Pentagastrin increases pepsin secretion without increasing its fractional synthetic rate.

We studied the effects of increasing doses of pentagastrin on gastric secretion of pepsin and on incorporation of L-[1-13C]leucine into gastric aspirate protein as an index of pepsin synthesis. Pentagastrin (0.25-4.0 micrograms.kg-1.h-1) significantly increased pepsin output from basal 76 mg/h to < or = 181 mg/h but did not significantly alter incorporation of L-[1-13C]leucine from the basal fractional synthetic rate of 3.63 +/- 0.05%/h. In four subjects in whom infusion of tracer leucine was continued for > 1 day, aspiration of pepsin between 24 and 27 h demonstrated that plateau 13C labeling of leucine in pepsin had been attained, but at a value that was only 48% of the 13C labeling of plasma alpha-ketoisocaproic acid (alpha-KIC) [0.730 +/- 0.02 (SE) vs. 1.520 +/- 0.14 atoms %excess]. This suggests that actual rates of pepsin synthesis were approximately double those calculated on the basis of alpha-KIC labeling. The results are consistent with an interpretation that increasing doses of pentagastrin cause increased secretion of pepsinogen by recruitment of gastric chief cells, each synthesizing pepsinogen at an unaltered rate. Plateau 13C enrichment of alpha-KIC may not be a valid surrogate for plateau 13C leucine enrichment when fractional synthetic rates of some secreted proteins are calculated.

Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group.

BACKGROUND: Lansoprazole is a H+.K(+)-ATPase (proton pump) inhibitor with an anti-secretory action and is therefore potentially useful in the treatment of gastro-oesophageal reflux. METHODS: This study was conducted to determine the efficacy and short-term safety of lansoprazole at doses of 30 mg or 60 mg once daily, compared with ranitidine 150 mg twice daily, in the treatment of patients with reflux oesophagitis. This was a double-blind, stratified, randomized, comparative, parallel group study conducted in five centres in the UK. A total of 229 patients (155 men) aged 18-79 years with endoscopically-confirmed oesophagitis were randomized to receive lansoprazole 30 mg p.o. daily, lansoprazole 60 mg p.o. daily, or ranitidine 150 mg p.o. b.d. Efficacy was assessed by endoscopic examination at 4 weeks and 8 weeks, together with symptom relief and antacid usage. RESULTS: Lansoprazole 30 mg and 60 mg were superior at 4 and 8 weeks (P < 0.01) to ranitidine in healing reflux oesophagitis: respective healing rates being 84%, 72% and 39% after 4 weeks and 92%, 91% and 53% after 8 weeks. Relief of heartburn with lansoprazole 30 mg and 60 mg was superior to that achieved with ranitidine at both week 4 (P < 0.01) and week 8 (P < 0.02). Sixty-four patients experienced a total of 85 adverse events, one-third of which were considered drug-related. The incidence and severity were similar in the three groups. CONCLUSION: Lansoprazole 30 mg and 60 mg once daily are more effective than ranitidine 150 mg twice daily in the short-term treatment of reflux oesophagitis.

Rapid healing of gastric ulcers with lansoprazole.

BACKGROUND: Lansoprazole is a new proton pump inhibitor which powerfully decreases acid secretion. METHODS: We compared the efficacy and short-term safety of lansoprazole against ranitidine in the healing of gastric ulcer. This was a parallel group, comparative multicentre, prospectively randomized, double-blind study which included 250 patients with gastric ulcer, 219 of whom had follow-up endoscopic data. RESULTS: Both lansoprazole 30 mg and 60 mg daily produced significantly more rapid healing of gastric ulcer than ranitidine 300 mg nightly with healing rates after 4 weeks of 78% (P < 0.05), 84% (P < 0.01) and 61%, respectively. After 8 weeks, the corresponding healing rates were 99%, 97% and 91% (P = 0.08). Symptom relief was similar for all treatment groups, but fewer antacids were used by patients receiving lansoprazole. Sixty-nine patients experienced 91 adverse events; the incidence, pattern and severity was similar across all three treatment groups. CONCLUSIONS: Lansoprazole 30 mg and 60 mg once daily had similar efficacy. Both were superior to ranitidine 300 mg nocte in healing gastric ulcer. The short-term safety profile of lansoprazole was similar to ranitidine. These data indicate that lansoprazole should be used at a dose of 30 mg once daily for the treatment of gastric ulcers.

Secretory and absorptive activity of oesophageal epithelium: evidence of circulating mucosubstances.

The space between the oesophageal basal and prickle epithelial cells appears empty by standard ultrastructural preparative techniques. Fixation of human oesophageal biopsies with a variety of agents, including tannic acid, glutaraldehyde-lysine, cetylpyridinium chloride and Ruthenium Red shows that this space is filled with mucosubstances, some free, some attached to the cells as a glycocalyx. There is evidence that this material is secreted constitutively by the basal and prickle cells. This secretion may be changed or blocked by incubating oesophageal biopsies in the presence of colchicine or dinitrophenol. Incubation at 16 degrees C has the same effect. Absorption from the intercellular space may be followed using the fluid phase marker, horseradish peroxidase. Early endosomes may also be shown by their acid phosphatase activity. Incubation of biopsies at 20-22 degrees C allows early endosomes to accumulate material, but not pass it on the late endosomes.

Problems with the interpretation of gastric pH measurement.

The present study examines some of the assumptions underlying the use of intragastric pH-metry for assessing the degree of therapeutic gastric inhibition. Three separate studies were performed to determine the relationship between pH and titratable hydrogen ion concentration in gastric juice and to assess the relationship between the concentration of acid and the rate of gastric secretion. The concentration of acid derived from pH measurements tended to be lower than the titrated hydrogen ion concentration. The difference between the two readings--the "buffered" hydrogen ion concentration--was increased by the presence of food and was reduced during gastric secretory inhibition with ranitidine. The titrated hydrogen ion concentration reflected more accurately the amount of hydrochloric acid added to a container in vitro than pH measurement. However, in vivo even the measurement of titratable acidity was poorly correlated with the volume of secreted gastric juice so that measurement of gastric acid concentration does not permit inferences about the rate of gastric secretion. The results of the present study indicate that measurement of intragastric pH is unsatisfactory for assessing gastric secretion, particularly in response to a food stimulus, so that measurement of gastric acidity alone does not reflect the rate, or changes in the rate, of gastric acid secretion.

Safety profile of ranitidine. A review.

Ranitidine has been used for the treatment of millions of patients during the past 10 years. A small proportion of patients have developed a reaction to the drug shortly after the start of treatment, usually as a result of 'individual idiosyncrasy'. Reactions during continuous, long term treatment with ranitidine are uncommon, so that maintenance treatment of the chronic peptic diseases with ranitidine for more than 10 years has not been associated with significant iatrogenic disease.

Improved symptom relief and duodenal ulcer healing with lansoprazole, a new proton pump inhibitor, compared with ranitidine.

The purpose of this study was to compare duodenal ulcer healing, symptom relief, and safety of lansoprazole (a new proton pump inhibitor) given at doses of 30 mg and 60 mg, in the morning with ranitidine 300 mg at bedtime. Two hundred and eighty nine patients were enrolled over a 20 month period in a double blind randomised parallel group comparative study set in outpatient endoscopy units of six United Kingdom medical centres. Patients were randomised to receive lansoprazole 30 mg in the morning (n = 95), 60 mg in the morning (n = 96), or ranitidine 300 mg at bedtime (n = 98) for four weeks. Efficacy was assessed by gastroscopy at study entry and after two and four weeks of treatment. Symptom relief was monitored by patient diaries and physician review at two and four weeks. Both doses of lansoprazole resulted in significantly greater ulcer healing than ranitidine after two and four weeks. Respective healing rates on lansoprazole 30 mg, 60 mg, and ranitidine 300 mg were 78%, 80%, and 60% after two weeks and 93%, 97%, and 81% after four weeks. Patients on lansoprazole 30 mg (p = 0.002) and lansoprazole 60 mg (p = 0.026) also recorded greater relief of night time pain in the diary cards during the first seven days of treatment than those on ranitidine. Patients on lansoprazole 60 mg reported significantly better pain relief at their two week visit compared with those receiving ranitidine (p = 0.007). There were no differences between treatment groups in the occurrence or pattern of adverse drug reactions during the trial. It is concluded that for patients with duodenal ulcer, lansoprazole 30 mg or 60 mg is associated with faster ulcer healing and better symptom relief than ranitidine 300 mg at bedtime. There were no significant differences between lansoprazole 30 mg and 60 mg. These data indicate that lansoprazole should be used at a once daily dose of 30 mg for the treatment of duodenal ulcer.

Trends in morbidity and mortality from peptic ulcer disease: Tayside versus Scotland.

Recent studies have shown that the prophylactic use of H2-receptor antagonists reduces both ulcer recurrence and the risk of ulcer complications. Despite these results, epidemiological studies have failed to show any evidence of an effect of gastric anti-secretory drugs on complicated ulcer disease in the community. Since 1979, it has been the policy of the gastroenterology department at Ninewells Hospital in Tayside to recommend long-term, continuous therapy with H2-receptor antagonists for patients with peptic ulcer; in contrast, prophylactic therapy is less commonly used in the rest of Scotland. The difference in the management of peptic ulcer between Tayside and Scotland presented an opportunity to study the population effects of the widespread use of continuous H2-receptor antagonists on the morbidity and mortality from ulcer disease. This study compared the trends in hospital admissions, gastric surgery, haemorrhage, perforation and mortality from ulcer disease using data supplied by the Information and Statistics Division of the Common Services Agency, Scottish Health Service, Edinburgh. During the 1980s, hospital admissions for peptic ulcer declined significantly in Tayside, whereas in Scotland there was no obvious downward trend. Gastric surgery for ulcer disease declined throughout Scotland although the fall was significantly steeper in Tayside than in the rest of Scotland. For the population in general, the rate of perforation decreased faster in Tayside than in the rest of Scotland, although the difference was not significant. The rate of admissions for ulcer haemorrhage declined substantially in Tayside whereas there was little change in Scotland as a whole. The decrease in mortality from ulcer disease in all groups except younger females was more marked in Tayside than in Scotland, although the differences were not significant. The magnitude of the differences between Tayside and Scotland, and in particular the consistency of these results across a broad range of indicators of ulcer disease, suggests that the policy of prescribing long-term, continuous therapy with H2-receptor antagonists has reduced both uncomplicated and complicated peptic ulcer in the community in Tayside.

A placebo-controlled investigation of duodenal ulcer recurrence after withdrawal of long-term treatment with ranitidine.

Ninety-two patients with duodenal ulcer disease, who had received long-term continuous treatment with ranitidine for an average of 7.5 years, participated in a double-blind, placebo-controlled study to determine whether stopping ranitidine resulted in ulcer recurrence. Patients were randomized to continue with ranitidine (n = 46) or to receive placebo (n = 46) and were followed up for six months. Treatment failure was defined as the first symptomatic recurrence of ulcer. The occurrence of epigastric pain during the follow-up period was significantly less frequent in the ranitidine group (13%) than in the placebo group (43%) (P = 0.001). At six months, 9% of the ranitidine group had developed ulcer recurrence, compared with 48% in the placebo group (P < 0.001, logrank test). Multivariate analysis using the Cox proportional hazards model showed that younger age (P = 0.041) and a long history of ulcer disease (P = 0.025) were risk factors for ulcer recurrence but gender, smoking and duration or dose of previous ranitidine treatment were not predictive of relapse during treatment with placebo. In conclusion, withdrawal of ranitidine after more than five years of continuous treatment results in almost half of the patients developing symptomatic ulcer recurrence within six months. Thus, long-term continuous therapy does not alter the natural history of duodenal ulcer disease. Younger patients and those with a long history of ulcer disease appear to be at increased risk of developing ulcer recurrence if long-term treatment is withdrawn.

The administration of supplementary oxygen to prevent hypoxia during upper alimentary endoscopy.

A prospective, randomized, controlled trial was conducted in 200 consecutive patients undergoing endoscopy of the upper alimentary tract. One hundred patients received supplementary oxygen at 4 liters/minute through nasal cannulae, while 100 patients received no additional oxygen. Within each of these two groups, 50 patients were sedated with midazolam and 50 patients with diazepam suspension ("Diazemuls"). The patients' weights were recorded and correlated with their height to assess whether they were over or under their ideal weight. Oxygen saturation was recorded at baseline and throughout the endoscopic procedure. The principal finding of this study was that hypoxia (oxygen saturation less than 93%) was prevented in all cases by the administration of 4 liters/minute of oxygen, whereas 48 of the 100 patients who did not receive oxygen exhibited falls in oxygen saturation to less than 93% (p < 0.0001). Those with the highest risk were the obese patients (p < 0.01). There was no significant difference between the two sedative drug groups in either frequency or severity of associated hypoxia (p = 0.77, patients not given oxygen; p = 0.31, patients receiving oxygen). The cost of administering oxygen during upper gastrointestinal endoscopy would be an average of 95 pence ($1.60) per patient. In conclusion, the administration of oxygen during endoscopy is a worthwhile prophylactic measure to prevent hypoxia and its potential adverse effects.

Increased expression of epidermal growth factor receptors in Barrett's esophagus associated with alkaline reflux: a putative model for carcinogenesis.

A 49-yr-old male was reviewed who had a 10-yr history of reflux esophagitis. He presented initially with frequent heartburn of moderate severity and, on subsequent endoscopy, was noted to have erosive esophagitis and, at that time, a high maximal gastric acid output. During the next 5 yr, his symptoms and acid output diminished. Eight years after presentation, he was noted to have developed a small area of Barrett's metaplasia, without dysplastic change. Ten years after the initial presentation he was completely asymptomatic, despite having extensive Barrett's metaplasia, now with high grade dysplasia. As a result, he was referred for esophagogastrectomy. At the time of surgery, he had alkaline reflux, with antacid gastric contents and, subsequently, hypochlorhydria was proven by a pentagastrin test. A second individual (male, 46 yr) who presented initially with reflux symptoms and gastric-type metaplasia, underwent gastric secretory studies that revealed a peak acid output of 16 mmol/L in 1986. During the period 1989 to 1991, his symptoms progressed despite H2 antagonist therapy. In this regard he was reinvestigated, and his peak acid output in 1991 was 0 mmol/L, and subsequent esophageal biopsies demonstrated intestinal metaplasia in four of six biopsies (two biopsies had high-grade dysplasia; the two others had gastric-type metaplasia). He has refused esophageal resection, and is being reviewed regularly at the endoscopy clinic. Flow cytometric analysis of the esophagus in both individuals revealed expression of epidermal growth factor receptor which was increased in the areas of high grade dysplasia, compared with Barrett's mucosa without dysplasia or normal cardiac mucosa. We conclude that alkaline reflux may accelerate the development of Barrett's esophagus (and intestinal type metaplasia) in patients with gastroesophageal reflux disease. The increased expressed of epidermal growth factor receptors in Barrett's mucosa with dysplasia compared with Barrett's mucosa without dysplasia may reflect the higher malignant potential of the former mucosa.

Expression of epidermal growth factor, transforming growth factor alpha and their receptor in gastro-oesophageal diseases.

This article is a review of aspects of the expression of the regulatory peptides; epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and their receptor (EGF-R) in the epithelium of the human oesophagus and stomach in health and disease. It has become clear that TGF-alpha has increased expression in metaplastic, dysplastic and neoplastic tissue of the oesophagus compared with normal mucosa. The degree of abnormal expression becomes more marked as dysplasia increases. TGF-alpha expression is also increased in gastric neoplasias. EGF has a different pattern of expression, being decreased in oesophagitis and increased in gastritis. Although EGF is present in Barrett's oesophagitis, the expression of EGF does not discriminate between dysplastic and neoplastic epithelium. EGF-R is normally expressed on all gastro-intestinal epithelia, but its expression is increased in Barrett's epithelium, as well as in adenocarcinomas of the oesophagus and the stomach. The two peptides bind to their receptors on the mucosal cell membranes, and the co-expression of peptide and receptor is positively associated with varying degrees of cellular proliferation. The density of receptor expression may modulate the proliferative stimulus, leading to either mitogenic (regulated) or oncogenic (unregulated) growth.

Oesophageal carcinoma: the need for screening.

Oesophageal cancer is a substantial cause of mortality in the Western world and recent data indicate that the incidence is increasing. Despite better understanding of the pathogenesis and in the surgical management of the disease, little improvement in the survival rates has been achieved anywhere in the world, especially because screening for detection of premalignant lesions cannot, at present, be adequately applied to populations at risk. The present review summarizes current knowledge of the use of conventional screening methods as well as possible applications of new techniques to targeted populations to permit earlier diagnosis of premalignant lesions of the oesophagus.

Maintenance therapy in duodenal and gastric ulcer disease: survey of practice amongst British gastroenterologists.

We have used a postal questionnaire to obtain data on the practice of maintenance therapy for peptic ulcer disease by members of the British Society of Gastroenterology. Completed questionnaires were returned by 434 members. Ninety-six per cent used maintenance therapy for patients with duodenal ulcer and 81% for gastric ulcer. Maintenance therapy was considered to be safe (duodenal ulcer 91%; gastric ulcer 78%), acceptable to patients (duodenal ulcer gastric ulcer 89%; gastric ulcer 80%) and to reduce the incidence of ulcer complications (duodenal ulcer 81%; gastric ulcer 68%). There was consensus that increasing age of patient, current use of non-steroidal anti-inflammatory drugs, previous ulcer complications, and ulcer relapse after surgery were relatively strong indications for maintenance therapy. However, the proportion of patients who received maintenance therapy varied widely amongst respondents (from < 10% to > 50%). There was no agreement on the optimal duration of therapy, nor on management of patients who relapsed during maintenance therapy. It appears that the criteria for use of maintenance therapy need to be better defined, and that established knowledge about the practice of maintenance therapy should be better disseminated and acted upon.

[Effectiveness and safety of long-term H2-receptor antagonist maintenance therapy]. / A hosszú távú, fenntartó H2-receptor antagonista kezelés hatásossága és biztonságossága.

The long-term maintenance therapy with an H2 receptor antagonist is currently the best treatment for ulcer disease. The treatment is effective in keeping most ulcers in remission, and is safe both by preventing ulcer complications and because the treatment itself is innocuous. Maintenance therapy achieves the objective of all treatment--it restores patients to normal health. Treatment of ulcer disease with an H2 receptor antagonist can be considered one of the triumphs of modern therapy.

Epidermal growth factor in the oesophagus.

Epidermal growth factor (EGF) has been implicated in mitogenesis and oncogenesis in the gastrointestinal tract. To determine the role of EGF in oesophageal disease, its quantity and distribution in the oesophageal mucosa of control subjects and patients with oesophageal disease were studied. Oesophageal biopsy specimens, taken 20-40 cm from the incisors in 72 patients, were graded histologically and adjacent specimens were taken for immunohistochemical analysis of the distribution of EGF. In patients with Barrett's columnar lined oesophagus, specimens were also taken from the gastric cardia for comparison. Twenty two biopsy specimens showed oesophagitis, 20 Barrett's mucosa, and 30 were histologically normal. EGF was found in the capillary endothelium of the normal oesophageal papillae and basal mucosa. Significantly more EGF positive papillae were found in the normal mucosa (81%) than in the inflamed mucosa (42%) (p < 0.001). The 20 patients with Barrett's mucosa showed abnormal expression of EGF in 25% of the isthmus and superficial epithelial cells. This study has shown that EGF is found only in the endothelial cells of the capillaries of the normal oesophageal mucosa and that the peptide is detectable significantly less frequently than normal in the inflamed oesophageal mucosa. EGF is also abnormally present, in large quantities, in the cytoplasm of the epithelial cells of Barrett's mucosa compared with gastric mucosa.