Dietary phosphilipids and sterols protective against peptic ulceration.

The prevalence of duodenal ulceration in regions of developing countries with a stable diet is related to the staple food(s) in that diet. A higher prevalence occurs in areas where the diet is principally milled rice, refined wheat or maize, yams, cassava, sweet potato or green bananas, and a lower prevalence in areas where the staple diet is based on unrefined wheat or maize, soya, certain millets or certain pulses. Experiments using animal peptic ulcer models showed that the lipid fraction in foods from the staple diets of low prevalence areas gave protection against both gastric and duodenal ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promoted healing of ulceration. The protective activity was found to lie in the phospholipid, sterol and sterol ester fractions of the lipid. Amongst individual phospholipids present in the phospholipid fraction, phosphatidyl ethanolamine (cephalin) and phosphatidyl choline (Lecithin) predominated. The sterol fraction showing activity contained ß-sitosterol, stigmasterol and an unidentified isomer of ß-sitosterol. The evidence shows that dietary phytosterols and phospholipids, both individually and in combination, have a protective effect on gastroduodenal mucosa. These findings may prove to be important in the prevention and management of duodenal and gastric ulceration including ulceration due to NSAIDs.

Mortality in Barrett's esophagus: three decades of experience at a single center.

BACKGROUND AND STUDY AIMS: There is a view that the majority of deaths in patients with Barrett's esophagus are from causes other than esophageal adenocarcinoma (EAC). The aim of this analysis was to establish the pattern of mortality for a number of causes in patients with Barrett's esophagus. PATIENTS AND METHODS: This was a single-center prospective cohort study of patients from Rotherham District General Hospital, which is a secondary referral center. The cohort consisted of 1239 patients who were diagnosed with Barrett's esophagus between April 1978 and March 2009.  Follow-up for mortality was undertaken by "flagging" the patients with the NHS Information Center. Causes of death were compared with UK Office of National Statistics age- and sex-specific mortality data for 1999, the median year of diagnosis. Analysis was by a "person - years at risk" calculation from date of diagnosis. RESULTS: The ratio of observed deaths from EAC compared with those expected in this cohort was 25.02 - a very large excess. There was no difference in mortality from colorectal cancer or circulatory disease and there were fewer deaths from cancers other than esophageal adenocarcinoma and colon cancer compared with national statistics. There was a small statistically significant difference in mortality from all causes but this disappeared completely when deaths from esophageal adenocarcinoma were excluded. CONCLUSIONS: Overall, mortality in Barrett's esophagus is increased significantly but only as a result of the large excess of deaths from EAC. This strengthens the case for endoscopic surveillance if successful interventions can be undertaken in patients with Barrett's esophagus to prevent development of esophageal adenocarcinoma.

Intestinal secretory and absorptive function in Trichinella spiralis mouse model of postinfective gut dysfunction: role of bile acids.

OBJECTIVE: Observations showing that bile acid malabsorption is frequent in irritable bowel syndrome (IBS) suggest that alterations in bile acid-induced secretion and absorption could contribute to IBS-associated diarrhoea. The secretory response to bile acids, fluid transport and bile absorption was examined in intestinal tissues from a Trichinella spiralis mouse model of postinfectious gut dysfunction in vitro. Changes in the protein expression of apical sodium-dependent bile acid transporter (ASBT) were also measured. DESIGN: T. spiralis-infected mice were killed at 18 and 25 days postinfection. Jejunal, ileal, proximal and distal colon segments were exposed to taurodeoxycholic acid (TDCA) or cholic acid. Short circuit current (SCC) increases were determined. Tritiated taurocholic acid (3H-TCA) absorption was determined in everted jejunal and ileal sacs. ASBT protein expression was determined by Western blot analysis and immunohistochemistry. RESULTS: Basal SCC increased in ileum and distal colon at 18 and 25 days postinfection, respectively. Ileal SCC responses to TDCA and cholic acid were enhanced at 18 days postinfection. Distal colon SCC response to TDCA was raised at 18 days postinfection but was significantly reduced by 25 days. Ileal 3H-TCA uptake was significantly reduced at 18 and 25 days postinfection. Surprisingly, increased ASBT expression was observed in infected animals. CONCLUSIONS: In a T. spiralis model of postinfectious gut dysfunction, decreased bile absorption and enhanced secretion in response to bile acids was observed. Decreased absorption was not, however, caused by decreased ASBT as increased expression was observed. If similar events occur postinfection, the combined effects of these disturbances may contribute to some symptoms observed in postinfectious IBS patients.

A clinical trial comparing pantoprazole and esomeprazole to explore the concept of achieving 'complete remission' in gastro-oesophageal reflux disease.

BACKGROUND AND AIM: The outcome of gastro-oesophageal reflux disease treatment is traditionally assessed by measuring endoscopically confirmed healing and symptom relief separately. Both terms together, indicating complete remission, are intuitively a more realistic clinical endpoint but are assessed less often. AIM: To explore this concept, we formally compared the efficacy of the proton pump inhibitors (PPIs) pantoprazole and esomeprazole using rates of complete remission judged against rates of healing and symptom relief separately. METHODS: Five hundred and eighty-two patients with erosive gastro-oesophageal reflux disease were randomized to treatment for 4, 8, or 12 weeks with either pantoprazole or esomeprazole 40 mg daily. Symptom relief was assessed with the validated ReQuesttrade mark-GI subscale. RESULTS: Approximately 75% of patients were free of symptoms or had no oesophageal lesions after 4 weeks' treatment, rising to about 93% and 96%, respectively, at 12 weeks. Complete remission rates were, however, lower at these time points; approximately 60% and about 90%, respectively. Both PPIs had similar efficacy. CONCLUSIONS: Endoscopically confirmed healing and symptom relief assessed separately over-estimated the benefits of both drugs. In contrast, complete remission indicates that patients may be treated inadequately when given the standard 4- to 8-week treatment. We suggest that complete remission is a more reliable and clinically relevant endpoint of treatment.

Characterisation of the haemodynamics of the superior mesenteric artery.

In contrast to its prevalence in the surrounding vasculature, occurrence of primary atherosclerotic disease in the superior mesenteric artery (SMA) is rare (Glagov et al., 1988. Hemodynamics and atherosclerosis, Insights and perspectives gained from studies of human arteries. Archives of Pathology and Laboratory Medicine 112(10), 1018-1031; Hansen et al., 2004. Mesenteric artery disease in the elderly. Journal of Vascular Surgery 40(1), 45-52). We hypothesise that this sparing might be attributed to more favourable haemodynamic characteristics in the SMA than in other vessels locally. Dynamic magnetic resonance imaging (MRI) images established that the SMA is highly mobile (Jeays, 2006. Investigation of blood flow in the superior mesenteric artery and its potential influence on atheroma and gut ischaemia. Ph.D. Thesis, University of Sheffield), and thus that an analysis based on rigid geometry might be inappropriate. This paper describes an efficient methodology for the construction of a patient-specific, time-dependent model of an arterial segment and reports the results of a haemodynamic characterisation of the SMA for one individual. A transient computational fluid dynamic (CFD) model was constructed by morphing a parametric mesh constructed from simple geometric primitives. This process has the merit that it is easy to control the element size distribution mapped onto the original geometric primitives. It is robust in operation, and is ideally suited to the generation of dynamic CFD meshes of arterial systems that are free from major pathology. Flow boundary conditions were determined based on phase contrast MRI velocity measurements. Comparative studies with rigid walls and with moving walls, based on the transient data, indicated that, despite the significant motion of the SMA (radial dilation of the order of 10% and translation of the order of the radius), the maximum (spatially and temporally-resolved) wall shear stresses changed by no more than 21.6% of a global norm, and the average change was less than 2.1%.

Systematic review: do we need a new gastro-oesophageal reflux disease questionnaire?

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is highly prevalent in Western countries. Because the majority of patients do not present with endoscopic abnormalities, the assessment of the symptom severity and quality of life, and their response to treatment, has become increasingly important. Self-assessed symptom questionnaires are now key instruments in clinical trials. AIM: To evaluate the validity of available GERD measurement tools. METHODS: An ideal GERD symptom assessment instrument, suitable as a primary end-point for clinical trials, should possess the following characteristics: (i) be sensitive in patients with GERD; (ii) cover the frequency and intensity of typical and atypical GERD symptoms; (iii) be multidimensional (cover all symptom dimensions); (iv) have proven psychometric properties (validity, reliability and responsiveness); (v) be practical and economical; (vi) be self-assessed; (vii) use 'word pictures' which are easy to understand for patients; (viii) respond rapidly to changes (responsiveness over short time intervals); (ix) be used daily to assess changes during and after therapy; and (x) be valid in different languages for international use. RESULTS: A literature review revealed five scales that met some of the above characteristics, but did not fulfil all criteria. CONCLUSION: There is a need for a new evaluative tool for the assessment of GERD symptoms and their response to therapy.

Evaluation of GERD symptoms during therapy. Part I. Development of the new GERD questionnaire ReQuest.

BACKGROUND/AIMS: The changes in gastroesophageal reflux disease (GERD)-related symptoms on treatment are variously described, but currently available questionnaires have shortcomings. We therefore developed a self-assessment reflux questionnaire (ReQuest). This article describes the process of development and testing. MATERIALS AND METHODS: For the first version of ReQuest the symptom spectrum of GERD and the various symptom descriptions were investigated. The 67 identified symptom descriptions were condensed empirically into 6 dimensions, to which a 7th dimension on general well-being was added. The symptom burden of the dimensions was measured by frequency and/or intensity. ReQuest was translated into different languages and then tested in focus groups. The initial validation was based on data from a clinical trial of patients with erosive GERD, treated with pantoprazole 20 or 40 mg daily for 28 days. Factor analyses determined the contribution of each symptom to the different dimensions. Additionally, correlation analyses between the identified factors and the dimensions were performed. RESULTS: On the basis of factor analyses, ReQuest was reduced to a 60-item scale. The factors generated correlated strongly with the dimensions and confirmed the empirical process mathematically. CONCLUSION: ReQuest provides a valuable, self-assessment tool for evaluating the daily treatment response in patients with erosive GERD.

International validation of ReQuest in patients with endoscopy-negative gastro-oesophageal reflux disease.

BACKGROUND: Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms. AIM: International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease. METHODS: In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients. RESULTS: Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale 0.6; Psychological General Well-being -0.4). CONCLUSION: ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.

Evaluation of GERD symptoms during therapy. Part II. Psychometric evaluation and validation of the new questionnaire ReQuest in erosive GERD.

BACKGROUND/AIMS: Evaluation of the response of gastroesophageal reflux disease (GERD) symptoms to treatment would be facilitated by a brief, valid, reliable and responsive, self-assessed GERD-sensitive scale. We therefore developed the Reflux Questionnaire (ReQuest). This publication describes the psychometric evaluation and validation of ReQuest. METHODS: This second phase of development was based on data from a clinical trial of patients with erosive GERD who received pantoprazole 20 or 40 mg daily for 28 days and completed weekly the long, and daily the short version of ReQuest. The psychometric analyses of ReQuest included internal consistency, test-retest reliability and responsiveness. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale (GSRS) and the Psychological General Well-Being (PGWB) scale. RESULTS: Validation of ReQuest indicated very high internal consistency (Cronbach's alpha = 0.90) and test-retest reliability (intraclass correlation coefficient 0.94 (long-long) and 0.86 (short-short)). This was also the case for the two subscales ReQuest-GI and ReQuest-WSO with Cronbach's alpha coefficients of 0.84 and 0.81. Responsiveness was high with a responsiveness index of >0.8 at day 28. Construct validity was good. CONCLUSION: ReQuest is a highly reliable, valid and responsive self-assessment tool for evaluating treatment response in patients with erosive GERD, and can be applied daily.

Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002.

BACKGROUND: While overall hospital admission rates for peptic ulcer declined in England in the 1990 s, they increased among the elderly, especially for complicated ulcer. However, peptic ulcer admissions fell for all age groups in the United States. AIM: To examine time trends in the incidence of hospital admissions, mortality and operations because of peptic ulcer in Scotland from 1982 to 2002, and the use of various drugs relevant to the aetiology and treatment of peptic ulcer from 1992 to 2002. RESULTS: There was a general decrease in admission rates, especially for younger individuals. For individuals aged above 74 years, admission rates actually increased for gastric ulcer with haemorrhage among men, and for duodenal ulcer haemorrhage between both sexes. The number of operations fell dramatically, especially for younger patients. Mortality rates generally declined. Case fatality rates were greater for women than men, and declined over the study period for gastric ulcer, but increased for duodenal ulcer. The use of low-dose aspirin, oral anticoagulants, selective serotonin reuptake inhibitors and proton-pump inhibitors increased while those of non-steroidal anti-inflammatory drugs and histamine-2 antagonists declined. CONCLUSIONS: Admission rates for peptic ulcer generally fell for younger individuals, but increased for older people with haemorrhage.

Reflux rising! An essay on witnessing a disease in evolution.

BACKGROUND AND AIM: The prevalence of gastro-oesophageal reflux disease is thought to be rising but supporting evidence is sparse. We assessed trends from data prospectively collected over 25 years at our centre which serves Rotherham's 250000 population. PATIENTS AND METHODS: Detailed computerised records have been kept of all patients investigated for upper gastrointestinal symptoms. DEFINITION: Erosive oesophagitis=endoscopy-verified erosive changes. Non-erosive reflux=heartburn+/-regurgitation but normal endoscopy. Gastro-oesophageal reflux disease=erosive oesophagitis+non-erosive reflux, i.e. total. RESULTS: The data, presented in 5-year time periods spanning 1977-2001, showed four major changing trends. (1) The numbers with newly diagnosed gastro-oesophageal reflux disease rose markedly, affecting both erosive oesophagitis and non-erosive reflux. Gastro-oesophageal reflux disease: n=714; 1587; 2381; 3812; 3880. (2) The proportion of women affected rose from 0.36 to 0.82. (3) Gastro-oesophageal reflux disease patients were older than the general population; the mean age at presentation rose from 48.0 to 53.5 years. (4) Presentation with haemorrhage (percentage of erosive oesophagitis) rose from 5.2% to 10.9% but, as with stricture (around 4%), remained uncommon. Throughout, few (4.4%) changed from non-erosive reflux to erosive oesophagitis. CONCLUSION: The marked increase in gastro-oesophageal reflux disease cannot be accounted for by greater awareness alone for the demographic profile has changed, or by misclassification as erosive oesophagitis was diagnosed on endoscopic appearances. The dramatic five-fold increase in gastro-oesophageal reflux disease is a new phenomenon, perhaps an example of a disease in evolution.

Breathomics--exhaled volatile organic compound analysis to detect hepatic encephalopathy: a pilot study.

The current diagnostic challenge with diagnosing hepatic encephalopathy (HE) is identifying those with minimal HE as opposed to the more clinically apparent covert/overt HE. Rifaximin, is an effective therapy but earlier identification and treatment of HE could prevent liver disease progression and hospitalization. Our pilot study aimed to analyse breath samples of patients with different HE grades, and controls, using a portable electronic (e) nose. 42 patients were enrolled; 22 with HE and 20 controls. Bedside breath samples were captured and analysed using an uvFAIMS machine (portable e-nose). West Haven criteria applied and MELD scores calculated. We classify HE patients from controls with a sensitivity and specificity of 0.88 (0.73-0.95) and 0.68 (0.51-0.81) respectively, AUROC 0.84 (0.75-0.93). Minimal HE was distinguishable from covert/overt HE with sensitivity of 0.79 and specificity of 0.5, AUROC 0.71 (0.57-0.84). This pilot study has highlighted the potential of breathomics to identify VOCs signatures in HE patients for diagnostic purposes. Importantly this was performed utilizing a non-invasive, portable bedside device and holds potential for future early HE diagnosis.

Pantoprazole in severe acid-peptic disease: the effectiveness and safety of 5 years' continuous treatment.

OBJECTIVE: This is our final report on the clinical effectiveness and safety of long-term pantoprazole in patients with severe peptic ulcer or reflux disease during continuous treatment for up to 5 years. METHODS: Patients (n= 150) with peptic ulcer or reflux erosive oesophagitis running an aggressive course or with complications, and refractory to H2-receptor antagonists, were entered into this 5-year programme. Assessment was by serial endoscopy, clinical examination, serum gastrin estimation, gastric mucosal histology and mucosal endocrine cell quantification. RESULTS: Healing results were presented earlier. The estimated rates of remission on maintenance treatment with pantoprazole (n = 115) were 82% at 1 year, 75% at 2 years, 72% at 3 years, 70% at 4 years and 68% at 5 years. Helicobacter pylori infection appeared not to influence the outcome in reflux patients, with roughly two-thirds continuing in remission irrespective of infection. Only four patients had adverse events considered to be definitely related to pantoprazole. Median gastrin levels rose by 1.5-2-fold and were higher in those with H. pylori infection; 13 patients had levels >500 ng/L on at least one occasion, but these high levels were not sustained. Histological changes were more marked in patients infected with H. pylori: chronic gastritis decreased in the antrum and increased in the corpus, which also showed atrophic changes. The total number of endocrine cells in the antrum showed little variation over 60 months but fell by around one-third in the corpus. CONCLUSION: Long-term treatment with pantoprazole is effective and safe.

Electrical bioimpedance readings increase with higher pressure applied to the measuring probe.

Electrical bioimpedance spectroscopy (EBIS) is a technique that uses a probe to calculate the transfer impedance from tissues. This transfer impedance can give information about the normal or pathological condition of the tissue. To take readings, pressure has to be applied to the probe in order to get a good contact between the electrodes and the tissue. We have been using EBIS to investigate the early diagnosis of dysplasia and cancer in the human cervix, oesophagus and bladder. We have found that, with increasing pressure (range used here was approximately 1 kPa to approximately 50 kPa), the resistivity readings increase in a consistent way up to 80%. In this paper, we show how this is a case in three different tissue types (oesophageal, gastric and vesical samples). These increases can be higher than those associated with the pathological changes that we are investigating (non-inflamed columnar tissue, for instance, shows values 50% higher than dysplastic columnar tissue). Finite-element modelling was also used to investigate the effect of volume reduction in the connective tissue or stroma. This simulation suggests no strong correlation between reduction of this structure and increase in resistivity. We hypothesize therefore that these changes may be mainly associated with the squeezing of water from the extracellular space. Finally, as pressure is difficult to control by hand, we raise the issue of the necessity of considering this variable when making EIS measurements.

Faecal calprotectin for differentiating between irritable bowel syndrome and inflammatory bowel disease: a useful screen in daily gastroenterology practice.

OBJECTIVE: To determine the best faecal calprotectin (FCP) cut-off level for differentiating between irritable bowel syndrome (IBS) and organic disease, particularly inflammatory bowel disease (IBD), in patients presenting with chronic diarrhoea. DESIGN: Retrospective analysis of patients who had colonoscopy, histology and FCP completed within 2 months. SETTING: District general hospital. PATIENTS: Consecutive new patients with chronic diarrhoea lasting longer than 4 weeks. INTERVENTIONS: Patients were seen by a single experienced gastroenterologist and listed for colonoscopy with histology. Laboratory investigations included a single faecal specimen for calprotectin assay (lower limit of detection: 8 µg/g), the results used for information only. MAIN OUTCOME MEASURES: Six FCP cut-off levels (range 8-150 µg/g) were compared against the 'gold standard' of histology: inflammation 'present' or 'absent'. RESULTS: Of 119 patients studied, 98 had normal colonoscopy and histology. The sensitivity of FCP to detect IBD at cut-off levels 8, 25 and 50 µg/g was 100% (with corresponding specificity 51%, 51%, 60%). In contrast, the lowest FCP cut-off, 8 µg/g, had 100% sensitivity to detect colonic inflammation, irrespective of cause (with negative predictive value (NPV) 100%). Importantly, 50/119 patients (42%) with FCP <8 µg/g had normal colonoscopy and histology. CONCLUSIONS: Our results suggest that using FCP to screen patients newly referred for chronic diarrhoea could exclude all without IBD and, at a lower cut-off, all without colonic inflammation, thus avoiding the need for colonoscopy. Such a major reduction has implications for resource allocation.

Development and application of a new electronic nose instrument for the detection of colorectal cancer.

Colorectal cancer is a leading cause of cancer death in the USA and Europe with symptoms that mimick other far more common lower gastrointestinal (GI) disorders. This difficulty in separating colorectal cancer from these other diseases has driven researchers to search for an effective, non-invasive screening technique. Current state-of-the-art method of Faecal Immunochemical Testing achieving sensitivity ~90%, unfortunately the take-up in the western world is low due to the low patient acceptability of stool samples. However, a wide range of cancers have been distinguished from each-other and healthy controls by detecting the gas/volatile content emanating patient biological media. Dysbiosis afforded by certain disease states may be expressed in the volatile content of urine - a reflection of the gut bacteria's metabolic processes. A new electronic nose instrument was developed at the University of Warwick to measure the gas/volatile content of urine headspace, based on an array of 13 commercial electro-chemical and optical sensors. An experimental setup was arranged for a cohort of 92 urine samples from patients of colorectal cancer (CRC), irritable bowel syndrome (IBS) and controls to be run through the machine. Features were extracted from response data and used in Linear Discriminant Analysis (LDA) plots, including a full 3-disease classification and one focussing on distinguishing CRC from IBS. The latter case was tested by the success of re-classification using an (n-1) K-nearest neighbour algorithm, showing 78% sensitivity and 79% specificity to CRC.

Is there any acid peptic disease that is refractory to proton pump inhibitors?

Non-healing and delayed healing during acid inhibition treatment depend on the extent to which acid and 'non-acid' factors are causative in the particular acid peptic disease, and on the effectiveness and duration of acid suppression. Refractoriness (defined arbitrarily) occurs less often with proton pump inhibitors than with H2-receptor antagonists as the former decrease acid more effectively; H2-receptor antagonist-refractory disease usually responds to treatment with proton pump inhibitors. In Rotherham, 5-10% of duodenal ulcer and gastric ulcer patients are refractory (not healed after > or = 3 months of standard-dose H2-receptor antagonist). In patients with oesophagitis 15% are refractory to high-dose H2-receptor antagonist (for example, 3.2 g cimetidine daily) and 5% to standard-dose proton pump inhibitors (for example, 20 mg omeprazole daily). In controlled clinical trials of patients with refractory duodenal ulcer, healing at 8 weeks with 40 mg omeprazole o.m. vs. continued standard-dose H2-receptor antagonist was 98% vs. 60%; and with 40 mg omeprazole vs. continued high-dose H2-receptor antagonist (2 g + 3 g cimetidine, that is, ultra-refractory disease) was 92% vs. 67%. After healing, in open studies, relapse with maintenance 400-800 mg cimetidine nocte was 45-69% at one year, but 0% with 40 mg omeprazole administered for up to 6.5 years. For 53 patients with refractory gastric ulcer, in an open study, healing with omeprazole 40 mg o.m. occurred in 94% at 8 weeks, and none relapsed on long-term maintenance treatment at this dose. In controlled trials of patients with refractory oesophagitis, healing at 12 weeks with 40 mg omeprazole o.m. vs. high-dose ranitidine (300 mg b.d.) was 90% vs. 47%, and with maintenance 20 mg omeprazole o.m. vs. 150 mg ranitidine b.d., relapse at 1 year was 32% vs. 88%. In conclusion, acid peptic disease refractory to H2-receptor antagonists is uncommon and treatment with proton pump inhibitors is effective. Refractoriness to proton pump inhibitors is rare.

Six years of continuous cimetidine treatment in peptic ulcer disease: efficacy and safety. Anglo-Irish Cimetidine Long-Term Study Group.

The management of peptic ulcer disease with up to 6 years of continuous cimetidine treatment has been studied at four centres in the UK and Ireland. Cimetidine, 1 g daily for up to 12 weeks, was used to heal duodenal or gastric ulceration, alternating with 400 mg each night to maintain remission. After an initial healing phase, 402 patients started maintenance therapy. Classical life-table analyses showed that after 5 years one-quarter of the patients had suffered a symptomatic relapse, about half during the first year of maintenance treatment. Prevalence analyses (reflecting the cyclical nature of H2-antagonist use in peptic ulcer disease) over 6 years show that, on average, over 97% remain free of symptomatic ulceration at any one time. Patients 'lost' to the study due to withdrawal or default may, however, bias the results. A model designed to account for these estimates that during the long-term management of peptic ulcer with cimetidine, on average around 95% of patients remain free of symptomatic ulceration at any one time. Safety studies, including haematological and biochemical testing over the whole period, revealed no previously unknown adverse reaction. Seven patients were withdrawn for events considered to be related to the drug. Eleven patients died; none of the deaths appears to be connected with the treatment. It is concluded that long-term use of cimetidine is effective in the management of peptic ulcer disease, and continuous treatment for up to 6 years has not revealed any previously unknown hazard.