycin, 5-fluorouracil, interferon, percutaneous ethanol injection, transarterial chemotherapy, the combination of lipiodol with transarterial chemotherapy, and tamoxifen. Results: Comparisons of survival between control groups showed substantial heterogeneity. There was no survival benefit at 1 year with adriamycin (mean difference 4%), 5-fluorouracil (mean difference −3%), percutaneous ethanol injection (mean difference 6%) or transarterial chemotherapy (mean difference −2%). For interferon, the survival benefit was significant with the Der Simonian & Laird method (mean difference 9%, 95% CI = 1–18%, P = 0.04) but not with the Peto et al. method (2.4 mean odds ratio, 95% CI = O.9–6.8). The meta-analysis of tamoxifen showed a borderline survival benefit (mean difference 25%, 95% CI = 0–49%, P = 0.05). However, in sensitivity analyses, the survival benefit of tamoxifen was no longer significant. Conclusions: No treatment has clearly proven efficacy in survival. 5-Fluorouracil, adriamycin and transarterial chemotherapy were not associated with survival benefit at 1 year. The number of randomized controlled trials was insufficient to enable a conclusion to be reached for interferon and percutaneous ethanol injection. Controversy persists concerning tamoxifen efficacy. Interferon and tamoxifen require new randomized controlled trials on a larger population of patients.

Review article: the use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease

Abstract: There is presently a lack of well conducted clinical trials demonstrating any significant benefits of probiotics in humans. With the exception of diarrhoea due to rotavirus infection in children there is little evidence from randomized, double-blind, placebo-controlled studies that bacterial probiotics have a significant beneficial action in preventing diarrhoea of any cause. The yeast Saccharomyces boulardii has been shown to be of benefit in the prevention of antibiotic-associated diarrhoea but not in preventing infection with Clostridium difficile. S. boulardii may also be of benefit in preventing relapse of C. difficile infection. Because of the simplicity of in vitro systems and some animal models, beneficial characteristics of probiotics such as the ability of bacteria to bind to epithelial surfaces are not always transferable to humans. Thus any postulated benefit from consumption of probiotic bacteria should only be accepted as fact after testing in clinical studies. This review outlines our present knowledge of the mode of action of probiotics and presents the data from clinical trials on their use.

The influence of cisapride on gastric tone and the perception of gastric distension

Abstract: Background: Delayed gastric emptying, impaired gastric accommodation to a meal and hypersensitivity to gastric distension have been implied in the pathophysiology of functional dyspepsia. Dyspeptic patients are often treated with the prokinetic drug cisapride. Aim: To assess the effects of cisapride on perception of gastric distension and gastric accommodation to a meal. Methods: Eighteen healthy volunteers underwent a gastric barostat study on two occasions, after pre-treatment with placebo or cisapride 10 mg q.d.s. Graded isobaric and isovolumetric distensions were performed until the subjects reported discomfort. Volume and pressure changes were recorded and perception was scored by a questionnaire. In 10 volunteers, the amplitude of the gastric accommodation to a mixed liquid meal was also measured. Results: Pre-treatment with cisapride significantly lowered thresholds for perception and for discomfort, both during isobaric (4.3 ± 0.7 vs. 3.2 ± 0.7 and 12.2 ± 1.2 vs. 9.2 ± 0.9 mmHg above minimal distending pressure (MDP), respectively, P < 0.05) and isovolumetric (256 ± 46 vs. 200 ± 35 and 644 ± 36 vs. 511 ± 40 mL, respectively, P < 0.05) distensions. Cisapride significantly enhanced the size of the meal-induced fundus relaxation (143 ± 37 vs. 270 ± 50 mL, P < 0.05). Conclusions: Cisapride enhances both the perception of gastric distension and the gastric accommodation to a meal. These data suggest that cisapride may provide benefit to patients with impaired postprandial relaxation of the fundus.

Antiinflammatory actions of cat's claw: the role of NF-kappaB.

Abstract: Background: Uncaria tomentosa is a vine commonly known as cat’s claw or ‘una de gato’ (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. Purpose: The aim of this study was to determine the proposed anti-inflammatory properties of cat’s claw. Specifically: (i) does a bark extract of cat’s claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events. Methods: Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 μM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-κB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL). Results: The administration of UG (100 μg/mL) attenuated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat’s claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-κB. Cat’s claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression. Conclusions: Cat’s claw protects cells against oxidative stress and negated the activation of NF-κB. These studies provide a mechanistic evidence for the widely held belief that cat’s claw is an effective anti-inflammatory agent.

The Leeds Dyspepsia Questionnaire: a valid tool for measuring the presence and severity of dyspepsia.

Abstract: Background There is currently no validated questionnaire that assesses both the presence and severity of dyspepsia. Aim To develop the Leeds Dyspepsia Questionnaire (LDQ) as a measure of the presence and severity of dyspepsia, and to assess the validity, reliability and responsiveness of this instrument. Methods Unselected patients attending either a hospital dyspepsia clinic or a general practice surgery were interviewed by a trained gastroenterologist or a general practitioner on the presence and severity of dyspepsia. This opinion was compared with the results of the nurse-administered LDQ. Test–retest reliability was assessed by the same research nurse re-administering the LDQ 4–7 days after the initial visit in a subgroup of hospital patients. In a further subgroup of patients one researcher interviewed the patients and a second researcher re-administered the LDQ within 30 min to evaluate inter-rater reliability. The responsiveness of the LDQ was measured by repeating it in patients with endoscopically proven peptic ulcer or oesophagitis 1 month after receiving appropriate therapy. Results The LDQ was administered to 99 general practice and 215 hospital patients. In the GP population 41/98 (42%) had dyspepsia according to the GP and the LDQ had a sensitivity of 80% (95% CI: 65–91%) and a specificity of 79% (95% CI: 66–89%). The weighted kappa statistic for the agreement between the LDQ and the clinician for the severity of dyspepsia was 0.58 in the GP population and 0.49 in hospital patients. The kappa statistic for test–retest reliability was 0.83 in 107 patients. The LDQ had excellent inter-rater reliability with a kappa statistic of 0.90 in 42 patients. The median LDQ score fell from 22.5 (range 9–36) to 4.5 (range 0–27) in 12 patients 1 month after receiving appropriate therapy (Wilcoxon signed rank test, P < 0.0001). Conclusion The LDQ is a valid, reliable and responsive instrument for measuring the presence and severity of dyspepsia.

Oral budesonide as maintenance therapy in Crohn’s disease—results of a 12‐month study

Abstract: Background: Budesonide is a corticosteroid with high topical anti-inflammatory activity and low systemic activity due to rapid inactivation. We have assessed the efficacy and safety of an oral controlled ileal release (CIR) preparation of budesonide for maintenance of remission in patients with ileal or ileocaecal Crohn’s disease. Methods: In a double-blind, multicentre trial, 75 patients in clinical remission (Crohn’s Disease Activity Index, CDAI, ≤ 150) were randomly assigned to receive placebo, budesonide 3 mg or budesonide 6 mg daily for 12 months. Trial drugs were given at a fixed dose and without concomitant medication. The primary outcome measure was relapse, defined as a CDAI > 150 together with an increase of at least 60 units from entry. A patient was also considered to have a relapse if withdrawn from the study due to clinical deterioration, whether or not a CDAI value could be calculated at that time. Results: There were no statistically significant differences in the relapse rate at any time-point throughout the study. By 12 months the proportion of patients having relapsed were 48, 46 and 60% in those patients treated with budesonide 6 mg, 3 mg and placebo, respectively (N.S.). Treatments were well tolerated, and the proportion of patients with suppressed adrenal function (according to predetermined criteria) were 50% (6 mg), 26% (3 mg) and 17% (placebo) (P = 0.096). Conclusions: In the present study, relapse rate and time to relapse were similar in the patients treated with budesonide CIR, 6 mg daily or 3 mg daily or with placebo, throughout 12 months. This is in contrast to the two previous trials with identical design, where a significant effect of budesonide CIR in prolonging the median time to relapse was found. Possible reasons for the negative results of the present study include small sample size, and the fact that there was a high placebo response.

Experimental colitis induced by dextran sulphate sodium in mice: beneficial effects of sulphasalazine and olsalazine

Abstract: Background: Animal models of inflammatory bowel disease are artificial and more or less representative of human disease. However, the dextran sulphate sodium (DSS) induced intestinal inflammation model has recently been shown to fulfil some pathological criteria for an adequate experimental model. Aim: To determine whether this form of experimental intestinal inflammation responds to established therapy used for human inflammatory bowel disease. Methods: DSS was used to induce intestinal inflammation in conventional Balb/c mice and athymic nu/nu CD-1(BR) mice, and the well-documented 5-aminosalicylic acid (5-ASA) based anticolitis drugs sulphasalazine (SASP) and olsalazine (OLZ) were used to study therapeutic effects. Parameters which have been shown to reflect DSS-induced intestinal inflammation (body weight, colon length, spleen weight, diarrhoea, and rectal bleeding) were measured in the Balb/c mice. Results: Significant amelioration was seen on these parameters after different treatment protocols. Survival in nu/nu CD-1 mice was studied, and after 16 days a death rate of 50% was noted in the DSS group. SASP (100 mg/kg/day) and OLZ (50 mg/kg/day) significantly prolonged the survival to 29 and 38 days, respectively. SASP and OLZ showed a dose-dependent effect in the range between 10 and 100 mg/kg/day, doses closely corresponding to those used in humans. Conclusions: SASP and OLZ are able to ameliorate the DSS-induced intestinal inflammation. The dose-response patterns suggested that the active therapeutic moiety for the two drugs appears to be mainly the liberated 5-ASA molecule.

Changes in Helicobacter pylori‐induced gastritis in the antrum and corpus during 12 months of treatment with omeprazole and lansoprazole in patients with gastro‐oesophageal reflux disease

Abstract: Background: Several studies have shown that treatment with omeprazole leads to aggravation of Helicobacter pylori gastritis in the corpus. Whether this also applies to lansoprazole, and whether, in comparison with omeprazole, there are differences in therapy-induced gastritis parameter changes remains unclear. Methods: In 111 patients infected with H. pylori and with gastro-oesophageal reflux disease we investigated the gastritis parameters in antral and corpus mucosa before and after 2, 6 and 12 months of treatment with 15 or 30 mg lansoprazole or 20 mg omeprazole/day. Results: In all groups the different treatments had a similar effect: in both regions of the stomach, suppression or partial elimination of H. pylori was seen. However, improvement in the inflammation was observed only in the antrum, while in the corpus most gastritis parameters worsened significantly. There was no increase in intestinal metaplasia or atrophy. Conclusion: In common with omeprazole, lansoprazole aggravates the gastritis parameters in the corpus but improves them in the antrum. Treatment with proton pump inhibitors does not result in any increase in the incidence of atrophy/intestinal metaplasia. However, as gastritis predominating in the corpus seems to be associated with an elevated carcinogenic risk, consideration should be given to prophylactic H. pylori eradication therapy before initiating proton pump inhibitor treatment.

Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis

Abstract: Background: Autodigestion of the pancreas, secondary to the activation of digestive enzymes, is the pathogenetic mechanism of acute pancreatitis (AP). Aim: Clinical trials in which somatostatin (SS), octreotide (OCT) and gabexate mesilate (FOY) were used to treat patients with AP, were submitted to a meta-analytical evaluation. Five end-points were evaluated: early and overall mortality, patients with complications, complication rate, and patients who needed surgery. Results: In mild AP, no agent proved of value. In severe AP, both SS and OCT were beneficial in improving the overall mortality: the odds ratios (OR) were, respectively, 0.36 (95% CI: 0.20–0.64, P = 0.001) and 0.57 (95% CI: 0.35–0.88, P = 0.006). FOY had no effect on either early or overall mortality, but was effective in improving complication rate (OR = 0.70, 95% CI: 0.56–0.88, P = 0.02), number of patients with complications (OR = 0.61, 95% CI: 0.41–0.91, P = 0.01), and number of cases submitted to surgery (OR = 0.60, 95% CI: 0.39–0.92, P = 0.01). SS and OCT had no effect on these latter outcomes. Conclusions: Antisecretory agents, such as SS and OCT, are able to reduce mortality without affecting complications, whereas antiproteases, such as FOY, have no effect on mortality but do reduce complications. A trial exploring the efficacy of combining antisecretory agents with antiproteases would be of great benefit in patients with severe AP.

The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease

Abstract: Background: Mosapride is a novel prokinetic agent facilitating acetylcholine release from the enteric cholinergic neurones through a selective 5-HT4 receptor agonistic action. It is also active through its main metabolite M1, which is a 5-HT3 antagonist. The importance of motor dysfunction in the pathogenesis of gastro-oesophageal reflux disease (GERD) makes it interesting to examine the effect of mosapride on oesophageal acid exposure. Methods: The effect of mosapride on oesophageal 24-h acid reflux variables was studied in 21 patients with GERD symptoms and a pre-entry total acid exposure time (pH < 4) of more than 5%. Ambulatory pH monitoring was performed after treatment with 40 mg mosapride citrate or placebo q.d.s. for 2 days in random order, using a double-blind crossover technique, with a washout period of at least 5 days. Results: Mosapride was significantly more effective than placebo in decreasing the total number of reflux episodes, the total number of reflux episodes lasting more than 5 min and the total time, as well as the amount of day time, of intra-oesophageal pH below 4. Consequently, mosapride also significantly improved total acid clearance time. Conclusion: Mosapride 40 mg q.d.s. is effective in decreasing acid reflux in the oesophagus in patients with GERD and therefore has the potential to be effective in the treatment of this disease.

Treatment of ulcerative colitis with germinated barley foodstuff feeding: a pilot study.

Abstract: Background Germinated barley foodstuff (GBF) has been shown to attenuate intestinal injury in animal models, largely by increasing luminal short-chain fatty acid production. Aim To investigate the safety and efficacy of GBF in the treatment of ulcerative colitis (UC). Methods Ten patients with active UC received 30 g of GBF daily for 4 weeks in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued. The response to treatment was evaluated clinically and endoscopically. Pre- and post-treatment stool concentrations of short-chain fatty acids were measured by gas-liquid chromatography. Results Patients showed improvement in their clinical activity index scores, with a significant decrease in the score from 6.9 ± 1.4 to 2.8 ± 1.5 (mean ± S.E.M., P < 0.05). The endoscopic index score fell from 6.1 ± 2.3 to 3.8 ± 2.3 (P < 0.0001). Patients showed an increase in stool butyrate concentrations after GBF treatment (P < 0.05). No side-effects were observed. Conclusions Oral GBF therapy may have a place in management of ulcerative colitis, but controlled studies are needed to demonstrate its efficacy in the treatment of this disorder.

Iron absorption in patients with Zollinger–Ellison syndrome treated with long-term gastric acid antisecretory therapy

Abstract: Background: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores. Aim: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger–Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs. Methods: One hundred and nine patients with ZES but without previous gastric resections were studied. All patients underwent assessment of acid control on antisecretory agents, determination of tumour extent, evaluation of haematological parameters (Hct, haemoglobin, WBC, MCV, MCHC), and determination of serum iron parameters (iron, ferritin, transferrin, iron/transferrin ratio). Acid control values for the last 4 years were reviewed, the presence or absence of acid hyposecretion determined using three different criteria and this result correlated with haematological and iron parameters. Results: Eighty-nine patients were taking omeprazole, nine patients were taking histamine H2-antagonists and 11 patients were taking no drugs following curative resection. The mean duration of omeprazole treatment was 5.7 years (range 0.7–12.5 years) and total duration of any treatment was 10.1 years (range 0.7–21 years). Acid hyposecretion was present by at least one criterion in 45% of patients. There were no significant differences between patients with or without acid hyposecretion, taking or not taking omeprazole, having different durations of omeprazole treatment or different durations of total time receiving any antisecretory treatment, for any serum iron parameter, haematological parameter, or for the frequency of iron deficiency. Males and females did not differ in percentage with low ferritin levels or percentage with iron deficiency. Conclusions: Continuous treatment with omeprazole for 6 years or continuous treatment with any gastric antisecretory drug for 10 years does not cause decreased body iron stores or iron deficiency. These results suggest that, in contrast to recent results which show yearly monitoring of vitamin B12 in such patients is needed, such monitoring for iron parameters is not necessary.

Relationship between Helicobacter pylori, atrophic gastritis and gastric cancer

Abstract: Helicobacter pylori causes chronic active inflammation of the gastric mucosa in the majority of infected patients. In a considerable number of them, this will eventually lead to a loss of gastric glands, and thus the establishment of atrophic gastritis. This is associated with the development of intestinal metaplasia and dysplasia. These consecutive conditions increase the risk for gastric cancer. particularly of the intestinal type. We reviewed the evidence that H. pylori plays an important role in this sequence of events that can lead to gastric cancer. This paper focuses on the difficulties in staging atrophic gastritis, the incidence and prevalence of this condition and the relation with H. pylori infection. Furthermore, it describes the evidence for the role of this organism and gastric mucosal atrophy in the aetiology of gastric cancer and focuses on the life-time incidence of gastric cancer in the presence of this bacterium.

Prospective study of the risk of Clostridium difficile diarrhoea in elderly patients following treatment with cefotaxime or piperacillin-tazobactam.

Abstract: Background Rates of Clostridium difficile diarrhoea have recently been rising, with the elderly being at highest risk. Aim To compare the incidence of C. difficile colonization and diarrhoea in elderly patients treated for presumed infection with either empirical cefotaxime (CTX) or piperacillin–tazobactam (PT). Methods A prospective, ward-based, crossover study was carried out on two well-matched care of the elderly wards at a UK tertiary care hospital, in patients requiring empirical broad-spectrum antibiotic treatment. Results There was a highly significant increased incidence of C. difficile colonization (26/34 vs. 3/14, P = 0.001) and diarrhoea (18/34 vs. 1/14, P = 0.006) in patients who received CTX as opposed to PT. DNA fingerprinting suggested that most infections arose from strains acquired from the hospital environment. Conclusions Elderly patients are significantly less likely to develop C. difficile diarrhoea after treatment with PT than after CTX. The source of C. difficile appears to be predominantly from the ward environment.

Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis.

Abstract: Background: Recent evidence suggests that the immunosuppressive drug cyclosporin may be of benefit in treating patients with severe colitis who are steroid resistant. Although cyclosporin appears to be effective in reducing colectomy rates in the short term, few data are available on the long-term follow-up of such patients. Aim: To investigate the short- and long-term outcome of patients with severe steroid-resistant ulcerative colitis treated with cyclosporin who were otherwise being considered for colectomy. Methods: Twenty-two patients with severe steroid-resistant exacerbations of ulcerative colitis who were being considered for colectomy were treated with cyclosporin (4 mg/kg i.v.) daily for 7 days followed by oral treatment (6 mg/kg/day) if colectomy was avoided. Results: Twenty of 22 patients (91%) avoided colectomy during their initial hospital admission. With a mean follow-up period of 39 months (range 31–59), eight of these patients have subsequently relapsed and required colectomy and 12 patients have avoided colectomy (53%). Of the 12 patients avoiding colectomy, seven have successfully been weaned on to azathioprine while five are maintained on an aminosalicylate alone. None of these long-term responders require maintenance corticosteroids. The main side-effects during treatment with cyclosporin were headaches (six patients, 27%), paraesthesia and tremors (four patients, 18%) and hypertension (four patients, 18%). Two patients developed renal impairment on cyclosporin which resolved on lowering the dose. In no case was cyclosporin discontinued because of an adverse reaction. No clinical or laboratory features could be identified that predicted which patients treated with cyclosporin would later require colectomy. Conclusion: This study shows that cyclosporin is a viable alternative to emergency colectomy in severe ulcerative colitis in the short term. Although these benefits are not maintained in all patients, more than half were found to avoid colectomy in the longer term.

Review article: Pathogenesis of the transformation from gastritis to malignancy.

Abstract: Helicobacter pylori acquisition is the main cause of chronic gastritis in humans. In up to half of the infected subjects, chronic gastritis progresses to atrophic gastritis and intestinal metaplasia. During this course, various mechanisms are triggered that may contribute to the pathogenesis of gastric cancer. Such mechanisms include the inflammation-related cascades of cytokine and free radical reactions, up- and downregulation of growth factors and their receptors, and the atrophy-related impairment of acid output and intraluminal acidity. An array of other factors may also have become significant including overgrowth of bacteria other than H. pylori in the hypochlorhydric or achlorhydric stomach, a high dietary consumption of salt, nitrate, or nitrite, smoking, deficiency of vitamins or micronutrients, influence of sex hormones, or an inherited liability of the dividing epithelial cells to gene errors. These factors may vary in effect between populations and individuals but, if active, may affect the cell genome which may further influence the course and progression of chronic gastritis, and can finally result in overt gastric neoplasia. The molecular biology of gastric cancer has revealed a spectrum of gene errors which vary in type and extent between different histological types of cancer, and between individual cases. There now is evidence that the intestinal metaplasia or the gastric epithelium in atrophic gastritis reveal signs of abnormal expression of various regulatory genes well before the appearance of gastric neoplasia. It is possible that the mechanisms leading to mutation of the genes in epithelial cells are triggered very early in the H. pylori gastritis cascade, and that atrophic gastritis and intestinal metaplasia result from these processes.

Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules.

Abstract: Background: Little information is available about the safety of high doses of mesalazine during pregnancy. Aim: To study the fate of pregnancy and foetal outcome in women taking 1–4 g/day of mesalazine microgranules for inflammatory bowel disease. Patients and methods: Case reports were collected from the Pharmacovigilance Department of Ferring SA, France, from a survey conducted in three gastroenterology units, and from a teratology information service. The evolution of pregnancy and foetal outcome were assessed by questionnaire. Results: The study covered a total of 123 pregnancies (126 foetuses). Ninety-six women took mesalazine during the first trimester, 85 during the second and 83 during the third. The mean daily dose was 2.1 ± 0.8 g; 86 women received <3 g/day (low-dose group), 37 women received ≥3 g/day (high-dose group). The following abnormalities were observed in the low-dose and high-dose groups, respectively: ectopic pregnancy (1/0), spontaneous abortions (1/1), foetal death (0/1), premature deliveries (3/5, P < 0.05), congenital malformations (3/1) and one case of lethal oxalosis. Abnormalities were not considered to be related to mesalazine. Conclusions: The use of oral mesalazine microgranules during pregnancy is safe at doses ≤ 2 g/day, and probably also at a dose of 3 g/day.

Continuous treatment with omeprazole 20 mg daily for up to 6 years in Barrett's oesophagus

Abstract: Background: Because of the malignant potential of Barrett’s oesophagus, an aim of treatment is to cause the columnar epithelium to regress. A logical approach is to decrease acid reflux which is an important aetiological factor in Barrett’s oesophagus. Treatment with omeprazole 20–80 mg over 1–3 years has yielded conflicting but largely disappointing results. Aim: To determine if treatment of Barrett’s oesophagus with omeprazole 20 mg daily for up to 6 years can cause regression of the Barrett’s epithelium. Patients and Methods: Forty-seven patients with Barrett’s oesophagus were treated in an open prospective study. Nine patients were treated for 2 years, 12 for 3 years, 10 for 4 years, eight for 5 years and eight for 6 years. Patients were endoscoped at 1–2-year intervals and endoscoped at the end of the treatment period. Results: No significant shortening of the length of the Barrett’s segment was seen during any treatment period, although omeprazole controlled reflux symptoms and was well tolerated. Macroscopic squamous islands appeared in 55% of patients, mostly in the first 2–3 years although in five patients they appeared later in treatment. Conclusion: Treatment of Barrett’s oesophagus with omeprazole 20 mg daily for periods of up to 6 years did not cause regression in the length of the Barrett’s segment, but it did lead in over half of the patients to partial re-epithelialization in the form of squamous islands.

Review article: one-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori.

Abstract: Background: One-week triple therapies have been endorsed as the treatment regimens of choice for eradication of Helicobacter pylori infection Those that include clarithromycin appear to be the most effective Aim: To review reports of triple therapies that include clarithromycin Methods: Reports were identified from the literature to May 1998 The variation between study designs prevents a formal meta-analysis A measure of the relative efficacies of regimens has, however, been gained by comparison and by pooling of intention-to-treat eradication rates Results: One hundred and ninety-two studies were identified which included 264 treatment arms of a 1-week triple therapy composed of clarithromycin with amoxycillin or a nitroimidazole (metronidazole or tinidazole), and either ranitidine bismuth citrate or a proton pump inhibitor (omeprazole, lansoprazole or pantoprazole) From reports of these studies, an intention-to-treat H pylori eradication rate could be determined from 210 treatment arms of 151 studies Conclusions: There is little to choose between the efficacies of 1-week clarithromycin-based triple therapy eradication regimens However, those comprising clarithromycin, a nitroimidazole and either ranitidine bismuth citrate or a high dose of omeprazole are, in general, the most effective Against antibiotic-resistant strains of H pylori, regimens including ranitidine bismuth citrate may be more effective than those including a proton pump inhibitor

Review article: antioxidant micronutrients and gastric cancer

Abstract: A review of the literature reveals a very consistent association between gastric cancer risk and low intake of fruits and vegetables. This observation has been documented in many countries with different epidemiological techniques: interpopulation correlations, case-control studies and follow up of several cohorts. Low serum levels of beta-carotene and alpha-tocopherol, but not vitamin C, have been reported in patients with gastric dysplasia. Helicobacter pylori infection has been associated with lower concentrations of vitamin C in the gastric juice. Detailed studies in Colombia and New Orleans have shown a gradient towards lower concentration in the gastric juice and lower ratios of gastric juice to serum concentration of vitamin C in the following comparisons: i) lower vs. higher gastric cancer risk; ii) mild vs. advanced gastric precancerous histopathologic lesions; iii) mild vs. advanced degree of atrophy; iv) mild vs. advanced damage to the surface gastric epithelium; v) lower vs. higher gastric pH. Such a gradient is not observed for serum levels of vitamin C. The role of infection with H. pylori in the metabolism of ascorbic acid is discussed, as well as the possible role of ascorbic acid in inhibiting cell damage by reactive oxygen species.