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Background: There has been a dramatic rise in incidences of Barrett's oesophagus and oesophageal adenocarcinoma. It has been suggested that the introduction and use of acid suppression therapy may be a factor in the rising incidences of Barrett's oesophagus and oesophageal adenocarcinoma., Methods: This was a record linkage study, using a prescribing database and an endoscopy database. Patients who had undergone their first endoscopy during the period 1992-1995 and received the diagnosis of Barrett's oesophagus or oesophagitis were identified. The prescribing of acid suppressants was compared for the 3 years prior to endoscopy, between those with Barrett's oesophagus and those with oesophagitis., Results: There was no significant difference between the Barrett's patients and the oesophagitis patients in the proportion that had been exposed to acid suppression therapy (53.4% vs. 51.7%, P=0.704). The mean number of days of prescribing among those who had been exposed to acid suppression therapy was higher in the Barrett's group (340.5 vs. 237.0 days, P=0.001)., Conclusions: Patients with Barrett's oesophagus have received more acid suppressant therapy prior to diagnosis. The reasons for this are not clear. However, 46.6% of Barrett's patients have not been exposed to acid suppressant therapy.

Background: Because of their tolerance and safety, low doses of H2-receptor antagonists are now increasingly used in some countries for self-care medication of gastro-oesophageal reflux symptoms., Aim: The purpose of this randomized, double-blind, placebo-controlled, five-way crossover study was to determine and to compare the effects of low doses of ranitidine and cimetidine both on gastric pH and on oesophageal acid exposure., Methods: Gastric and oesophageal pH were simultaneously monitored in 20 healthy subjects using two glass pH electrodes, after placebo and single doses of ranitidine 75 mg and cimetidine 200 mg (effervescent and tablet forms), for 4 h before and after a meal., Results: During the fasting period, median gastric pH rose significantly with both drugs, but more rapidly with the effervescent forms; the oesophageal acid exposure was significantly decreased by all drug regimens. After the meal, although there was no significant difference in gastric pH values, oesophageal acid exposure was significantly decreased in comparison with placebo with both forms of ranitidine (P < 0.05), and also for ranitidine tablets in comparison with cimetidine tablets (P < 0.05)., Conclusions: Low doses of ranitidine and cimetidine increase gastric pH, with a more pronounced effect for ranitidine. Effervescent formulations of both drugs induce a slightly more rapid initial increase in pH than tablets. Ranitidine demonstrates a more prolonged effect than cimetidine and decreases oesophageal acid exposure monitored after a meal ingested 4 h after the drug intake.

Aim: To compare the effects of ranitidine 75 mg with those of either cimetidine 200 mg or placebo given on demand for relief of typical symptoms of gastro-oesophageal reflux disease during a 15-day period., Methods: A total of 1336 patients (aged > or = 18 years) with heartburn episodes were recruited and randomly assigned to a ranitidine 75 mg, cimetidine 200 mg or placebo group. Depending on the occurrence or persistence of heartburn, treatment was administered as required up to three times daily, with at least 2 h between drug doses. Antacids were allowed as rescue medication if symptoms persisted for at least 2 h after the third medication on any given day. The primary end-point was defined as the proportion of patients with relief of at least 75% of heartburn episodes during the study period (i.e. relief occurring within 2 h after drug ingestion and lasting for at least 5 h)., Results: Analysis was performed in an intention-to-treat population comprising 504 subjects in the ranitidine group, 515 in the cimetidine group and 270 in the placebo group. Primary end-point success rates were 41, 38 and 28%, respectively, for the three groups (P < 0.001 for ranitidine vs. placebo, P = 0.274 for ranitidine vs. cimetidine). Ranitidine 75 mg was significantly more effective than placebo in providing overall heartburn relief (P < 0.001). The differences between the ranitidine and cimetidine groups were not significant, except for a greater reduction in heartburn frequency in the ranitidine group at the end of the study period (P < 0.05). Drug dose was lower and less rescue medication was used in the ranitidine group than the placebo group. The three treatment groups did not differ in terms of tolerability., Conclusion: On-demand ranitidine 75 mg or cimetidine 200 mg are safe and effective treatment for reflux-related symptoms.

Background: Amongst the low-dose H2-receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH., Aim: To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose., Methods: Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders., Results: Over the 12 h post-dose period the mean area under the pH/time curve (AUC) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0-12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post-dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to = 8 h., Conclusions: Inhibition of gastric acidity over the 12 h post-dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H2-receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film-coated tablets.

Aim: To compare the efficacy of cimetidine and tripotassium dicitrato bismuthate (TDB) in arthritic patients who had developed gastric (GU) or duodenal (DU) ulceration while taking non-steroidal anti-inflammatory drugs (NSAIDs)., Methods: Eighty-six rheumatoid arthritis (RA) patients affected by endoscopically proven DU (n = 44) or GU (n = 42), and on chronic NSAID therapy which was not suspended during anti-ulcer therapy, were randomized to cimetidine (400 mg t.d.s.) or TDB (120 mg q.d.s.). A repeat endoscopy was planned after 4 weeks (and 8 weeks, in case of failed healing). The patients who were unhealed after 8 weeks of therapy were allocated to the alternative anti-ulcer drug for a further 8 weeks without interrupting the anti-inflammatory therapy., Results: At week 4 of therapy. 14/24 (58%) DU and 9/20 (45%) GU patients treated with cimetidine were healed, compared with 12/20 (60%) and 10/22 (45%) TDB-treated patients (N.S.). At week 8 of therapy, the DU healing rates were 15/24 (63%) with cimetidine and 14/20 (70%) for TDB. The corresponding GU healing rates were 12/20 (60%) with cimetidine and 13/22 (60%) for TDB (N.S.). At week 16, complete healing with cimetidine was observed in 67% of DU and 57% of GU patients unhealed with TDB; the corresponding figures in the patients crossed to TDB were 83% for DU and 63% for GU patients (N.S. vs. cimetidine)., Conclusions: No statistically significant difference was found between the healing activities of cimetidine and TDB in rheumatoid arthritis patients with peptic ulcer who did not interrupt their NSAID treatment for arthritis. This trial showed that the continued consumption of NSAIDs appears to slow the ulcer healing process, especially in GU patients.

Background: There is documentation of the long-term use of omeprazole 10 mg o.d. in patients with reflux oesophagitis but not in the large number of gastrooesophageal reflux disease (GERD) patients without oesophagitis. There is also a paucity of data on the long-term use of cimetidine in GERD patients., Methods: One hundred and fifty-six patients (100 male) who previously had symptomatic non-ulcerative oesophagitis (81%) or symptoms without oesophagitis (19%), were recruited. All patients were in symptomatic remission following 4 weeks of omeprazole 20 mg o.d. or cimetidine 400 mg q.d.s. and, if required, a further 4 weeks of omeprazole 20 mg o.d. Patients were randomized to receive, double-blind, either omeprazole 10 mg o.m. (n = 77) or cimetidine 800 mg nocte (n = 79) for 24 weeks., Results: A greater proportion of patients receiving omeprazole, compared with cimetidine, were in symptomatic remission after 12 (69 vs. 27%) and 24 weeks (60 vs. 24%) (each P < 0.0001). The median time to symptomatic relapse was longer for patients receiving omeprazole (169 vs. 15 days) (P = 0.0001). Of patients leaving the study in symptomatic remission, a greater proportion receiving omeprazole, compared with cimetidine, was free of oesophagitis (84 vs. 53%) (P < 0.05)., Conclusion: Omeprazole 10 mg o.m. is more effective than cimetidine 800 mg nocte in the prevention of recurrence of GERD-associated heartburn and the occurrence of underlying oesophagitis.

Aims: To compare the effects on intragastric acidity of a single evening dose of either standard or effervescent formulations of ranitidine (300 mg) or cimetidine (800 mg)., Methods: Twelve healthy subjects were studied, using a four-period randomized cross-over design and an ambulatory intragastric pH monitoring technique. The subjects received a standard evening meal at 17.00 hours and one of the H2-receptor antagonist formulations was given at 23.00 hours., Results: Both effervescent formulations caused a transient rapid increase in intragastric pH, reaching a maximum at about 3 min after ingestion. After both effervescent formulations a significantly higher pH was measured during the first 45 min after ingestion (P < 0.05), compared to the regular formulations. The onset of action of the H2-receptor antagonists was similar for both formulations of ranitidine and the effervescent cimetidine, but tended to be slower for the regular cimetidine (P = 0.06). Nocturnal intragastric pH was significantly increased by all four formulations, but more effectively so by the two ranitidine formulations. The duration of action (taken as time with pH > 4) of both ranitidine formulations was longer than that of both cimetidine formulations (P < 0.002)., Conclusions: A single evening dose of 300 mg ranitidine produces a stronger decrease of nocturnal gastric acid secretion than 800 mg cimetidine. The effervescent formulations of both drugs offer the advantage of a rapid decrease (within minutes) of intragastric acidity, with preservation of the sustained systemic effect.

It is now becoming common practice to co-administer H2-receptor antagonists and anti-reflux agents in the treatment of reflux oesophagitis. The mechanism by which anti-reflux agents achieve flotation requires a small amount of gastric acid to be present in the stomach. This study investigated whether an anti-reflux agent would remain effective after the decrease in acid secretion produced by a typical clinical dosage regimen of cimetidine (400 mg q.d.s., 7 days). Gastric distribution and residence of a meal and an anti-reflux agent were assessed in 12 normal subjects using gamma scintigraphy. The area under the gastric and fundal emptying curves demonstrated that Liquid Gaviscon (sodium alginate compound) had a significantly greater gastric residence than the meal, both during the control period and after cimetidine pretreatment, and that the majority of the Gaviscon was located in the fundus. The distribution of Gaviscon into the fundus was not affected by cimetidine pretreatment. Cimetidine pre-treatment slightly, but not significantly, increased the time for half the meal and the Gaviscon to empty from the stomach. The results suggest that the mechanism of action of Liquid Gaviscon is not compromised by concurrent H2-antagonist therapy.

Plasma alcohol concentration following oral ingestion of 0.3 g/kg of alcohol (ethyl alcohol), one hour after an evening meal, was measured in four groups of 12 healthy subjects. Each group had a control study and a repeat study after 7 days dosing with either placebo or an H2-receptor antagonist (300 mg ranitidine nocte, 800 mg cimetidine nocte, or 40 mg famotidine nocte). There was no significant difference between the control and post-dosing studies in the integrated 4-h plasma alcohol concentration, peak plasma alcohol concentration, or time to reach peak alcohol concentration. This study shows that post-prandial alcohol absorption after 0.3 g/kg of alcohol is not affected by ranitidine, cimetidine or famotidine.

One hundred and twenty-five patients with symptoms of heartburn and acid regurgitation but without endoscopic abnormalities were randomized to receive 200 mg cimetidine suspension four times daily or placebo for two weeks. Daily dairy cards were kept to evaluate the frequency and degree of symptoms. At two weeks cimetidine was significantly more effective than placebo. It is concluded that placebo suspension has a considerable effect on gastro-oesophageal reflux disease symptoms, but cimetidine suspension provides significantly better relief.

The effects of 100 mg and 200 mg bedtime doses of cimetidine on nocturnal gastric acid secretion were examined in nine healthy subjects in a double blind, placebo controlled, randomised three way crossover study. Treatment was given at 23.00 hours and the gastric contents continually aspirated from midnight until 07.00 hours the following morning. Hourly aliquots were analysed for pH and acid output. Relative to placebo the 100 mg and 200 mg doses of cimetidine respectively increased mean pH by 2.22 and 2.63 units/h (P less than 0.001) with mean acid output decreasing by 0.95 and 0.98 mmol/h (P less than 0.001). Whilst mean pH was higher and mean acid output was lower for 200 mg cimetidine compared to 100 mg cimetidine the difference was not statistically significant. Mean hourly pH was consistently above pH 3 for 100% of the time for both doses of cimetidine whereas mean pH failed to reach this value at anytime on placebo. Low doses of cimetidine taken at bedtime effectively reduced nocturnal gastric acid secretion in healthy individuals.

This multicentre, double-blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine-treated patients (35 of 82, 43%) than placebo-treated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P = 0.02) and 91% (69 of 76, P = 0.02) heal rates for cimetidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine-treated patients were free of daytime and night-time pain than placebo-treated patients; the differences were statistically significant for night-time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.

A large number of clinical studies have been performed to establish the safety and efficacy of H2-receptor antagonist therapy. Few if any of these studies have attempted to address the rationale for the dosage and/or dosage regimens being studied. This study is the first large-scale clinical trial, the purpose of which is to validate the chosen regimen and to address the issue of an optimal therapy for a specific patient population. A regimen of a single nightly dosage is generally acknowledged to offer the potential for improved patient compliance. Furthermore, recent research had suggested that suppression of nocturnal acid secretion is all that is required to heal duodenal ulcers. Hence such a regimen offered the potential for an effective lowered dosage of cimetidine with minimal interference with gastric physiology, increased safety and substantial efficacy. This multicentre, double-blind, placebo-controlled trial therefore evaluated a 4-week course of single night-time dosage of cimetidine. After 4 weeks of treatment the cumulative, endoscopically proven, ulcer healing rate with an 800 mg regimen was 73%, which was statistically higher and significantly superior to the 41% healing seen with placebo (P less than 0.001). The 400 mg nocte dosage regimen of cimetidine normally used as maintenance therapy was significantly inferior to the 800 mg nocte regimen (P = 0.01), and increasing the dosage to 1600 mg nocte for 4 weeks failed to provide a significant improvement in healing over the 800 mg nocte regimen. This 800 mg nocte regimen provided rapid pain relief, with 75% of the patients being free of night-time pain and 65% free of day-time pain, by the end of the first week. The 400 mg 'maintenance dosage' was unable to provide this degree of rapid, complete and early relief to patients with a duodenal ulcer. Furthermore, increasing the dosage to 1600 mg nocte failed to increase the level of early pain relief significantly, perhaps because the extensive response of duodenal ulcer patients to the 800 mg nocte regimen leaves little room for improvement. Based both on the early symptom relief and the ulcer healing rate during 4 weeks of treatment, it is concluded that an 800 mg night-time dosage of cimetidine may be an optimal regimen for many duodenal ulcer patients, particularly those who in the physician's opinion will benefit from a once-daily regimen.

Enteric-coated microspheres of pancreatin were compared with non-enteric-coated pancreatin combined with cimetidine taken 40 min before meals in the treatment of patients with cystic fibrosis. Fourteen adults with steatorrhoea due to cystic fibrosis were investigated in an open, randomized crossover study, over two consecutive 28-day treatment periods. Lipase intake was adjusted to each patient's previous requirements and was the same during both months; they were instructed to continue with their normal diet. Patients collected faeces for 72 h at the end of each month and completed diary cards daily throughout. Bowel actions were less frequent on enteric-coated microspheres of pancreatin than on non-enteric-coated pancreatin/cimetidine (1.7 vs. 2.4/day; P less than 0.001) and stool character was improved (P less than 0.001). Mean daily faecal weight was similar on enteric-coated microspheres of pancreatin to that on the combination (254 g vs. 291 g; N.S.), whereas daily faecal fat excretion tended to be less on enteric-coated microspheres of pancreatin (21 g vs. 27 g; N.S.), and percentage fat absorption tended to be greater (81% vs. 73%; N.S.). Mean body weight increased by 0.3 kg on enteric-coated microspheres of pancreatin and fell by 0.1 kg on the combination (N.S.). These data indicate that enteric-coated microspheres of pancreatin are at least as effective as non-enteric-coated pancreatin with cimetidine in the treatment of steatorrhoea in cystic fibrosis.

Overnight gastric secretion was studied in 32 patients with acute duodenal ulcers before treatment and whilst taking cimetidine 400 mg b.d. After 6 weeks of treatment with cimetidine 400 mg b.d. 13 patients had healed ulcers, seven patients had healed ulcers but a persistent erosive duodenitis, and 12 patients had persisting ulceration. Inhibition of nocturnal gastric secretion by cimetidine 400 mg b.d. was most profound in patients who healed their ulcers completely; a less profound inhibition of nocturnal gastric secretion was seen in the non-healing and duodenitis groups. In patients with persisting ulcers and poor inhibition of nocturnal gastric secretion by cimetidine, gastric secretion could be suppressed by either cimetidine 400 mg b.d. in combination with pirenzepine 50 mg b.d., or by cimetidine 1600 mg nocte, but suppression of nocturnal gastric secretion was more effective with cimetidine 1600 mg than cimetidine with pirenzepine.

Famotidine (40 mg) and 800 mg cimetidine as single night-time doses were compared in a randomized, double-blind, multicentre study of acute treatment for duodenal ulceration. Fifteen centres recruited 304 patients into the study. Of these, 274 were included for analysis, with 136 receiving famotidine and 138 receiving cimetidine. After 4 weeks, 75% of the patients who received famotidine and 77% of the patients who received cimetidine were healed. At 6 weeks the cumulative healing rates were 91% with famotidine and 87% with cimetidine. Differences between the groups were not significant at 4 or 6 weeks. No significant difference in healing rates between smokers and non-smokers was found. Day and night pain resolved rapidly in both groups. Both treatments were well-tolerated; adverse events were reported in 17 patients on famotidine and 18 on cimetidine, with headache the most frequent event in both groups. Famotidine is effective and well-tolerated in the short-term treatment of duodenal ulcer.

Intragastric pH was measured continuously from 1800 to 1200 hours the following day in 22 duodenal ulcer patients and in eight gastric ulcer patients, all of whom had been admitted as emergencies with acute upper gastrointestinal haemorrhage. The effects of intravenous cimetidine or ranitidine were compared with no treatment. In patients with duodenal ulcer, median intragastric pH was 1.8 (range 1.0-4.9) in the group receiving no treatment. In the cimetidine group (400 mg, 6-hourly, n = 8) median pH was 4.7 (range 1.5-7.7) and after ranitidine (50 mg, 6-hourly, n = 10) it was 3.8 (range 1.2-7.8). The pH remained above 4.0 for 67% of the recording time with cimetidine, 47% with ranitidine and for only 3% with placebo. Intragastric pH in gastric ulcer patients without treatment was higher (median 3.4, range 1.0-6.9) than in duodenal ulcer patients with treatment. Both H2 antagonists raised intragastric pH in patients with gastric ulcer and maintained a gastric pH of greater than 4.0 for at least 50% of the time. Presently recommended i.v. doses of cimetidine and ranitidine do not consistently maintain gastric pH above 4.0 for long periods in patients with peptic ulcer bleeding.