bluuebunny/crossref_metadata_2025 huggingface dataset:
Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial
Authors:   THE BRITISH–ITALIAN GALLSTONE STUDY GROUP, Petroni M. L. , Jazrawi R. P. , Pazzi P. , Lanzini A. , Zuin M. , Pigozzi M. G. , Fracchia M. , Galatola G. , Alvisi V. , Heaton K. W. , Podda M. , Northfield T. C.
Published: March 2003

Background:

Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization.

Aim:

To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy.

Patients and methods:

A total of 154 symptomatic patients with radiolucent stones (≤ 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6‐monthly oral cholecystography and ultrasonography for up to 24 months.

Results:

Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side‐effects or dropout rate. Complete gallstone dissolution on an intention‐to‐treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively.

Conclusion:

There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.
Up‐regulation of cyclooxygenase‐1 and ‐2 in human gastric ulcer
Authors: To K. F. , Chan F. K. L. , Cheng A. S. L. , Lee T. L. , Ng Y. P. , Sung J. J. Y.
Published: March 2003

Background:

The expression of cyclooxygenase (COX) in human gastric ulcers is unknown.

Aim:

To study the expression and cellular localization of cyclooxygenase in human gastric ulcers.

Methods:

A total of 38 surgical gastric ulcer specimens were studied; 20 were Helicobacter pylori‐positive and 18 were associated with NSAID use. Twenty non‐ulcerated, histologically normal gastric specimens were used as controls. The cellular localization of COX‐1 and COX‐2 were determined by immunohistochemistry and double immunofluorescence. Cyclooxygenase messenger RNA (mRNA) was measured by reverse transcription‐polymerase chain reaction and localized by in situ hybridization.

Results:

In control specimens, COX‐1 was detected in stromal cells in the lamina propria. There was focal and weak immunostaining for COX‐2 in the foveolar epithelium. At the ulcer edge, COX‐1 was significantly increased in lamina propria cells whereas COX‐2 was strongly expressed in the hyperplastic foveolar epithelium in H. pylori‐ and non‐steroidal anti‐inflammatory drugs (NSAID)‐associated ulcers. At the ulcer base, there was strong expression of COX‐1 and COX‐2 in myofibroblasts, macrophages and endothelial cells in the granulation tissue, irrespective of H. pylori status or NSAID use. Messenger RNA of COX‐1 and COX‐2 were demonstrated by reverse transcription‐polymerase chain reaction. Double immunofluorescence and in situ hybridization confirmed the cellular localization of cyclooxygenase at protein and mRNA levels, respectively.

Conclusion:

Both COX‐1 and COX‐2 are up‐regulated in human gastric ulcers.
Once versus divided daily dosing with delayed‐release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters
Authors: Hussain F. N. , Ajjan R. A. , Kapur K. , Moustafa M. , Riley S. A.
Published: March 2003

Background:

Delayed‐release mesalazine is traditionally taken as three divided doses. However, it is well‐recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable.

Methods:

We measured serum, urinary, faecal and rectal tissue concentrations of 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid in 24 healthy volunteers following dosing with delayed‐release mesalazine, 1.2 g or 2.4 g daily, given as either a single daily dose at 08:00 hours or in three divided doses at 08:00, 13:00 and 18:00 hours.

Results:

Urinary and faecal excretion and rectal tissue concentrations of 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid were similar following single or divided daily dosing, at both doses studied. Peak serum concentrations were found at 06:00–09:00 following divided dosing and at 17:00–20:00 following once daily dosing. However, peak and trough serum levels and serum area under curve values (AUC) were similar with both regimens and at both doses.

Conclusions:

Urinary, faecal and rectal tissue concentrations are similar following single or divided daily dosing. Minor differences in serum levels were apparent but maximum, minimum and AUC values were similar. Clinical trials should examine the efficacy and toxicity of once daily dosing in patients with ulcerative colitis.
Quality of life in functional dyspepsia: responsiveness of the Nepean Dyspepsia Index and development of a new 10‐item short form
Authors: Talley N. J. , Verlinden M. , Jones M.
Published: March 2003

Background:

The Nepean Dyspepsia Index is a reliable and valid measure of quality of life in functional dyspepsia, but responsiveness has been little studied. The Nepean Dyspepsia Index originally contained 42 items designed to measure impairment of a subject’s ability to engage in relevant aspects of their life because of dyspepsia, and their enjoyment of these aspects; in addition, the individual importance of areas was assessed. It was subsequently shortened to 25 items, yielding five sub‐scales.

Aim:

To test the Nepean Dyspepsia Index’s responsiveness and develop a responsive, very short form.

Methods:

A randomized, double‐blind controlled trial was performed in 589 patients with documented functional dyspepsia. Symptoms and quality of life were measured at baseline, 2 and 4 weeks. Responsiveness of the Nepean Dyspepsia Index quality‐of‐life section was evaluated by correlation with symptom scores and calculation of standardized changes in scores. Two items from each sub‐scale which best represented the area of life (by factor loadings) were selected to create the 10‐item short form (SF; short form‐Nepean Dyspepsia Index). Internal consistency was assessed by Cronbach’s alpha and responsiveness was assessed as above.

Results:

The Nepean Dyspepsia Index quality‐of‐life scales demonstrated excellent responsiveness to change in both the active and placebo arms (standardized response means all > 1.0). The Nepean Dyspepsia Index accounted for only 8% of the variance in percentage change in symptoms (by visual analogue scales), indicating that it was evaluating areas of life not covered by symptoms. The 10‐item short form had adequate internal consistency (all scales ≥ 0.70) and all strongly (and significantly) correlated with the long form sub‐scales; it was also highly responsive.

Conclusion:

The Nepean Dyspepsia Index is a responsive disease‐specific quality‐of‐life measure; the 10‐item short form can be applied in clinical trials of functional dyspepsia.
Meta‐analysis of randomized controlled trials comparing standard clinical doses of omeprazole and lansoprazole in erosive oesophagitis
Authors: Sharma V. K. , Leontiadis G. I. , Howden C. W.
Published: March 2003

Background:

Omeprazole and lansoprazole are used to treat erosive oesophagitis in the respective daily doses of 20 and 30 mg.

Aim:

To investigate, by meta‐analysis, whether treatment with lansoprazole 30 mg increases erosive oesophagitis healing rates over omeprazole 20 mg.

Methods:

We searched for randomized, double‐blind trials comparing omeprazole 20 mg and lansoprazole 30 mg in endoscopically diagnosed erosive oesophagitis. After assessing for homogeneity, non‐heterogeneous trials were combined and pooled healing rates derived. We calculated the relative benefit increase, absolute benefit increase and number needed to treat.

Results:

Six trials without significant heterogeneity met predetermined inclusion criteria. By per protocol analysis, pooled healing rates for omeprazole 20 mg and lansoprazole 30 mg were, respectively, 74.7% and 77.7% after 4 weeks and 87.0% and 88.7% after 8 weeks. The corresponding figures by intention‐to‐treat analysis were 70.8% and 72.7% after 4 weeks and 81.8% and 83.3% after 8 weeks. In each analysis the absolute benefit increase for lansoprazole was small and its 95% confidence interval encompassed zero.

Conclusion:

Lansoprazole 30 mg produces healing rates in erosive oesophagitis that are not statistically significantly different to those of omeprazole 20 mg.
Efficacy of parenteral methotrexate in refractory Crohn’s disease
Authors: Chong R. Y. , Hanauer S. B. , Cohen R. D.
Published: March 2003

Background:

Methotrexate is steroid‐sparing in short‐term trials for refractory Crohn’s disease. This study assesses the impact of dosing and administration on the long‐term utility of methotrexate in Crohn’s disease.

Methods:

The efficacy and tolerability of methotrexate were assessed in all refractory Crohn’s disease patients treated at the University of Chicago from 1 September 1989 to 6 June 1997.

Results:

Seventy‐six patients were identified: 43% male, mean age 35 years, mean Crohn’s disease duration 9.5 years. Mean methotrexate duration was 55 weeks; mean dose was 20 mg/week. Drug administration was parenteral (78%), oral (13%), or combination (8%). Improvement occurred in 63% after a mean of 9 weeks, for a mean duration of 65 weeks. Remission occurred in 37% after a mean of 22 weeks, for a mean duration of 59 weeks. Improvement and remission were highest with parenteral therapy, but dose‐independent. Parenteral therapy maintained remission in 46%. Improvement (P=0.05) and remission (P=0.01) were more likely for patients under 40. Improvement rates were higher with concurrent steroids (P=0.02) or antibiotics (P=0.01). Side‐effects occurred in 46%, resulting in discontinuation in 18%. Prednisone was decreased in 78%, and stopped in 40%.

Conclusions:

Long‐term therapy with methotrexate in Crohn’s disease is safe, effective, steroid‐sparing, and most efficacious in younger patients and when given parenterally.
Usefulness of Helicobacter pylori stool antigen test to monitor response to eradication treatment in children
Authors: Oderda G. , Rapa A. , Marinello D. , Ronchi B. , Zavallone A.
Published: March 2003

Background:

The monitoring of the results of eradication treatment is a crucial step for patients with Helicobacter pylori gastritis. A non‐invasive test for H. pylori antigens in stools (HpSA) was recently validated for children.

Aim:

To evaluate the accuracy of HpSA in monitoring eradication treatment in children.

Methods:

In 60 children, H. pylori gastritis was diagnosed by endoscopy and the 13C‐urea breath test. The children were treated and returned for a follow‐up 13C‐urea breath test 6 weeks after the end of treatment. Children were considered cured when the 13C‐urea breath test was negative. Stool were collected at baseline, and at 2 and 6 weeks. Stool antigens were measured by HpSA.

Results:

According to 13C‐urea breath test, 6 weeks after the end of treatment 49 children were cured and 11 were still H. pylori‐positive. The sensitivity and specificity of HpSA on stools collected 2 weeks after therapy were 100%. At 6 weeks specificity was 93.9 and sensitivity 100%. Results by visual reading were concordant with the plate‐reader in all but two cases at baseline.

Conclusions:

HpSA is accurate for monitoring treatment in children as early as 2 weeks after therapy, when information is most useful and unachievable with other tests. Results by visual reading are accurate, and this can make the test cheaper and more practical.
A drug therapy for the prevention of variceal haemorrhage
Authors: Tripathi D. , Hayes P. C.
Published: March 2003

The development of varices is a major complication of cirrhosis, and variceal haemorrhage has a high mortality. There have been major advances in the primary and secondary prevention of variceal haemorrhage over the last 20 years involving endoscopic, radiological and pharmacological approaches. This review concentrates principally on drug therapy, particularly on the numerous haemodynamic studies. Many of these drugs have not been studied in clinical trials, but provide data about the underlying pathogenesis of portal hypertension.

Also covered in this review are the randomized controlled trials and meta‐analyses that involve a large number of patients. These trials involve relatively few drugs such as non‐selective beta‐blockers and nitrates. Correlations between haemodynamic and clinical parameters are discussed.

Despite the recent increase in the use of alternative endoscopic therapies, an effective and well tolerated drug remains a clinically important research goal.
A molecular rationale for the how, when and why of colorectal cancer screening
Authors: Souza R. F.
Published: March 2003

Colorectal cancer remains a leading cause of cancer‐related mortality in the United States. Recently, colorectal cancer screening and colorectal cancer prevention have gained national attention. In response, the American Gastroenterological Association, the American College of Gastroenterology and the Agency for Healthcare Policy and Research have published recommendations for colorectal cancer screening and surveillance in patients with sporadic as well as hereditary forms of colorectal cancer. This review will focus on the basic molecular differences underlying the formation of carcinoma in patients with sporadic colorectal cancer, and the heritable syndromes of familial adenomatous polyposis (FAP), hereditary non‐polyposis colorectal cancer (HNPCC), and juvenile polyposis (JPS). By appreciating the molecular mechanisms underlying these four types of polyp cancer syndromes, the differences in clinical time course for progression from polyp to carcinoma and in current screening recommendations for patients with sporadic adenomas, FAP, HNPCC and JPS can be better understood.
The potential role for photodynamic therapy in the management of upper gastrointestinal disease
Authors: Barr H. , Dix A. J. , Kendall C. , Stone N.
Published: March 2003

Photodynamic therapy involves the activation of an exogeneously administered, or an endogenously gen‐erated, photosensitizer with light to produce localized tissue destruction. It is an attractive, predominantly endosopic technique for the palliation of advanced upper gastrointestinal cancer and the eradication of early neoplastic and pre‐neoplastic lesions. The nature of the biological response allowing safe healing and the exploitation of tissue threshold effects mean that adjacent tissue damage can be minimized.

This review used a database of 368 papers. The nature of the photosensitizer is critical to the depth of tissue damage and the risk of adjacent tissue damage and stricture formation. The generation of protoporphyrin IX following administration of 5‐aminolaevulinic acid has proved useful for the treatment of high‐grade dysplasia in Barrett’s oesophagus. A double‐blind randomized placebo controlled trial has confirmed that it is a safe and effective method for the ablation of low‐grade dysplasia. The treatment of more advanced lesions requires exogeneously administered photo‐sensitizers. However, recent data indicate that the neoplastic potential remains in some patients and continued follow‐up is necessary.

Photodynamic therapy can be used to eradicate early neoplasia and palliate advanced cancer, but caution is required before a definitive cure can be claimed.
Oral tacrolimus long‐term therapy in patients with Crohn’s disease and steroid resistance
Authors: Ierardi E. , Principi M. , Francavilla R. , Pisani A. , Rendina M. , Ingrosso M. , Guglielmi F. W. , Panella C. , Francavilla A.
Published: March 2003

Aim:

To report the results of a prospective, open‐label, uncontrolled study in 13 patients affected by Crohn’s disease with resistance to steroids.

Methods:

The patients were treated long‐term with oral tacrolimus, aiming to both resolve acute attacks and maintain remission. Tacrolimus was administered at the dose of 0.1–0.2 mg.day/kg and adjusted in order to achieve levels of 5–10 ng/mL; only mesalazine was continued concomitantly. Steroids and total parenteral nutrition were tapered when appropriate.

Results:

Median treatment was 27.3 months. Only one patient dropped out due to adverse events. Crohn’s disease activity index score significantly decreased after 6 months in 11 patients; for 1 year in nine of them, and 7 years in two of them. The inflammatory bowel disease life‐quality questionnaire score significantly increased over the same periods. A marked drop in hospitalizations was recorded. In three out of six patients complete closure of fistulas occurred. Tacrolimus allowed total parenteral nutrition to be withdrawn in three out of five patients. Supplementation with low‐dose steroids was required in five patients. Two patients underwent surgery.

Conclusions:

Tacrolimus therapy appears to be associated with both short‐ and long‐term benefits, and may represent a therapeutic option in Crohn’s disease when conventional therapies fail. This study encourages its use in controlled trials.
Food hypersensitivity and irritable bowel syndrome
Authors: Zar S. , Kumar D. , Benson M. J.
Published: March 2003

Irritable bowel syndrome is a common condition but its pathophysiology remains poorly understood. Many irritable bowel syndrome patients give a history of food intolerance, but data from dietary elimination and re‐challenge studies are inconclusive. Multiple aetio‐pathological mechanisms have been postulated.

The gut has an extensive immune system but current understanding of processing of food antigens in health and disease is limited. There is no clinically useful marker available to test for food hypersensitivity in irritable bowel syndrome. Researchers have employed both skin tests and serum immunoglobulins (IgG and IgE) as markers of food hypersensitivity in various disorders including irritable bowel syndrome, but published data are equivocal.

In this article, the evidence for the role of food hypersensitivity in irritable bowel syndrome is reviewed and, based on the available data, a possible pathophysiological hypothesis has been formulated.
Infliximab induces potent anti‐inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease
Authors: Cornillie F. , Shealy D. , D'Haens G. , Geboes K. , Van Assche G. , Ceuppens J. , Wagner C. , Schaible T. , Plevy S. E. , Targan S. R. , Rutgeerts P.
Published: March 2003

Background:

Anti‐TNFα therapy with infliximab is effective for Crohn’s disease. Infliximab neutralizes the biological activities of TNFα, a cytokine involved in host‐defence against certain infections.

Aim:

To evaluate the effects of infliximab on the gut and peripheral immune system functions.

Methods:

Biopsies and blood samples from three clinical trials of infliximab in Crohn’s disease were analysed. Pharmacokinetics, changes in leucocyte counts and T cell subsets, T cell function, and cytokine profiles of lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) were analysed.

Results:

Infliximab has a serum half‐life of 9.5 days and is still detectable in serum 8 weeks after infusion. Leucocyte counts showed consistent changes from baseline toward normal values after therapy. Monocytes and lymphocytes were modestly increased, while neutrophils were decreased 4 weeks after treatment. Lymphocyte subsets and T cell proliferative responses were not altered after therapy. The proportion of PBMCs capable of producing IFNγ and TNFα did not change, while Th1 cytokine production by stimulated LPMC was decreased after infliximab therapy.

Conclusion:

The clinical efficacy of infliximab is based on local anti‐inflammatory and immunomodulatory effects in the bowel mucosa, without generalized suppression of systemic immune functions in Crohn’s disease patients.
Role of reactive oxygen metabolites in aspirin‐induced gastric damage in humans: gastroprotection by vitamin C
Authors: Pohle T. , Brzozowski T. , Becker J. C. , Van Der Voort I. R. , Markmann A. , Konturek S. J. , Moniczewski A. , Domschke W. , Konturek J. W.
Published: March 2003

Background:

The roles of active oxygen metabolites and anti‐oxidative defenses in aspirin (ASA)‐induced gastric damage have been little studied.

Aim:

We determined the effects of aspirin (400 mg b.d.) with or without vitamin C (480 mg b.d.) for 3 days on gastric mucosa in human volunteers.

Methods:

Gastric injury was assessed endoscopically; gastric blood flow, reactive oxygen release (quantified by chemiluminescence), lipid peroxidation, myeloperoxidase, superoxide dismutase and glutathione peroxidase activity and intragastric vitamin C content were measured. Expression of superoxide dismutase and glutathione peroxidase mRNAs was assayed semi‐quantitatively.

Results:

ASA produced erosions, a marked increase in chemiluminescence, lipid peroxidation, and myeloperoxidase activity. It also resulted in a suppression of gastric blood flow, intragastric vitamin C levels, superoxide dismutase and glutathione peroxidase activities. The addition of vitamin C significantly attenuated gastric damage and reversed the effects of ASA on these parameters. Superoxide dismutase and glutathione peroxidase mRNAs were decreased in ASA‐treated subjects; the addition of vitamin C restored their regular levels.

Conclusions:

(i) free radical‐induced lipid peroxidation and suppression of antioxidizing enzymes play an important role in gastric damage induced by aspirin; (ii) increased myeloperoxidase activity suggests activated neutrophils to be the major source of these radicals; (iii) vitamin C protects against ASA‐induced damage due to its anti‐oxidizing activity.
The genetics of inflammatory bowel disease
Authors: Ahmad T. , Satsangi J. , Mcgovern D. , Bunce M. , Jewell D. P.
Published: March 2003

Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn’s disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome‐wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3—the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ‘positional’ candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.
Pioglitazone, a specific PPAR‐γ ligand, inhibits aspirin‐induced gastric mucosal injury in rats
Authors: Naito Y. , Takagi T. , Matsuyama K. , Yoshida N. , Yoshikawa T.
Published: March 2003

Background:

Neutrophils activation and tumour necrosis factor‐α (TNF‐α) induction play a critical role in aspirin‐induced gastric mucosal injury. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR‐γ ligand, can ameliorate aspirin‐induced gastric mucosal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF‐α expression.

Methods:

Aspirin‐induced injury was produced by the intragastric administration of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 mL/kg). Pioglitazone was given to the rats by gastric intubation 1 h before the aspirin administration. Thiobarbituric acid‐reactive substances and tissue‐associated myeloperoxidase activity were measured in gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The gastric concentration of TNF‐α and the expression of TNF‐α mRNA was determined by ELISA and reverse transcriptase‐polymerase chain reaction.

Results:

The intragastric administration of acidified aspirin induced hyperemia and haemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited by treatment with pioglitazone in a dose‐dependent manner. The increases in thiobarbituric acid‐reactive substances and myeloperoxidase activity after aspirin administration were both significantly inhibited by pre‐treatment with pioglitazone (10 mg/kg). The gastric content of TNF‐α increased and the expression of TNF‐α mRNA was up‐regulated after aspirin treatment. However, the peak TNF‐α mRNA expression 1 h after aspirin administration was inhibited by pioglitazone.

Conclusion:

Based on these data, the beneficial effects of pioglitazone on aspirin‐induced gastric mucosal injury may be attributed to its anti‐inflammatory properties.
Guidelines for adults on self‐medication for the treatment of acute diarrhoea
Authors: Wingate D. , Phillips S. F. , Lewis S. J. , Malagelada J.‐R. , Speelman P. , Steffen R. , Tytgat G. N. J.
Published: March 2003

Acute uncomplicated diarrhoea is commonly treated by self‐medication. Guidelines for treatment exist, but are inconsistent, sometimes contradictory, and often owe more to dogma than evidence. Anad hocmultidisciplinary group has reviewed the literature to determine best practice.

In general it is recognized that treatment of acute episodes relieves discomfort and social dysfunction. There is no evidence that it prolongs the illness. Self‐medication in otherwise healthy adults is safe.

Oral loperamide is the treatment of choice. Older anti‐diarrhoeal drugs are also effective in the relief of symptoms but carry the risk of unwanted adverse effects. Oral rehydration solutions do not relieve diarrhoea, and confer no added benefit for adults who can maintain their fluid intake. Probiotic agents are, at present, limited in efficacy and availability. Antimicrobial drugs, available without prescription in some countries, are not generally appropriate for self‐medication, except for travellers on the basis of medical advice prior to departure.

Medical intervention is recommended for the management of acute diarrhoea in the frail, the elderly (> 75 years), persons with concurrent chronic disease, and children. Medical intervention is also required when there is no abatement of the symptoms after 48 h, or when there is evidence of deterioration such as dehydration, abdominal distension, or the onset of dysentery (pyrexia > 38.5 °C and/or bloody stools).
Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials
Authors: Hawkey C. J. , Laine L. , Harper S. E. , Quan H. U. I. , Bolognese J. A. , Mortensen E. ,   For The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group
Published: March 2003

Background:

Highly selective inhibitors of the inducible cyclooxygenase‐2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies.

Aim:

To evaluate the influence of risk factors for NSAID‐induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen.

Methods:

We analysed pooled data from two identical double‐blind, randomized, 12‐week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (< 65, ≥ 65 years), sex, race (white, nonwhite), Helicobacter pylori status, presence of gastroduodenal erosions at baseline, a history of upper gastrointestinal disease, prior NSAID use within 30 days of study entry, and smoking. We also evaluated these factors for possible association with the development of clinically‐evident gastrointestinal perforations, ulcers or bleeds over 12 weeks.

Results:

Across all treatment groups, the likelihood of detecting endoscopic ulcers, or of clinical presentation with a bleed, over 12 weeks was increased approximately 4–5‐fold in patients with previous upper gastrointestinal disease (relative risk [95% confidence interval] of 4.2 [2.5, 7.1] for endoscopic ulcers; 3.8 [1.4, 10.6] for bleeds), or those with gastroduodenal erosions at baseline endoscopy (relative risk of 4.4 [2.6, 7.5] for endoscopic ulcers; 5.0 [1.9, 13.5] for bleeds). H. pylori infection did not increase the risk of endoscopic ulcers or bleeds (relative risk of 1.1 [0.8, 1.6] for endoscopic ulcers; 0.3 [0.1, 0.9] for bleeds). The risk factor sub‐group effects were constant across all treatment groups, and the significantly higher incidence of ulcers with ibuprofen as compared to rofecoxib and placebo was maintained in all risk factor subgroups.

Conclusions:

Gastroduodenal erosions at baseline and a clinical history of upper gastrointestinal disease, but not H. pylori colonization, increased the risk for endoscopically‐detected ulcers and clinical bleeds. Rofecoxib did not magnify the risk in any of the patient subgroups studied.
In vivo and in vitro permeability in coeliac disease
Authors: Vogelsang H. , Schwarzenhofer M. , Steiner B. , Wyatt J. , Oberhuber G.
Published: March 2003

Background:

An increased permeability to sugars is found in the intestine of untreated patients with coeliac disease after oral ingestion.

Aim:

To test whether in vitro permeability resembles in vivo permeability tests and whether an in vitro gliadin gluten challenge could be performed by an in vitro permeability test.

Methods:

We measured in vivo (urinary excretion after sucrose–lactulose–mannitol ingestion) and in vitro permeability (by mini‐Ussing chambers) in 25 healthy controls, 12 relatives of coeliac disease patients, 19 treated, eight partly treated and 16 untreated patients with coeliac disease.

Results:

In vivo sugar permeability was increased in nearly all coeliac patients. Additionally, in vitro permeability to lactulose (P=0.0007), mannitol (P=0.004) and sucrose (P=0.042) was higher in untreated patients with coeliac disease. It correlated with in vivo permeability (sucrose τ=0.61, P=0.006; lactulose τ=0.41, P < 0.0001; mannitol τ=– 0.56, P=0.62) and was dependent on mucosal damage. An in vitro gliadin challenge over 24 h could not significantly change in vitro permeability in treated patients with coeliac disease.

Conclusions:

An in vitro permeability test capable of measuring elevated permeability in coeliac mucosa was described, but this test cannot replace oral gluten challenge by in vitro gliadin incubation.
Apoptosis and proliferation in Helicobacter pylori‐associated gastric intestinal metaplasia
Authors: Leung W. K. , Yu J. , To K. F. , Go M. Y. Y. , Ma P. K. , Chan F. K. L. , Sung J. J. Y.
Published: March 2003

Background:

Imbalance between apoptosis and proliferation may be one of the mechanisms underlying H. pylori associated gastric carcinogenesis.

Aim:

To examine the cell kinetics of gastric intestinal metaplasia and the effect of H. pylori eradication.

Methods:

Endoscopic gastric biopsies were obtained from 100 H. pylori‐infected patients. Apoptosis was determined by triphosphate nick‐end labelling (TUNEL) and apoptotic nuclei counting, whereas proliferation was assessed by Ki67 immunostaining. Gastric biopsies were repeated in a sub‐group of intestinal metaplasia patients after H. pylori eradication.

Results:

Antral apoptotic index was significantly lower in intestinal metaplasia than in non‐intestinal metaplasia (0.19% vs. 0.51%; P < 0.0001) whereas the level of proliferation was comparable (28% vs. 22%, P=0.15). Serial antral biopsies taken from 14 intestinal metaplasia patients before and 1 year after H. pylori eradication showed a significant drop in proliferation in both intestinal metaplasia (50% vs. 12%, P < 0.001) and non‐intestinal metaplasia area (47% vs. 9%, P < 0.001). A similar fall in apoptosis was detected in non‐metaplastic region (0.58% vs. 0.38%, P < 0.001) but not in intestinal metaplasia (0.24% vs. 0.27%, P=0.56), resulting in a significant increase in the apoptosis/proliferation ratio (0.005–0.021; P=0.03).

Conclusions:

Dysregulation in apoptosis control of gastric intestinal metaplasia may contribute to gastric carcinogenesis, which may be retarded by clearance of H. pylori.
Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism
Authors: Hokari K. , Sugiyama T. , Kato M. , Saito M. , Miyagishima T. , Kudo M. , Nishikawa K. , Ishizuka J. , Komatsu Y. , Mizushima T. , Kagaya H. , Hige S. , Takeda H. , Asaka M.
Published: March 2003

Background:

Rabeprazole is a new, potent, proton pump inhibitor. The metabolism of rabeprazole is less dependent on CYP2C19 genetic polymorphism.

Methods:

A total of 102 Helicobacter pylori‐positive patients with gastric ulcer were randomly allocated to three groups: rabeprazole 10 mg (RAC10), rabeprazole 20 mg (RAC20) or rabeprazole 40 mg (RAC40) plus amoxicillin 750 mg and clarithromycin 200 mg twice daily for 7 days. CYP2C19 genotype was determined by the polymerase chain reaction‐restriction fragment length polymorphism method.

Results:

All‐patients‐treated‐based eradication rates in patients treated with RAC10, RAC20 and RAC40 were 83%, 77% and 90%, respectively, and per protocol‐based eradication rates were 83%, 80% and 90%, respectively. The eradication rates in the three groups were not significantly different. There was also no significant difference between the all‐patients‐treated‐based eradication rate in CYP2C19 extensive metabolizers and that in poor metabolizers (86% vs. 77%). Adverse events were 12% in extensive metabolizers and 23% in poor metabolizers, and the difference in these incidence rates was also not statistically significant.

Conclusions:

Triple therapy with 10 mg of rabeprazole combined with amoxicillin/clarithromycin is effective for Japanese patients with H. pylori infection, and the H. pylori eradication rate is not affected by CYP2C19 genetic polymorphism.
Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH
Authors: Shirai N. , Furuta T. , Moriyama Y. , Okochi H. , Kobayashi K. , Takashima M. , Xiao F. , Kosuge K. , Nakagawa K. , Hanai H. , Chiba K. , Ohashi K. , Ishizaki T.
Published: March 2003

Background:

Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non‐enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual’s CYP2C19 status.

Aim:

To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes.

Methods:

Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post‐dose days 1 and 8, 24‐h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined.

Results:

After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed.

Conclusions:

The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.
Lansoprazole vs. omeprazole for gastro‐oesophageal reflux disease: a pH‐metric comparison
Authors: Frazzoni M. , De Micheli E. , Grisendi A. , Savarino V.
Published: March 2003

Background:

Lansoprazole and omeprazole are widely used proton pump inhibitors for the management of gastro‐oesophageal reflux. Normalization of oesophageal acid exposure is an important goal in the management of complicated and atypical gastro‐oesophageal reflux disease.

Aim:

To compare the efficacy of lansoprazole and omeprazole in the abolition of abnormal reflux as assessed by oesophageal pH monitoring.

Methods:

Seventy patients with complicated or atypical gastro‐oesophageal reflux disease were randomly assigned to receive 30 mg lansoprazole or 20 mg omeprazole once daily. Three to four weeks after the start of treatment, patients underwent oesophageal pH monitoring while on therapy. If the results were still abnormal, the proton pump inhibitor dosage was doubled and 24‐h pH‐metry was repeated after 20–30 days.

Results:

Thirty‐six patients were randomized to receive lansoprazole and 34 patients to receive omeprazole. Ten of the 36 (29%) patients treated with 30 mg lansoprazole once daily and 23 of the 34 (68%) patients treated with 20 mg omeprazole once daily had persistently abnormal reflux at oesophageal pH monitoring (P < 0.001). In all such cases, repeat pH monitoring after doubling the proton pump inhibitor dosage gave normal results.

Conclusions:

At the currently marketed dosages of lansoprazole and omeprazole, normalization of oesophageal acid exposure in patients is accomplished more easily with lansoprazole.
A double‐blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis
Authors: Green J. R. B. , Mansfield J. C. , Gibson J. A. , Kerr G. D. , Thornton P. C.
Published: March 2003

Background:

Sulfasalazine is well established in the treatment of active ulcerative colitis. Intolerance to sulfasalazine, however, is a common problem. Balsalazide has been designed to deliver 5‐aminosalicylic acid to the colon without the poor tolerability of sulfasalazine.

Aim:

To compare the safety and efficacy of balsalazide, 6.75 g daily, with sulfasalazine, 3 g daily, in the treatment of active ulcerative colitis of all grades of severity.

Methods:

Balsalazide and sulfasalazine were compared in a multicentre, double‐blind, parallel group study over 12 weeks. Patients were stratified for disease severity and topical and/or oral steroids were co‐administered where clinically necessary.

Results:

Fifty‐seven patients were randomized: 28 to receive balsalazide and 29 to receive sulfasalazine. Significantly fewer patients withdrew from the balsalazide group due to adverse events (2/28 vs. 9/29, P=0.041). These data confirm that balsalazide is better tolerated than sulfasalazine. In patients able to tolerate the treatment, similar improvements were recorded in clinical, sigmoidoscopic and histological assessments in both treatment groups.

Conclusions:

This study confirms the better tolerability of balsalazide compared to sulfasalazine, and supports the use of balsalazide in ulcerative colitis of all grades of severity.
Lectins can reverse the distal intestinal atrophy associated with elemental diets in mice
Authors: Sasaki M. , Fitzgerald A. J. , Grant G. , Ghatei M. A. , Wright N. A. , Goodlad R. A.
Published: March 2003

Background:

Elemental diets cause intestinal atrophy and reduced intestinal integrity, which can lead to significant increases in intestinal permeability and bacterial translocation. Recently, several lectins have been shown to have trophic effects on the intestine.

Aims:

We examined the effects of concanavalin‐A and phytohaemagglutinin on cell proliferation and crypt fission throughout the intestine of mice fed on elemental diets.

Methods:

Mice were randomized to chow fed, elemental diet, elemental diet plus concanavalin‐A and elemental diet plus phytohaemagglutinin groups. Cell proliferation and crypt fission were estimated in microdissected crypts. Plasma gastrin and enteroglucagon levels were measured by radioimmunoassay.

Results:

Elemental diet feeding significantly decreased cell proliferation and crypt fission of the middle and distal small intestine and throughout the colon. Phytohaemagglutinin significantly increased the weight of the intestine, but concanavalin‐A had little effect. Cell proliferation in the small intestine was significantly increased by both lectins. However, in the stomach and colon, only phytohaemagglutinin increased proliferation. Crypt fission in the colon was dramatically increased by phytohaemagglutinin. Phytohaemagglutinin increased the plasma gastrin level, but not the enteroglucagon level.

Conclusions:

Lectins have significant trophic effects on the small intestine and colon of mice fed elemental diets, and these actions vary between different sites in the gastrointestinal tract.
Sulphide‐induced energy deficiency in colonic cells is prevented by glucose but not by butyrate
Authors: Hulin S. J. , Singh S. , Chapman M. A. S. , Allan A. , Langman M. J. S. , Eggo M. C.
Published: March 2003

Background:

In ulcerative colitis, hydrogen sulphide is postulated to impair colonocyte butyrate metabolism, leading to cellular energy deficiency and dysfunction.

Aims:

To determine the effects of sulphide exposure on butyrate metabolism and adenosine triphosphate levels of HT29 colonic epithelial cancer cells, and to establish whether energy deficiency can be prevented by increased butyrate concentrations or the presence of glucose.

Methods:

HT29 cells were maintained in medium containing 3 mM butyrate, 5 mM glucose, or both substrates. Oxidation rates were measured by 14CO2 release from 14C‐labelled substrates. Cellular adenosine triphosphate was assayed using the luciferin/luciferase chemiluminescent method. The effects of sulphide (0–5 mM) on substrate oxidation and adenosine triphosphate levels and of increasing butyrate concentration (0–30 mM) with sulphide were observed.

Results:

HT29 cells showed similar energy substrate usage to primary colonocyte cultures. Sulphide exposure inhibited butyrate oxidation and led to a reduction in cellular adenosine triphosphate. This fall was prevented by co‐incubation with glucose, but not by increasing concentrations of butyrate.

Conclusions:

HT29 cells utilize butyrate as an energy substrate and represent a useful in vitro model of the effects of sulphide on colonocytes. Sulphide inhibits butyrate oxidation and leads to demonstrable energy deficiency, prevented by the presence of glucose but not by increased butyrate concentrations.
Randomized, controlled trial of recombinant human interleukin‐11 in patients with active Crohn's disease
Authors: Sands B. E. , Winston B. D. , Salzberg B. , Safdi M. , Barish C. , Wruble L. , Wilkins R. , Shapiro M. , Schwertschlag U. S. ,   THE RHIL‐11 CROHN'S STUDY GROUP
Published: March 2003

Background:

Interleukin‐11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin‐11 (rhIL‐11) in patients with Crohn's disease.

Aim:

To determine the safety and preliminary estimate of efficacy of rhIL‐11 in treating active Crohn's disease.

Methods:

Patients with mild to moderately active Crohn's disease, defined as a Crohn's disease activity index (CDAI) ≥ 220 and ≤ 450, were enrolled in a multicentre trial. Stable doses of 5‐aminosalicylates, antibiotics, 6‐mercaptopurine or azathioprine were permitted with appropriate wash‐in periods. Oral, intravenous or rectally administered corticosteroids were not allowed. Patients were randomized to 6 weeks of subcutaneous injection with rhIL‐11 15 μg/kg or placebo weekly, or rhIL‐11 7.5 μg/kg or placebo twice weekly. The primary end‐point was per cent change in CDAI at week 6; the major secondary end‐point was the proportion of patients in remission, defined as a 100 point decrease in CDAI and absolute CDAI ≤ 150.

Results:

Baseline characteristics were similar among the 148 evaluated patients (49 placebo, 49 rhIL‐11 15 μg/kg once weekly, 50 rhIL‐11 7.5 μg/kg twice weekly). Treatment was well‐tolerated, with mild injection site reactions occurring more frequently among patients treated with rhIL‐11. Headache, oedema, and increased platelet count occurred significantly more often in the rhIL‐11 7.5 μg/kg twice weekly group, but not the 15 μg/kg once weekly group. There was a trend toward decreased mean per cent change in CDAI in the rhIL‐11 15 μg/kg once weekly group vs. placebo (–31.5% vs. – 18.5%, 95% confidence interval for the difference – 27.9–1.6%). A significantly greater proportion of patients receiving rhIL‐11 15 μg/kg once weekly achieved remission compared to placebo (36.7% vs. 16.3%, 95% confidence interval for the difference 3.4–37.4%; 16.4% for rhIL‐11 7.5 μg/kg, N.S.).

Conclusions:

Weekly subcutaneous injection with rhIL‐11 15 μg/kg is safe and effective in inducing remission in a subset of patients with active Crohn's disease.
Effect of acute and chronic levosulpiride administration on gastric tone and perception in functional dyspepsia
Authors: Distrutti E. , Fiorucci S. , Hauer S. K. , Pensi M. O. , Vanasia M. , Morelli A.
Published: March 2003

Background:

Altered visceral perception is common in functional dyspepsia (FD). Dopaminergic pathways control gastrointestinal motility, but whether they modulate visceral sensitivity is unknown.

Aim:

To investigate whether levosulpiride, a D2 antagonist, modulates gastric sensitivity and compliance in dyspeptic patients.

Methods:

Eight healthy subjects and 16 dyspeptic patients underwent graded gastric distensions using a tensostat. In dyspeptic patients the same isotonic distensions were repeated during either levosulpiride or saline administration. Eight FD patients were evaluated after 4‐week treatment with oral levosulpiride. Gastrointestinal symptoms were evaluated using a 100 mm visual analogue score. Perception was scored on a scale of 0 to 6.

Results:

Although healthy subjects and FD patients had similar gastric compliance, FD patients tolerated lower tension levels. At the same distending tension levels, levosulpiride decreased gastric compliance and perception score (14 ± 6% and 38 ± 10% change, respectively; P < 0.05 vs. saline) only in FD patients. Isotonic distensions exhibited very reproducible perception. Chronic levosulpiride administration significantly reduced dyspeptic symptoms and increased discomfort threshold.

Conclusions:

Compared with healthy subjects, FD patients show marked gastric hypersensitivity. In FD patients levosulpiride decreased the perception of gastric distension with an action unrelated to change of gastric tone. Chronic levosulpiride administration significantly ameliorates gastrointestinal symptoms and increases the discomfort threshold.