Current management of bleeding peptic ulcer. A review.

In the United Kingdom, acute bleeding from peptic ulcer is estimated to account for 25 admissions to hospital per 100,000 population annually. Overall mortality has been reported at around 10%. Accurate initial assessment for the identification of high risk groups, prompt resuscitation, close monitoring and timely intervention for rebleeding improves survival. In patients not responding to initial resuscitation and those who rebleed, emergency endoscopy identifies the source of bleeding in the majority and is essential to enable endoscopic therapy. Injection of a vasoconstrictor and/or sclerosant into a visible or bleeding vessel, or thermal coagulation, reduces the incidence of rebleeding and probably decreases mortality. In general terms, 'early' surgical intervention is indicated for those aged over 60 years in whom bleeding recurs or continues despite endoscopic measures. The low mortality (< 5%) reported from specialist units and units adhering to strict protocols of management should become the norm. The use of antacids, histamine H2-receptor antagonists or omeprazole does not influence mortality or the incidence of early rebleeding in patients with acute haemorrhage from peptic ulcer. Although not used routinely, tranexamic acid has been shown to have significant benefit.

Antacids and ulcer healing. A review of the evidence.

There have been a number of controlled trials of antacids in the treatment of patients with peptic ulcer disease. As a general rule the size of studies has been small and there have been difficulties ensuring adequate binding, because of the formulation and taste of the antacids. Despite these difficulties, antacids appear to be effective ulcer healing agents with efficacies resembling those of other antiulcer drugs. Definite dose relationships are unclear but high doses of buffering capacity over 200 mmol/day appear unnecessary and are associated with increasingly frequent adverse effects. Low dose maintenance treatment is effective at limiting duodenal ulcer relapse.

The effects of roxatidine acetate on 24-hour intragastric acidity. Investigations in healthy volunteers and comparison with ranitidine and placebo.

In a series of double-blind randomised studies in normal volunteers with continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine acetate, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate 75 mg twice daily decreased median 24-hour gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate 150 mg at bedtime raised median 24-hour pH in the same 17 subjects to 2.4 and nocturnal pH to 5.9. In the second experiment, in 14 volunteers, roxatidine acetate 150 mg at bedtime was as effective as ranitidine 300 mg at night, raising median nocturnal pH from 1.4 to 6.65 compared to 6.7 for ranitidine. However, when drugs were taken after the evening meal (post cenam nocte; PCN) roxatidine acetate 150 mg was less potent than ranitidine 300 mg, with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg PCN produced the greatest rise of pH, to 4.9, suggesting that the true potency ratio of the 2 drugs is between 1 and 2.

Co-administration of misoprostol or ranitidine with indomethacin: effects on pharmacokinetics, abdominal symptoms and bowel habit.

This three-way randomized crossover study in 18 healthy male volunteers compared the pharmacokinetics of 50 mg indomethacin b.d. during concomitant twice daily dosing with 400 micrograms misoprostol, 150 mg ranitidine or placebo. Plasma indomethacin concentrations were determined by HPLC assay of samples collected over 12 h after the first dose, and over 14 h after the last dose on Day 8 of each dosing period. A daily diary of bowel habits, and the occurrence and severity of abdominal symptoms, was kept by each subject throughout the study. Statistical comparisons were made by analysis of variance. In the presence of misoprostol there was a 13% decrease in the area under the plasma concentration-time curve of indomethacin over one dosing interval on Day 1 (P less than 0.01), and at steady state there was a 24% decrease in the maximum plasma concentration (P less than 0.02). The pharmacokinetics of indomethacin were not affected by co-administration of ranitidine. Accumulation of indomethacin after repeated oral dosing was not significantly altered by the co-administration of either misoprostol or ranitidine. The frequency and severity of abdominal symptoms was significantly increased (P less than 0.01) during misoprostol dosing, compared with either ranitidine or placebo plus indomethacin. When the dosing phase (Days 1-8) was compared with the washout phase (Days 9-15) in each period, misoprostol, but not ranitidine or placebo, plus indomethacin resulted in an increase (P less than 0.001) in abdominal symptom severity, frequency of bowel motions and a decrease in faecal consistency.

Effects of oral pantoprazole on 24-hour intragastric acidity and plasma gastrin profiles.

Pantoprazole selectively blocks gastric parietal cell H+,K(+)-ATPase. To define a dosage regimen for clinical trials we compared the effect of pantoprazole 40 and 60 mg daily on 24-h intragastric acidity and plasma gastrin concentrations using a double-blind, randomized, cross-over design. Eleven men took each of the three regimens (placebo, 40, 60 mg) for 5 days. On Day 5, 24-h pHmetry and plasma gastrin profile were performed. A consistent decrease in intragastric acidity with each dosage regimen was shown by a rise in 24-h median pH from 1.4 (1.2-1.8, IQR) on placebo to 2.3 (1.8-4.4, P = 0.0022) during pantoprazole 40 mg and to 3.5 (2.6-4.9, P = 0.0017) during 60 mg. Pantoprazole 40 and 60 mg maintained the intragastric pH above 3 for 33% and 58% of time, respectively, compared with 15% time with placebo. Twenty-four-hour integrated plasma gastrin concentration rose from 478 to 1798 and 1962 pmol.h/L, respectively. The drug was well tolerated. The decrease of acidity was dose related and should result in clinical efficacy similar to other antisecretory drugs. It is not known whether higher doses might abolish acid secretion. The optimal dose of pantoprazole is yet to be established.

Helicobacter pylori eradication in a clinical setting: success rates and the effect on the quality of life in peptic ulcer.

BACKGROUND: Helicobacter pylori eradication for peptic ulcer has been widely taken up. Evidence for the efficacy of different regimens is often derived from small series in clinical trials but there is little reporting of everyday practice with unselected patients. Freedom from ulcer relapse has been demonstrated, but not whether this equates with clinical success. METHODS: We report on a series of 706 patients with H. pylori infection who, between January 1991 and April 1995, received eradication therapy followed by assessment of H. pylori status. Two-hundred and seven of these patients were followed-up by postal questionnaire, validated by parallel questionnaires to their general practitioners, covering clinical outcome measures. RESULTS: The overall eradication rate was 81.7%, and a 1-week course of omeprazole plus two antibiotics was significantly better than a 2-week course of standard triple therapy (85.0% vs. 78.0%, P < 0.05). Amongst 21 first-time failures, a 7-day course of a clarithromycin-containing triple therapy succeeded in 18. The questionnaire replies indicate that, following successful H. pylori eradication, ulcer patients are less likely to consult with ulcer symptoms (P < 0.0005), take medication (P < 0.0005), require further prescription (P < 0.0005), or lose work-time because of their ulcer (P < 0.005). They are more likely to have a subjective sense of ulcer cure (P < 0.0005). CONCLUSIONS: In addition to clear cost savings, social benefits are now demonstrated when H. pylori is eradicated. A well-tolerated 1 week regimen is genuinely effective in everyday practice.

Effect of ranitidine and indomethacin on nocturnal gastric acidity in normal subjects.

To assess the effect of indomethacin on gastric acidity and to identify a potential pharmacodynamic interaction between indomethacin and ranitidine, we measured nocturnal acidity on half-hourly aliquots of gastric contents from 10 volunteers on the seventh day of four dosing regimens given in a randomized double-blind manner. These were indomethacin (50 mg t.d.s.) and ranitidine (300 mg in the evening) together or alone with matching placebos. Median nocturnal acidity on placebo was 41.7 mmol/L (range 67.6-25.1 mmol/L) and was 39.8 mmol/L (63.1-24.0 mmol/L) on indomethacin (N.S.). During ranitidine dosing it was 0.4 mmol/L (21.3-0.0 mmol/L) without and 0.8 mmol/L (43.7-0.0 mmol/L) with concurrent indomethacin, representing 99 and 98% decreases in gastric acidity (P less than 0.01) compared with placebo. Indomethacin did not increase overnight gastric acidity and did not influence the suppression of acidity produced by ranitidine. It is unlikely that the ulcerogenic potential of indomethacin is explicable by an effect on gastric acidity.

Low-dose famotidine and ranitidine as single post-prandial doses: a three-period placebo-controlled comparative trial.

BACKGROUND: Low-dose H2-receptor antagonists are available without prescription for the self-medication of dyspepsia. METHODS: To investigate the relative abilities of low doses of famotidine and ranitidine to raise intragastric pH after a single post-prandial evening dose, 25 healthy volunteers completed a three-period cross-over trial of famotidine 10 mg, ranitidine elixir 75 mg and placebo. A standard meal was given at 18.30 h and drug or placebo at 19.30 h to subjects fasted for 5.5 h. Intragastric pH was recorded with nasogastric electrodes from 18.00 to 07.30 h by GastrograpH II recorder. RESULTS: The geometric mean area under the pH-time curve for the 5-9 h post-dose period was 1.49 pH units/h following placebo, 3.43 pH units/h following famotidine 10 mg (agent/placebo ratio 2.3; P < 0.001, ANOVA) and 2.6 pH units/h following ranitidine 75 mg (1.75; P < 0.001). The geometric mean area under the pH-time curve ratio of famotidine 10 mg to ranitidine 75 mg was 1.32 (P < 0.016). Median pH over the 5-9 h period was 1.1 following placebo, 2.7 following famotidine 10 mg (P < 0.05 by comparison with placebo) and 1.9 following ranitidine 75 mg (P < 0.05); comparison of median pH showed no significant difference between the active drugs. The percentage of pH values greater than 3.0 for the period 0-12 h post-dose was 9.7% following placebo, 30.0% following famotidine 10 mg (P < 0.05) and 24.9% following ranitidine 75 mg (P < 0.05); there was no significant difference between the active drugs. CONCLUSIONS: We conclude that both famotidine 10 mg and ranitidine 75 mg significantly raise intragastric pH when given as single post-prandial doses. Famotidine 10 mg may have a greater effect than ranitidine elixir 75 mg over the 5-9-h period after dosing.

Intragastric pH monitoring in acute upper gastrointestinal bleeding and the effect of intravenous cimetidine and ranitidine.

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.

The effects of roxatidine acetate (HOE-760) on 24-hour intragastric acidity in healthy volunteers: comparison with ranitidine and placebo.

In a series of double-blind randomized studies in normal volunteers using continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, decreased median 24 h gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate, 150 mg at bedtime, raised median 24 pH of the same 17 subjects to 2.4 and nocturnal pH to 5.9. In another series of experiments, 150 mg roxatidine acetate at bedtime was as effective as ranitidine 300 mg nocte raising median nocturnal pH (14 volunteers) from 1.4 to 6.65 compared to 6.7, respectively. However, when drugs were taken after the evening meal (post cenam nocte, pcn) roxatidine acetate 150 mg was less potent than ranitidine 300 mg with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg pcn raised the pH to 4.9 suggesting that roxatidine is 1-2 times as potent as ranitidine, on a milligram-for-milligram basis.

A comparison of roxatidine and ranitidine for the acute treatment of duodenal ulcer.

Roxatidine acetate is a new histamine H2-antagonist of about twice the potency of ranitidine on a weight-for-weight basis. Two hundred and thirty-two patients participated in a double-blind randomized trial of duodenal ulcer healing comparing 300 mg ranitidine nocte with 150 mg roxatidine nocte. Endoscopy was repeated fortnightly to 4 weeks in each of four participating centres. Usual exclusion criteria applied but NSAID users were allowed. There were no important demographic differences between treatment recipients. Three analyses were used: protocol (dropouts and violators not included), intention-to-treat I (dropouts considered failures), and intention-to-treat II (dropouts considered failures, but violators outcome included). Healing rates differed markedly (but not significantly) with each analysis. After 2 weeks of treatment ulcers had healed in 51% versus 45% using the intention to treat I analysis with roxatidine and ranitidine, respectively; by the protocol analysis the healing proportions were 60% and 55%. These differences between treatments were not significant. After 4 weeks of treatment healing rates ranged from 71% to 83% on roxatidine and between 69% and 84% on ranitidine depending on the analysis. Differential healing proportions of smokers and non-smokers were non-significant (83% vs. 79%). Both drugs were well tolerated and adverse events were similar with each agent. Roxatidine should prove as effective as ranitidine for acute duodenal ulcer treatment.

Twenty-four-hour intragastric acidity and clinical trial of bedtime enprostil 70 micrograms compared with ranitidine 300 mg in duodenal ulcer.

The effects of bedtime 70 micrograms and twice daily 35 micrograms doses of enprostil on 24-hour intragastric acidity were investigated in nine duodenal ulcer patients in remission. Median nocturnal acidity decreased significantly by 30% with 35 micrograms twice daily, and by 48% with 70 micrograms at bedtime. In a clinical trial using bedtime dosing, 102 duodenal ulcer patients randomly received either ranitidine 300 mg or enprostil 70 micrograms. More ulcers healed after 4 and 8 weeks treatment with ranitidine than with enprostil (76% ranitidine vs 52% enprostil, at 4 weeks p = 0.0065 and 94% vs 68%, respectively at 8 weeks, P = 0.0007). However, 6 months after cessation of treatment there was no material difference in overall outcome. Despite combining mucosal protection with acid inhibition enprostil treatment conferred no advantage over simple acid inhibition.

Comparison of ranitidine 300 mg twice daily, 300 mg at night and placebo on 24-hour intragastric acidity of duodenal ulcer patients.

Continuous measurement of 24-hour intragastric acidity was performed in 12 duodenal ulcer patients in remission during treatment with placebo, ranitidine 300 mg nocte and ranitidine 300 mg b.d. Median 24-hour acidity was 79.4 mmol litre-1 during placebo treatment; it decreased to 28.2 mmol litre-1 during treatment with ranitidine 300 mg nocte and to 3.6 mmol litre-1 during treatment with ranitidine 300 mg b.d. The two regimens decreased intragastric acidity to a similar degree during the night, but significantly greater inhibition of daytime and 24-hour acidity followed use of ranitidine 300 mg b.d.

Clinical importance of the new H2-antagonists.

The first H2-receptor antagonist, cimetidine, has been succeeded by ranitidine, and more recently nizatidine and famotidine. Others will doubtless follow. The pharmacodynamic differences between cimetidine and ranitidine, in terms of potency, are not obviously translated into therapeutic differences. Some studies have shown that the increased potency of standard doses of ranitidine affords an advantage, in terms of ulcer healing and relapse, over cimetidine. The therapeutic effects of these drugs can be predicted from their pharmacodynamic profiles and in the doses recommended differences between the newest agents and ranitidine would not be expected. It is, thus, difficult to define a specific clinical role for the newer drugs on the grounds of efficacy. Their importance may relate to the provision of encouragement for future drug development.

Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin.

OBJECTIVE: To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding. DESIGN: Randomised crossover trial. SETTING: Academic department of therapeutics. SUBJECTS: Twenty healthy male volunteers aged 19-22. INTERVENTIONS: On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6. END POINT: Loss of blood over 10 minutes into gastric washings. MEASUREMENTS AND MAIN RESULTS: Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin. CONCLUSIONS: Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE: To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN: Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING: The medical wards of University and City Hospitals, Nottingham. SUBJECTS: 1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES: Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS: Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS: Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.

Prostaglandin treatment for peptic ulcer.

Prostaglandin analogues have been expected to outperform other antisecretory drugs as ulcer healing agents. This expectation arises from their ability to combine 'cytoprotection' with gastric secretory inhibition. Evidence of the existence of these two separate functions abounds in animals and in humans, but a clinical advantage has not evolved. Whereas most clinical trials show no difference between prostaglandin analogues and H2-receptor antagonists, some studies have shown the prostaglandins to be significantly less effective or no better than placebo. The role of cytoprotection in ulcer healing (as opposed to prevention) may be questioned and the present clinical role for these agents is unclear.

Prostaglandins and peptic ulcer therapy.

The expectation that prostaglandin analogues would improve the ulcer healing abilities of other agents by combining mucosal protection with decreased acid secretion has been proved unwarranted. The ulcer healing capabilities of these drugs reflect their antisecretory potency. A role for these drugs in ulcer healing is questionable but their use has been advocated most strongly to prevent ulceration developing during treatment with non-steroidal anti-inflammatory drugs. While some evidence supports this role, an important clinical benefit of reducing complication rates has yet to be demonstrated.

Twenty-four hour intragastric acidity during treatment with oral omeprazole.

In a series of 59 experiments on nine duodenal ulcer patients, 24-hour intragastric acidity was measured before, during and after treatment with daily oral omeprazole. Omeprazole, 10, 20, ro 30 mg/day for 1 week, caused a 37%, 90%, and 97% decrease respectively of 24-hour intragastric acidity. No further decrease of acidity was observed when the dose of omeprazole was doubled to 60 mg/day, or after a second week of treatment with 30 mg/day. One week after stopping treatment with omeprazole (14 doses), there was still a significant 26% decrease of 24-hour intragastric acidity, with full recovery 7 weeks later. Fasting plasma gastrin concentration was significantly elevated during treatment with all doses of omeprazole. The optimal dose of omeprazole is 30 mg/day for a maximal decrease of 24-hour intragastric acidity in duodenal ulcer patients.

Investigations on the penetration of ranitidine into the cerebrospinal fluid and a comparison of the effects of ranitidine and cimetidine on male sex hormones.

Cerebrospinal fluid (CSF) ranitidine concentrations were measured in 13 normal subjects undergoing routine myelography following either one, or two doses ranitidine 200 mg. Small amounts of the drug were detectable in the CSF. A separate investigation of duodenal ulcer patients compared the effects of ranitidine 150 mg twice-daily and cimetidine 1 g daily on basal and stimulated levels of male reproductive hormones in the plasma. Although cimetidine treatment resulted in a small rise in basal and stimulated testosterone, neither drug was associated with significant changes in basal or stimulated hormone levels.