Twelve healthy volunteers were given one week's oral treatment with each of 300 mg nizatidine, 40 mg famotidine, and placebo once daily in a randomised, placebo controlled, double blind study. Three hours after administration, nizatidine led to a significant reduction in the mean (SD) resting heart rate compared with placebo (63.6 (6.4) beats/minute on placebo to 55.9 (7.2) beats/minute on nizatidine (p less than 0.05)), whereas famotidine did not influence the heart rate significantly. Both drugs, however, increased significantly the pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time on mechanocardiography and led to a significant decrease in cardiac output on impedance cardiography. The exercise heart rate on nizatidine as well as the resting heart rate on concurrent administration of nizatidine and the beta receptor blocking agent atenolol were subsequently investigated in the same volunteers. Nizatidine slightly inhibited exercise tachycardia by 4.4% (p less than 0.05). When compared with placebo, the mean resting heart rate was decreased on atenolol alone by a mean of 10.6 beats/minute (p less than 0.01) and fell further on co-administration with nizatidine to a total of 16.1 beats/minute (p less than 0.05 versus atenolol alone). In conclusion, the effect of nizatidine in reducing the heart rate needs careful evaluation in elderly patients with heart failure or those also taking beta blockers. In contrast to famotidine, long term treatment with 300 mg nizatidine a day has mainly negative chronotropic effects.

The effects of atrial natriuretic peptide were investigated on water and electrolyte transport in the human jejunum. Six healthy male volunteers (aged 21-33 years) were studied using a triple lumen perfusion technique. A plasma like electrolyte solution containing polyethylene glycol (5 milligrams) as a non-absorbable marker was perfused into the jejunum at 10 ml/min, and net water and electrolyte transport and transepithelial potential difference were measured. Subjects were studied single blind on two occasions with either intravenous atrial natriuretic peptide (6 pmol/min/kg for 90 minutes) or placebo (saline), both after controlled sodium intake over three days. Plasma atrial natriuretic peptide concentrations rose from (mean (SD)) 10.3 (3.6) pmol/l to a peak of 96.0 (61.8) pmol/l. Jejunal net water and electrolyte fluxes and potential difference were identical in both the atrial natriuretic peptide and the control studies. Compared with placebo atrial natriuretic peptide induced a significantly greater diuresis (peak 10.2 (6.0) v 1.8 (1.0) ml/min, p less than 0.05) and natriuresis (peak 1069 (351) v 376 (208) mumol/min, p less than 0.01) and haemoconcentration (haematocrit 0.405 (0.040) v 0.368 (0.018), p less than 0.01). There was no difference in blood pressure, pulse rate, plasma electrolytes, and plasma osmolality between the two studies. There was no evidence to suggest an effect of atrial natriuretic peptide on jejunal water and electrolyte transport in healthy human subjects.

Some patients with gastro-oesophageal reflux disease have delayed gastric emptying. This study investigates the effect of cisapride on gastric emptying in 34 patients with proved reflux and delayed gastric emptying of solids. They were enrolled in a double blind controlled crossover study. Placebo or cisapride (10 mg) tablets were given three times a day for three days followed by further assessment of gastric emptying. The protocol was repeated with the crossover tablet. Gastric emptying was assessed by a dual radionuclide technique. The percentage of a solid meal remaining in the stomach at 100 minutes (% R100 minutes) and the time taken for 50% of the liquid to empty (T50 minutes) were calculated and analysed by the Wilcoxon matched pairs signed ranks test and expressed as medians (ranges). For gastric emptying of solids the initial % R100 minutes (70 (60-100)%) was not significantly different from placebo (71 (35-100)%). After cisapride treatment a significant acceleration (p less than 0.001) in gastric emptying occurred (% R100 minutes, 50.5 (28-93)%). Similarly with gastric emptying of liquids, the initial T50 minute value was 26.5 (12-82) minutes, after placebo the value was 28 (11-81) minutes, but this was significantly accelerated with cisapride (p less than 0.03) to 22.5 (6-61) minutes. The acceleration in gastric emptying occurred in the proximal portion of the stomach for gastric emptying of both solids and liquids suggesting that this is the principal site of action of cisapride. We conclude that cisapride significantly accelerates gastric emptying of both solids and liquids in patients with gastro-oesophageal reflux disease and delayed gastric emptying.

The ability of hypnosis to modulate the orocaecal transit time of 10 g lactulose was tested in six healthy volunteers. Orocaecal transit time was measured by the hydrogen breath test during three periods in random order. During the control period the subjects remained throughout the test in a semirecumbent position without moving. During the hypnotic relaxation period subjects were hypnotised before lactulose ingestion and were instructed to experience relaxation till the orocaecal transit time had elapsed. During the acceleration suggestion period subjects were hypnotised before lactulose ingestion and were repeatedly instructed to imagine the acceleration of lactulose through the intestine until transit time had elapsed. The mean orocaecal transit time was significantly longer during the hypnotic relaxation period (mean (SEM) 133 (8) min) than during the control period (93 (13) min). The mean orocaecal transit time during the acceleration suggestion period was 105 (26) minutes and was not significantly different from the mean transit time during the control period. The individual values during the acceleration suggestion period were scattered. We conclude that lactulose orocaecal transit time is delayed during hypnotic relaxation.

We tested the hypothesis that the gastric H+/K+ adenosine triphosphatase inhibitor, omeprazole, because of its different mode of action and pronounced inhibitory effect on gastric acid secretion, may be more effective in peptic ulcer that is refractory to histamine H2 receptor antagonist treatment than continuing the same therapy. Altogether 107 patients (duodenal ulcer, n = 88; prepyloric ulcer, n = 14; gastric ulcer, n = 3; mixed sites, n = 2) with refractory peptic ulcer - that is ulcer unhealed after at least two months' treatment with cimetidine 0.8 g or 1 g daily or with ranitidine 0.3 g daily - were randomly allocated to receive either omeprazole 40 mg daily (n = 54) or to continue treatment with the same H2 receptor antagonist and at the same dose (n = 53) for up to eight weeks. The patients in the two treatment groups were well matched demographically. Healing by 'intent to treat' analysis was as follows: at four weeks, omeprazole 46 of 54 (85%), H2 receptor antagonist 18 of 53 (34%) (p less than 0.0001); and at eight weeks, 52 of 54 (96%) and 30 of 53 (57%) respectively (p less than 0.0001). One patient was lost to follow up but of the 22 patients whose ulcers were shown to be unhealed at endoscopy after receiving continued H2 receptor antagonist treatment, 21 healed in four to eight weeks when changed to omeprazole. Daytime epigastric pain cleared at four weeks in 43 of 47 (91%) patients on omeprazole and in 32 of 46 (70%) on H2 receptor antagonists (p=0.01) and relief of all dyspeptic symptoms occurred in 39 of 47 (83%) and 23 of 45 (51%) (p=0.0009) patients respectively. Adverse events occurred in 11 of 54 (20%) patients on omeprazole and in 12 of 35 (34%) on cimetidine but in none on ranitidine. The events were mild and none required treatment withdrawal. The commonest event in patients on omeprazole was loose stools or diarrhoea (n=5). Omeprazole was significantly better than continued H2 receptor antagonist treatment for the short term management of refractory peptic ulcer as judged by healing rate and pain relief, and it was safe.

In a multicentre study the effect of ranitidine on healing non-steroidal anti-inflammatory drug (NSAID) associated peptic ulcers was compared in a group of patients who had stopped NSAID treatment with another group who continued with NSAID treatment. A total of 190 patients with confirmed ulcers were randomised to continue or stop NSAID treatment. All patients in addition received ranitidine 150 mg twice daily. Patients were endoscopically monitored at four, eight, and 12 weeks. Gastric ulcers at eight weeks had healed in 63% of those taking NSAIDs compared with 95% of those who had stopped NSAID treatment. For duodenal ulcer the healing rates at eight weeks were 84% in the group continuing NSAIDs compared with 100% in those who stopped NSAIDs. The differences in healing rates were statistically significant for both gastric ulcer (p = 0.001) and for duodenal ulcer (p = 0.006). At 12 weeks, 79% of gastric ulcers and 92% of duodenal ulcers were healed in the group continuing with NSAIDs. All patients with gastric and duodenal ulcers who stopped taking NSAIDs were healed at 12 weeks. The study shows that ranitidine 150 mg twice daily effectively heals NSAID associated peptic ulcers. Healing is more successful when NSAID treatment stops but even if these drugs are continued, substantial healing rates are achievable.

The hypothesis that oesophageal peristalsis can be modified voluntarily was explored. Six healthy male volunteers and eight female patients with angina like chest pain underwent oesophageal manometry. Each was asked to take a series of swallows, and to vary their size, in random order, by taking either a big gulp or a little swallow. None of the subjects experienced difficulty in doing so. In both groups the amplitude of oesophageal contractions were significantly greater after big gulps than little swallows (p less than 0.01) and this was true for wet (82.0 v 68.9 mmHg) and dry swallows (52.3 v 43.3 mmHg). For the patients' wet swallows the mean values were 73.0 and 56.0 mmHg. Thus, the amplitude of oesophageal peristalsis can be controlled voluntarily. This effect may account for some of the within subject variation in the amplitude of oesophageal contractions. During oesophageal manometry subjects should be encouraged to standardise the size of their swallows whenever possible. Patients with symptoms related to abnormal oesophageal peristalsis such as dysphagia, heartburn, and chest pain may benefit from biofeedback training.

Morphometric measurements were performed on rectal biopsy specimens from 10 normal control subjects and 33 patients with a relapse of distal ulcerative colitis before and after treatment for four weeks in a double blind controlled trial with oral eudragit S coated 5 amino salicylic acid (n = 12) or rectal prednisolone enemas (n = 15). Measurements were assessed using a computer aided measuring system and a counting technique. When untreated patients were compared with the control group there were significant decreases in the area and height of the surface epithelium, in the area of crypt epithelium, and in the ratios of goblet cells to epithelial cells and of surface epithelium to lamina propria. The vascular and lamina propria areas and the number of intraepithelial polymorphs were increased. Treatment with 5 amino salicylic acid and corticosteroids resulted in similar morphological improvements: there was an increase in the area and height of the surface epithelium and the ratios of surface epithelium to lamina propria and of surface to crypt cell height. The ratio of goblet cells to epithelial cells also increased after treatment, while the numbers of polymorphs in the surface and crypt epithelium and lumen decreased. In conclusion, computerised morphometry is valuable for the assessment of the treatment of patients with ulcerative colitis and that in the doses used both treatments were of similar efficacy.

Two hundred patients received either ranitidine 150 mg or 300 mg at night for 18 months to prevent duodenal ulcer relapse. Recurrence rates were lower in patients receiving the higher dose of ranitidine (3.1% v 9.7%, p = 0.78; 6.5% v 16.7%, p = 0.037; and 8.9% v 17.0%, p = 0.121 at six, 12, and 18 months respectively). In patients receiving ranitidine 150 mg, recurrences were significantly more common in smokers than non-smokers after 12 and 18 months, while in patients receiving ranitidine 300 mg recurrence rates were similar in smokers and non-smokers. Ranitidine 300 mg at night abolishes the adverse effect of smoking observed during maintenance treatment with ranitidine 150 mg at night and may therefore be an appropriate maintenance dose for smokers who relapse during standard dose maintenance treatment.

Since it is not known whether the symptoms and bowel function of patients with the irritable bowel syndrome are truly abnormal we used diaries and frequent telephone interviews over a 31 day period to assess symptoms, defecation, and stool types in 26 unselected female hospital patients with the irritable bowel syndrome, 27 women who admitted to recurrent colonic pain but had not consulted a doctor (non-complainers), and 27 healthy control subjects. Unexpectedly, abdominal pain and bloating occurred in most of the control subjects. Pain, however, was six times more frequent in the patients and was more often considered severe. Bloating occurred three times more often. Defecation was more frequent, more erratic in timing and stool form, and more likely to produce stools of extreme forms, indicating rapid fluctuations in intestinal transit time. Urgency was four times more prevalent in patients than control subjects. Straining to finish defecating was nine times more prevalent and was often accompanied by feelings of incomplete evacuation--a combination which could lead to the misdiagnosis of constipation. The normal relation between stool form and the above symptoms was distorted, possibly due to rectal irritability. Non-complainers were intermediate between patients and control subjects in almost every parameter but were closer to control subjects than to patients. Patients with the irritable bowel syndrome have real cause for complaint and their bowel function is truly abnormal.

It has been proposed that the hypergastrinaemia in subjects with Helicobacter pylori infection is caused by the action of the ammonia produced by the organism's urease activity on the antral G cells. To investigate this hypothesis we examined the effect on plasma gastrin of increasing the bacterium's ammonia production by infusing urea intragastrically to eight H pylori positive duodenal ulcer patients. After a 60 minute control intragastric infusion of dextrose solution at 2 ml/minute, a similar infusion containing urea (50 mmol/l) was continued for four hours. During the urea infusion, the median gastric juice urea concentration rose from 1.1 mmol/l (range 0.3-1.6) to 15.5 mmol/l (range 7.9-21.3) and this resulted in an increase in the ammonium concentration from 2.3 mmol/l (range 1.3-5.9) to 6.1 mmol/l (range 4.2-11.9) (p less than 0.01). This appreciable rise in ammonia production did not result in any change in the plasma gastrin concentration. The experiment was repeated one month after eradication of H pylori, at which time the median basal gastrin was 20 ng/l (range 15-25), significantly less than the value before eradication (30 ng/l range 15-60) (p less than 0.05). On this occasion, the gastric juice ammonium concentration was considerably reduced at 0.4 mmol/l (range 0.1-0.9) and the urea infusion did not raise the ammonium concentration or change the plasma gastrin concentration. In conclusion, augmenting H pylori ammonia production does not cause any early change in plasma gastrin.

Strategies for the treatment of cancer of the oesophagus depend on the tumour stage at the time of diagnosis. Resection, the only curative treatment, is confined to early tumour stages. Tumours with local infiltration are usually unresectable and require palliative treatment. Computed tomography has been widely used for preoperative staging but often fails to define this correctly. Endoscopic ultrasound allows direct visualisation of the parietal wall and may be useful in staging gastrointestinal tumours. In a comparative prospective study, 52 patients with tumours of the oesophagus were investigated preoperatively both by endoscopic ultrasound and computed tomography to determine the stage of tumour infiltration and local lymph node involvement. Thirty seven of these patients underwent operation, resection, or dissection and entered the study. The intraoperative findings or the histopathological assessment, or both, were taken as a reference. For all TN stages of oesophageal tumours, correct preoperative staging was accomplished by endoscopic ultrasound in 89% for T stage and 69% for N stage compared with 51% and 51% respectively by computed tomography (highly significant using Fisher's exact test). This study shows that endoscopic ultrasound is useful in preoperative TN staging of tumours of the oesophagus.

Results of continuous 12 hour overnight pH monitoring (duration of pH less than 4) were reviewed in 112 patients with heartburn or regurgitation, or both, and in 56 normal subjects. Patients had more reflux than normal subjects. Medically controlled patients (n = 51) had less acid reflux than patients who subsequently underwent reflux surgery (n = 61), but there was a considerable overlap between those two groups. Surgery was followed by a reduction in acid reflux to a value similar to that in normal subjects. Patients in whom surgery was deemed to have failed had more reflux after the operation than those in whom it was successful, but no difference could be found in the preoperative reflux values of these two subgroups. Monitoring pH is not of value in selecting candidates for surgery since the results are not a good predictor of outcome, but it is useful in the objective evaluation of surgical results.

Urinary excretion of orally administered lactulose and 51 chromium labelled ethylenediamine tetra-acetate (51Cr-EDTA) was measured in 12 healthy adult subjects and in six patients with ileostomies to assess intestinal permeability. In normal subjects, 24 hour urinary recovery of 51Cr-EDTA was significantly greater than that of lactulose (mean (SEM) 2.27 (0.15) v 0.50 (0.08)% oral dose; p less than 0.001), but in ileostomy patients recovery of the two markers was the same. In normal subjects, therefore, the difference between the two markers may arise from bacterial break-down of lactulose but not of 51Cr-EDTA in the distal bowel, urinary excretion of lactulose representing small intestinal permeation and that of 51Cr-EDTA representing both small and large intestinal permeation. The markers were then given simultaneously to nine patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis and osteoarthritis. The 24 hour urinary recovery of 51Cr-EDTA in the patients was significantly greater than normal (4.64 (1.20) v 2.27 (0.15)% oral dose; p less than 0.01), but that of lactulose was not significantly affected. Moreover, the increase in 51Cr-EDTA recovery was most noticeable in the later urine collections. Both of these findings suggest that NSAIDs may increase colonic permeability.

The efficacy of biofeedback treatment on faecal incontinence and anorectal function was evaluated in eight patients with faecal incontinence treated with biofeedback training and medical therapy. Outcome and anorectal function were compared with nine faecal incontinent patients who received medical therapy alone. Three month follow up showed that 50% of patients in the biofeedback plus conventional treatment group and 56% of those treated conventionally only had improved. One year follow up showed that 13% in the biofeedback group were free of soiling and an additional 25% had improved. The results were similar in the conventionally treated group--11% were free of soiling and an additional 44% improved. Anal pressures at rest and squeeze, the rectal distension volume that induced sustained inhibition of both the external and internal anal sphincter, and continence to rectally infused saline were significantly reduced in both groups of patients compared with controls (p less than 0.05). Biofeedback treatment had no effect on these abnormal anorectal functions in either patients who improved or those who did not. The improvement in faecal incontinence was probably due to medical intervention or regression of symptoms with time, or both, and not the result of biofeedback training.

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.

We used continuous variable rate infusions of famotidine in eight normal volunteers under fasting conditions to raise intragastric pH to 5.0. An intragastric glass electrode continuously monitored acidity and this information was automatically computed to regulate an intravenous infusion system (GastroJet). The computer was programmed to aim for pH 6.0, increasing and lowering infusion rates accordingly. Two regimens were compared with placebo (10 mg bolus followed by infusion or infusion of famotidine alone). Volunteers were admitted to an investigation ward and each study was preceded by a standard normal meal. Hydration was maintained with intravenous fluids. During placebo treatment the median pH was 1.5 and the pH was less than 5.0 for 98% of the time. All volunteers responded to famotidine but dosage requirements varied (range 41 mg to 126 mg). The median pH rose to 6.5 when infusions of famotidine followed boluses and to 6.6 when infusions alone were used - the pH was less than 5.0 for 20% and 16% of the time respectively (p less than 0.05 Wilcoxon compared with placebo). Mean drug use was greater with boluses (98 mg v 87 mg p = 0.03: paired Student's t test) and onset was not apparently faster. Blood famotidine concentrations followed infusion rate changes. Famotidine infused by GastroJet maintains a high fasting intragastric pH and priming boluses are probably unnecessary.

Sixty nine patients with non-ulcer dyspepsia have been studied with endoscopy, biopsy, quick urease (CLO) test, Helicobacter pylori culture, and the 13C-urea breath test before and after treatment with tripotassium dicitratobismuthane (DeNol) two tablets twice daily for four weeks. Symptoms of non-ulcer dyspepsia were recorded using a standard questionnaire. Using H pylori culture as the gold standard, the sensitivity of the 13C-urea breath test was 90%, the specificity 98.6%, and the accuracy 94.8% with a positive predictive value of 98.2% and a negative predictive value of 92.5%. Conversion rate from H pylori positive to negative status after treatment with tripotassium dicitratobismuthate was 17.9%. Symptoms of non-ulcer dyspepsia improved appreciably after treatment irrespective of H pylori status. The 13C-urea breath test is an accurate research tool suitable for serial testing and population surveys.

The relation between gastric emptying and the intragastric distribution of 300 ml radiolabelled beef consommé with and without 60 g margarine was investigated by performing randomised, paired gammacamera studies in seven healthy male volunteers (aged 20-22 years). The low calorie bland meal emptied rapidly from both the proximal and distal stomach after a short lag period (4-6 min), during which 24-50% of the liquid passed into the distal stomach. Addition of margarine to the liquid test meal increased the lag period (median 32 min, range 7-60 min; p less than 0.01) and decreased the slope of emptying (T1/2 lag period 88 min, 49-146 min v 15 min, 10-57 min; p less than 0.01). During the lag period there was an initial filling of the distal stomach, similar to that with the bland liquid, followed by a redistribution of between 19% and 61% (median 46%) of the distal stomach contents back into the proximal stomach. At the onset of emptying, the distal stomach filled (median 30%, range 16-34%) and during this time the proximal stomach emptied twice as fast as the whole stomach (p less than 0.05). Thereafter, the distal stomach capacity remained relatively constant while both the proximal and whole stomach emptied at similar rates. This study shows that the delay in gastric emptying of a liquid that has a high fat content is due in part to a redistribution of distal stomach contents back into the proximal stomach.