Morning and evening administration of pantoprazole: a study to compare the effect on 24-hour intragastric pH.

OBJECTIVE: To determine whether the time of administration (morning vs. evening) of pantoprazole influences the effect of a 40 mg dose upon intragastric pH in healthy subjects. DESIGN: Randomized, double-blind, two-period crossover study to compare intragastric pH following treatment with pantoprazole, 40 mg once daily for 7 days, the drug being given as either a morning or an evening dose before meals. METHODS: Intragastric pH was measured for 24 h on three occasions. The baseline recording was made 2 days prior to the first treatment period and subsequent measurements were made on days 6 to 7 of each period. Adverse events were recorded and fasting laboratory variables measured. RESULTS: Twelve subjects were evaluable for efficacy. Increases in median pH over 24 h were observed in all subjects with both dosage regimens. There was a greater increase from baseline in 24-h median pH values following morning than evening administration of pantoprazole (P < 0.05). This difference was due to a greater effect on median daytime pH (07.00-19.00 h, P < 0.01) compared with that after evening administration. No adverse events were reported and there were no clinically significant changes in laboratory variables. CONCLUSION: The study supports the recommendation of a once-daily morning dosage regimen of pantoprazole 40 mg in the treatment of acid-related diseases.

Pantoprazole versus omeprazole in the treatment of acute gastric ulcers.

BACKGROUND: Pantoprazole is a new substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+,K(+)-ATPase. METHODS: The proton pump inhibitors pantoprazole and omeprazole were compared in a randomized, double-blind study in 219 patients with benign gastric ulcers. Patients received either pantoprazole 40 mg (n = 146) or omeprazole 20 mg (n = 73), once daily before breakfast for 4 weeks. Treatment was extended for a further 4 weeks if the ulcer had not healed. RESULTS: After 4 weeks, complete ulcer healing was seen in 88% of protocol-correct patients given pantoprazole and in 77% given omeprazole (between-group difference P < 0.05). At 8 weeks, the corresponding values were 97% and 96% (not significant). In the comparative intention-to-treat analysis there were no statistical differences between the treatment groups. Among the patients who had ulcer pain prior to treatment, 79% of the pantoprazole group and 68% of the omeprazole group were pain-free after 2 weeks, and after 4 weeks 88% and 81%, respectively (not significant). Pronounced improvement in the other gastrointestinal symptoms was seen in both groups. Only 10% of patients in each group reported adverse events. There were moderate increases in fasting serum gastrin levels with both treatments at 4 and 8 weeks. CONCLUSION: Pantoprazole, 40 mg once daily in the morning, is a highly effective, well tolerated treatment for acute, benign gastric ulcer. Pantoprazole and omeprazole were equally safe in the therapy of gastric ulcer.

A review of treatment of duodenal and gastric ulcers--pantoprazole vs. omeprazole.

The efficacy and safety of pantoprazole in the treatment of duodenal and gastric ulcers has been compared with that of the first proton pump inhibitor omeprazole in two (previously reported) clinical studies. Pantoprazole (40 mg/day) administered orally was an effective and well-tolerated treatment for both indications. Pantoprazole was as effective as omeprazole (20 mg/day) and had a similar safety profile. For gastric ulcers, the healing rate with pantoprazole was superior to that with omeprazole at 4 weeks.

Influence of stress on the healing and relapse of duodenal ulcers. A prospective, multicenter trial of 2109 patients with recurrent duodenal ulceration treated with ranitidine. RUDER Study Group.

The influence of psychologic factors on the healing and relapse of duodenal ulcers under treatment with ranitidine was studied in a prospective, multicenter trial in 2109 patients with an endoscopically proven duodenal ulcer (DU) and a history of recurrent duodenal ulceration. All patient received ranitidine (300 mg daily), and, after healing, 1899 patients continued maintenance treatment (ranitidine, 150 mg daily) for 2 years. A physician's assessment of stress (stress or no stress) was made at every consultation. In the healing phase an overall classification of stress as absent, intermittent, or continuous was made, and in the maintenance phase patients were classified dichotomously as having stress (stress on at least half of the follow-up consultations) or no stress. In addition, at the start of the healing phase stress was measured by means of a standardized questionnaire. Continuous stress, as assessed by the physicians, was associated with a lower 14-day healing rate (35.7%) than intermittent or absent stress (42.4%; relative risk (RR) for delayed healing in patients with continuous stress, 1.19; 95% confidence interval (CI), 1.06-1.33; P < 0.02). Differences in the 14-day healing rate for patients with low and moderate stress scores (43.1%) compared with those with high and very high stress scores (37.9%) just failed to reach statistical significance (RR for patients with stress, 1.14; 95% CI, 0.998-1.29; P = 0.051). During the 1st year of maintenance treatment 18.3% of patients with stress, but 10.9% of patients without stress, had a DU relapse (RR of stress for DU relapse during the first year, 1.73; 95 CI, 1.44-2.09; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of patients at high risk for colorectal carcinoma from biopsy studies of the apparently normal colorectal mucosa. A multivariate analysis.

A number of phenotypic abnormalities of the colorectal mucosa which appears normal have been described to be biomarkers of cancer development. To improve their sensitivity and specificity, we simultaneously determined 10 morphological and histochemical parameters in biopsies from the colonoscopically normal mucosa of the descending colon, sigmoid, and rectum. The results were analysed by multivariate statistical methods. We tested the discriminating power of proliferative, morphometric, enzyme and mucin histochemical parameters from 80 patients either at average risk (controls), with an increased risk for colorectal carcinoma (high-risk), or with a manifest carcinoma. The following parameters were investigated: number of mitotic figures per crypt, crypt length, apical, medial and basal crypt diameter, crypt surface, activity of succinate dehydrogenase (EC 1.3.99.1), activity of acid beta-galactosidase (EC 3.2.1.23), sulpho- and sialomucin contents. Univariate statistical analyses revealed that crypt length, crypt diameter and crypt surface were significantly increased in the high-risk group, the carcinoma carriers having intermediate values between average-risk and high-risk patients. In a two-group discriminant analysis, high-risk or carcinoma patients could be separated from average-risk patients with a sensitivity of 92.9% and a specificity of 100%. When the analysis was repeated for three groups (carcinoma carriers separated from high-risk patients), sensitivity and specificity were 100% for each group. We conclude that identification of patients at risk for colorectal carcinoma is possible from the normal-appearing left colonic and rectal mucosa by morphometric and cytochemical analysis of biopsies.

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.

The effect of an anthraquinone laxative on colonic nerve tissue: a controlled trial in constipated women.

Anthraquinone containing laxatives have been accused to cause degenerative changes in the colonic nerve tissue; prospective studies, however, are not available. This article reports the result of a semiprolective study in 11 matched pairs of chronically constipated women. Each pair consisted of one women having regularly taken an anthraquinone containing laxative for at least one year and a control person without such a medication. Six endoscopic biopsies were taken from the left colon and rectum which were evaluated by electron microscopy and subsequent ultramorphometry for the ratio of damaged to intact neurons, density of neurosecretory vesicles, axonal diameter and number of lysosomes. Medians of the three colonic locations were calculated in each individual and for each variable, and they were compared by non-parametric statistics. Medians of the ratio of damaged to intact neurons in anthraquinone treated women and controls were 0.162 and 0.146 (p = 0.0326, one-tail), medians of the number of type I vesicles were 293 and 348.5 per 100 microns 2 (p = 0.0365, one-tail), respectively. None of the other variables were different between groups. These data do not support the hypothesis that anthraquinone containing laxatives are able to provoke relevant degenerative changes in the colonic nerve tissue since the variables are either similar in both groups or only slight differences could be found which are unlikely to be of pathophysiological relevance.

[Antisecretory effect of the H2-histamine receptor antagonist ranitidine in water-soluble tablets and film-coated tablets. Results of a randomized, placebo-controlled crossover study in humans]. / Antisekretorische Wirksamkeit des H2-Histaminrezeptor-Antagonisten Ranitidin in Form von wasserlöslichen Tabletten und Filmtabletten. Ergebnisse einer randomisierten, Plazebo-kontrollierten Cross-over-Prüfung an Probanden.

This clinico-pharmacological trial aimed to prove equivalence between the known film-coated tablets of ranitidine (Sostril Filmtabletten) and the novel dispersible tablets for the preparation of a drinkable solution (Sostril Aquatabs) on a pharmacodynamic level. Therefore, the influence of single oral doses of the two ranitidine preparations (2 X 150 mg p.e.m. each) and placebo on the gastric hydrogen ion concentration was studied in 12 healthy volunteers using a randomized cross-over design. pH-values of the gastric juice were measured and recorded continuously for 24 h. Median pH-values for the entire study period were 2.20, 2.15 and 1.40 for dispersible tablets, filmcoated tablets and placebo, respectively. During the night-time median pH-values of 3.45 for both ranitidine preparations and 1.40 for placebo were calculated. From these results it can be concluded that the novel dispersible tablets are equivalent to the ranitidine filmcoated tablets with regard to their pharmacodynamic potency.

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.

Pattern of 24 hour intragastric acidity in active duodenal ulcer disease and in healthy controls.

Twenty four hour intragastric acidity was measured by continuous recording using intragastric combined glass electrodes in 46 duodenal ulcer patients within 48 hours of endoscopic confirmation of active ulceration. Acidity during predefined time periods was compared with that measured in 40 healthy controls without gastrointestinal disease: it was significantly higher in duodenal ulcer patients at all times, but 25% of ulcer patients had median 24 hour acidity within the interquartile range of the normal group. During the evening (18,00 to 22,00 h) ulcer patients had considerable acidity with a median of 39.8 (63.1-31.6) mmol/l (interquartile range) compared with 5.6 (22.3-0.4) mmol/l of controls. It is suggested that antisecretory treatment be directed to decrease this period of unbuffered acidity, as well as during the night, which is presently considered of prime importance.

Early evening ranitidine administration promotes faster duodenal ulcer healing.

In a prospective double-blind clinical trial, 141 patients with endoscopically diagnosed duodenal ulcer were randomly assigned to treatment with ranitidine 300 mg, taken either at 6 PM or at 10 PM. After 2 wk of treatment, 52 of 70 patients (74%) in the 6 PM treatment group had healed, compared with 32 of 64 patients (50%) taking ranitidine at 10 PM (p less than 0.01). After 4 wk, the cumulative healing rates were 100% and 94%, respectively, for the 6 PM and 10 PM treatment regimens. These results suggest that ranitidine, taken as a single daily 300-mg dose at 6 PM after dinner, provides more rapid duodenal ulcer healing than the same dose of the drug taken at 10 PM.

Continuous intravenous infusions of famotidine maintain high intragastric pH in duodenal ulcer.

Three double blind crossover studies were carried out to assess the ability of primed infusions of famotidine to raise intragastric pH over 24 hours in 12 duodenal ulcer patients. pH was measured continuously using intragastric electrodes and solid state recording devices. The studies compared the effects of placebo, famotidine 10 mg bolus injection iv followed by continuous infusions of 3.2 mg/h and 4 mg/h in random order. Gastric acidity decreased significantly with both dose regimens (p less than 0.0005) but the effects of either dosage were similar. During fasting median pH rose from 1.35 to 7.1 and 7.05 respectively. During the day, when standard meals were taken, median pH rose from 1.30 to 4.3 and 3.65 respectively. Despite continuous infusions the H2-antagonist was less effective during this time. The latter finding raises questions about gastric secretory control during the day when food is eaten.

Day-to-day variation of 24-hour intragastric acidity.

Twenty-four-hour intragastric acidity was measured continuously using an intragastric electrode in 13 normal volunteers studied four times. Subjects were studied twice in the hospital and twice as outpatients. The dietary conditions were strictly controlled and the replicate studies were compared to assess the variability of such recordings of acidity. The accuracy of the technique was assessed, and a detection limit for differences was calculated for commonly used time periods. Over 24 h, during the night, during the day, and during the evening the technique is able to detect consistent changes of pH of greater than 0.1 units. During separate 5-min periods the limits of detection were considerably greater. This study demonstrates the variability of 24-h intragastric acidity and confirms that continuous monitoring is able to detect important changes of acidity under both hospitalized and ambulant conditions.

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.

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.

Assessment of intragastric acidity in man: modern aspects, reproducibility of intragastric pH-monitoring, and pharmacodynamic results obtained with H2-receptor antagonists.

Unlike other methods for assessing intragastric pH or total acid output, the reproducibility of ambulatory pH-monitoring is excellent but is critically dependent on the electrode system and the recording device. In three double-blind randomized studies in normal volunteers the effects of different dosage regimens of roxatidine acetate were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, raised median 24-h gastric pH from 1.6 to 3.2 and median nocturnal pH from 1.5 to 3.0 Roxatidine acetate, 150 mg at bedtime, raised median 24-h pH to 2.4 and nocturnal pH to 5.9. Roxatidine acetate, 150 mg at bedtime, was as effective as ranitidine, 300 mg at night, in raising median nocturnal pH. However, when drugs were taken after the evening meal, 150 mg roxatidine acetate was less potent than 300 mg ranitidine or 300 mg roxatidine acetate.

Double blind comparison of the effects of cimetidine, ranitidine, famotidine, and placebo on intragastric acidity in 30 normal volunteers.

Continuous measurement of 24 hour intragastric acidity was carried out in 30 normal volunteers during treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, and famotidine 40 mg in a double blind study. Medication was taken after the evening meal (post cenam nocte, PCN). Median 24 hour acidity decreased with all H2-receptor antagonists from 25.1 mmol/l on placebo to 10 mmol/l (-60.1%) during cimetidine, to 3.2 mmol/l (-87.25%) during ranitidine and to 2.5 mmol/l (-90.0%) during famotidine treatment (p less than 0.0005). All drugs significantly inhibited night time acidity but only famotidine decreased acidity during the late morning compared with placebo. Significantly greater acid reduction was seen with famotidine and ranitidine compared with cimetidine but no difference was found between famotidine and ranitidine.

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.

Single dose treatment with H2 receptor antagonists: is bedtime administration too late?

Using ambulatory ph-metry, intragastric acidity was measured over three separate 24 hour periods in each of 12 healthy volunteers receiving either (a) placebo (1800 h and 2200 h), (b) 300 mg ranitidine (1800 h) and placebo (2200 h), or (c) placebo (1800 h) and 300 mg ranitidine (2200 h). Ranitidine was significantly more effective in decreasing 24 h median intragastric acidity when the drug was administered at 1800 h rather than at 2200 h. Median pH (and interquartile range) was 1.45 (1.4-1.7) on placebo, 2.55 (2.05-3.2) on ranitidine given at 2200 h and 3.35 (2.5-3.85) on ranitidine given at 1800 h (p less than 0.004). The total duration of highly acidic electrode readings (pH less than 1.5) over a 24 h period was reduced significantly by administering the H2-receptor antagonist at 1800 h compared with the later administration. It is suggested that treatment of duodenal ulcers by single administration of ranitidine in the early evening should be evaluated by clinical trial.