Misoprostol for the treatment of peptic ulcer and antiinflammatory-drug-induced gastroduodenal ulceration.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
R P Walt
Publications and source records attributed to R P Walt.
Continuous intravenous famotidine for haemorrhage from peptic ulcer.
Peptic ulcer bleeding often stops spontaneously but rebleeding may be catastrophic. Emergency surgery carries risks so safe medical therapies are needed. Since platelet function and plasma coagulation are both pH sensitive and since pepsin lyses clot at low pH the maintenance of gastric pH close to neutrality might influence rebleeding rates. Previous trials with H2 antagonists have been inadequate although a 1985 meta-analysis did support an important clinical effect. We report here a large multicentre trial of famotidine in ulcer bleeding. 1005 patients admitted to one of sixty-seven hospitals in the UK or Eire with haemorrhage from peptic ulcer with endoscopic signs of oozing, black slough, fresh clot or visible vessel were randomly allocated to famotidine (10 mg bolus followed by 3.2 mg/h intravenously) or matching placebo for 72 h. This famotidine regimen had previously been shown to maintain pH near 7 in such patients. 497 patients received famotidine and 508 placebo. The treatment groups were similar in respect of age, sex, ulcer site, and signs and severity of bleeding. Case fatality (6.2% famotidine vs 5.0% placebo), rebleeding (23.9% vs 25.5% placebo), and surgery (15.5% vs 17.1% placebo) rates were not significantly different between the two groups. This trial suggests that potent inhibition of gastric secretion does not influence the natural history of peptic ulcer haemorrhage.
Aged↗
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.
Age Factors↗
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.
2-Pyridinylmethylsulfinylbenzimidazoles↗
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.
Abdominal Pain↗
Bleeding peptic ulcers.
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Endoscopy, Gastrointestinal↗
The cephalic and gastric phases of gastric secretion during H2-antagonist treatment.
The antisecretory effects of H2-receptor antagonists are limited by food ingestion. The contributions of the cephalic-vagal and gastrinergic mechanisms to this interaction were examined in two 14-hour randomized, cross-over studies in 24 healthy volunteers. In the first study, either ranitidine or placebo was administered IV by a pH-feedback-controlled infusion pump during fasting, modified sham feeding, or food ingestion. Sham feeding resulted in a well-defined and abrupt interaction with the antisecretory effect of ranitidine (lasting 2-3 hours), after which fasting pH levels were regained. The second study, with the same design, showed that gastrin release occurred during this cephalic-vagal phase but was not attenuated by the additional infusion of the anticholinergic pirenzepine. Following eating, intragastric acidity increased and remained elevated for more than 6 hours. This increase was accompanied by prolonged hypergastrinemia, which was not diminished by pirenzepine. Pirenzepine did, however, enhance the antisecretory effect of ranitidine after both sham feeding and food ingestion. The interaction of food or sham feeding with the antisecretory effect of H2 antagonists is a consistent phenomenon. In both the cephalic-vagal and the gastric phases of secretion, this interaction appears to be partially mediated by a noncholinergic release of gastrin.
Adult↗
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.
Adult↗
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.
Antacids↗
Cigarette smoking, gastric acidity and peptic ulceration. What are the relationships?
The influence of cigarette smoking on intragastric acidity was assessed in duodenal ulcer patients in symptomatic remission and in healthy volunteers in a retrospective study. Continuous 24-hr pH recordings in 150 nonsmokers and 174 smokers receiving placebo treatment were compared. Daytime intragastric acidity was higher in smokers with a median pH (interquartile range) of 1.56 (1.34-1.80) than in nonsmokers, who had a median pH of 1.70 (1.45-1.97) (P less than 0.001). There was no difference in 24-hr and nighttime median pH between the two groups. The small difference in daytime intragastric acidity in smokers and nonsmokers is unlikely to account for the increased prevalence of peptic ulcer disease in smokers. The analysis of smoking status in duodenal ulcer patients and healthy controls and males and females supports the general trend towards higher daytime acidity in smokers. Again, no differences in pH during the 24-hr or night period were found between the groups. The epidemiological and clinical correlation between smoking and duodenal ulcer disease is not adequately explained by increased intragastric acidity.
Circadian Rhythm↗
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.
Adult↗
Use of automatic computerised pump to maintain constant intragastric pH.
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.
Adult↗
Effect of food on H2-receptor blockade in normal subjects and duodenal ulcer patients.
Two separate studies of 24 hour intragastric acidity were carried out in normal volunteers and duodenal ulcer patients to define the interaction of food and the antisecretory effects of H2-receptor blockers. Both investigations were double blind randomised comparisons using ranitidine 300 mg with either different meal times or ad libitum snacks after an evening meal. Meals taken after drug administration nearly abolished measurable antisectory effects. Median 24 hour pH was 1.3 on placebo, 2.6 when ranitidine was administered after the evening meal and 1.9 when administered before the evening meal. Snacks taken after evening dosing with ranitidine also significantly decreased pharmacodynamic efficacy. During placebo, median night-time pH was 1.3 without snacks and 1.4 with snacks. pH rose to 5.9 during ranitidine treatment when snacks were forbidden but was only 3.1 when snacks were allowed. These findings could be of therapeutic importance and should rationalise dietary advise to patients receiving H2 blockers. The timing of drug administration can be adjusted according to individual life styles.
Adult↗
Analysis and statistical evaluation of continuous pH recordings.
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Data Interpretation, Statistical↗
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.
Alprostadil↗
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.
Adult↗
Dark adaptation compared with electrooculography in primary biliary cirrhosis.
In a series of asymptomatic patients with primary biliary cirrhosis there was a significant impairment of dark adaptation thresholds as compared with a control group. Vitamin A levels were abnormally low in only two of the patients and these two both showed high dark adaptation thresholds. The electrooculogram was reduced in only the most severely affected case. It is suggested that visual function tests should be performed alongside vitamin A level measurements before deciding on treatment.
Adult↗
Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine.
1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.
Adult↗