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.

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.

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.

Loss of acid suppression during dosing with H2-receptor antagonists.

The suppression of intragastric acidity with H2-receptor antagonists may diminish with repeated administration. To assess the degree and dose-dependence of this tolerance after short-term dosing, two doses of the H2-receptor antagonists, ranitidine (300 mg nocte or q.d.s.) and sufotidine (300 mg or 600 mg b.d.), were given to healthy volunteers for 1 and 2 weeks, respectively. After 1 and 7 days of dosing with ranitidine 300 mg q.d.s. the median 24-h and night-time pH, measured by continuous 24-h pH-metry, dropped from 3.7 to 2.2 and 5.8 to 3.2, respectively (P less than 0.0001 for both). The decline in median pH with ranitidine 300 mg nocte was only significant during the night (from 4.1 to 2.9) (P less than 0.04). There was little change in plasma gastrin concentrations between days 1 and 7 with either dosage. With sufotidine 300 mg b.d. and 600 mg b.d. for 1 and 14 days, the median 24-h pH fell from 3.7 to 2.1 and from 4.6 to 2.6, respectively (P less than 0.0001). The equivalent medians for the night decreased from 6.3 to 2.3 and from 6.6 to 3.1 (P less than 0.0001). Gastrin concentrations did not change after 14 days of dosing with sufotidine 300 mg b.d., but increased significantly during dosing with sufotidine 600 mg b.d. (P less than 0.001). Significant tolerance developed in 7-14 days and it seemed to show some dose relationship. The mechanisms behind tolerance and the role of gastrin are discussed, but remain unclear.

Tolerance during dosing with H2-receptor antagonists. An overview.

Diminution of antisecretory effect of H2-receptor antagonists with repeated oral dosing, termed tolerance, has been established in healthy volunteers. Anecdotal evidence indicates the development of tolerance with intravenous dosing. These findings demonstrate that tolerance may be clinically relevant in diseases where tight control of acidity is required. Patients with duodenal ulcer disease, however, do not develop significant tolerance, according to the sparse investigations available. Tolerance will, at most, only be of minor clinical significance in failures of DU to heal. The mechanisms implicated in the development of tolerance remain unclear.

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.

Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing?

BACKGROUND/AIMS: Prolonged infusions of H2-antagonists are commonly used in intensive care units, although little is known about their antisecretory efficacy beyond the initial 24 hours of dosing. The aim of this study was to assess the antisecretory effects of infusions of ranitidine and omeprazole for a period of 72 hours. METHODS: Twelve healthy volunteers received individually titrated 72-hour intravenous infusions of omeprazole, ranitidine, or placebo in a double-blind, crossover study. Gastric pH and dosing requirements were compared. RESULTS: The median percentage of time with pH > 4 (interquartile range) was 93% (88%-95%) on day 1 and 96% (94%-99%) on day 3 with omeprazole and 67% (56%-78%) and 43% (31%-51%), respectively, with ranitidine (both P < 0.001 vs. omeprazole). The mean doses (+/- SD) required on days 1 and 3 for omeprazole were 235.8 +/- 44 mg and 134.0 +/- 37 mg (P < 0.0001), and ranitidine doses were 502.5 +/- 76 mg and 541.8 +/- 25 mg, respectively (P = 0.05). CONCLUSIONS: Omeprazole infusions consistently maintained gastric pH above 4 over a period of 72 hours with progressively lower doses. Significant tolerance to the antisecretory effect of ranitidine infusion developed in 72 hours, which was not overcome despite individually titrated doses of more than 500 mg/24 hours. Consequently, application of pharmacodynamic results of single-day H2-blocker and proton-pump inhibitor studies to prolonged infusion trials for stress ulcer-related bleeding is inappropriate.

Tolerance and rebound to H2-receptor antagonists: intragastric acidity in patients with duodenal ulcer.

Tolerance to the antisecretory effects of H2-receptor antagonists develops consistently in healthy volunteers. The aim of this study was to determine whether tolerance occurs with repeated dosing of H2-receptor antagonists in patients with duodenal ulcer. Continuous intragastric 24-hr pH measurements were performed in 12 patients with duodenal ulcer in symptomatic remission before, on days 1 and 29, and two days after receiving ranitidine 300 mg four times a day for 34 days. The 24-hr median intragastric pH (interquartile range) was 5.4 (4.4-6.1) on day 1 and 4.6 (4.0-5.2) on day 29 of dosing with ranitidine (not significant). Median nighttime pH was 6.8 (6.3-7.0) on day 1 and 6.8 (6.6-7.1) on day 29 (not significant). During the daytime, the median pH decreased marginally from 4.7 (3.8-5.2) on day 1 to 3.8 (3.0-4.6) on day 29 (P less than 0.03). There was no difference in median intragastric pH during 24-hr, day and night periods before and two days after ranitidine dosing. No significant tolerance or rebound to H2-receptor antagonists was observed in patients with duodenal ulcer disease. This contrasts with data gathered in healthy volunteers and may be due to defects in the regulation of acid secretion in duodenal ulcer disease.

Is the time of dosing of a potent long-acting H2-receptor antagonist critical? Twenty-four-hour pH measurements with SKF-94482.

Reduction of daytime as well as nighttime acidity is important in the healing of duodenal ulceration and reflux oesophagitis. The importance of the time of dosing of potent, long-acting H2 blockers for optimal suppression of intragastric acidity is unknown. The efficacy of different oral dosage regimens of SKF-94482, a new, competitive and long-acting H2-receptor antagonist, in reducing daytime and nighttime intragastric acidity was studied with 24-h pH-monitoring in 3 double-blind, randomized, crossover trials in 45 fed, healthy subjects. In study A 200 mg, 400 mg, or 600 mg SKF-94482 or placebo was given at 0830 h for 6 days. In study B the above doses were taken at 1830 h. In study C 200 mg or 300 mg of SKF-94482 or placebo was given at 0830 and 1830 h for 6 days. SKF-94482, 400 mg, was the most effective dose, and twice daily dosing was of no additional pharmacodynamic benefit. When 400 mg SKF-94482 was given at 0830 h, the median 24-h, day (0800-1800 h) and night (1800-0800 h) pH (interquartile range) were 2.6 (2.2-3.2), 2.3 (2.1-3.8), and 2.6 (1.8-3.6), respectively. When the time of dosing was 1830 h with 400 mg SKF-94482, median 24-h, day and night pH were 3.4 (2.5-4.0), 3.4 (3.1-4.3), and 3.7 (2.8-5.9), respectively. Early-evening dosing of this long-acting H2 antagonist resulted in substantially greater suppression of intragastric acidity than morning dosing.

Safety and efficacy of roxatidine acetate. Evidence from pharmacodynamic and clinical trials.

The effects of a new H2-receptor antagonist, roxatidine acetate, have been investigated in both clinical and pharmacodynamic trials in Europe and the United States. A series of four double-blind randomized studies are reviewed, reporting the effects of different dose regimens of roxatidine acetate compared with ranitidine and placebo in healthy volunteers using continuous intragastric pH monitoring. These pharmacodynamic studies clearly demonstrate that roxatidine acetate is an effective gastric antisecretory agent, which is up to twice as potent as ranitidine. The results of several clinical studies of roxatidine acetate in patients with gastric as well as duodenal ulcer conducted in Europe, Japan, and the United States are also reviewed. These studies show that roxatidine acetate is comparable to other potent H2-receptor antagonists in terms of cumulative healing rates, pain relief, and safety. Overall, the pharmacodynamic and clinical data indicate that the efficacy of roxatidine acetate 75 mg twice-daily (b.i.d.) does not differ significantly from ranitidine 150 mg b.i.d. Roxatidine acetate is equally effective in the treatment of peptic disease including gastric ulcer, duodenal ulcer, and reflux esophagitis.

Diurnal secretory patterns and tolerance during individually titrated infusions of ranitidine.

BACKGROUND: Gastric acid secretion in humans shows chronobiological patterns that modify the efficacy of antisecretory agents. The ability of individually titrated ranitidine infusions to overcome circadian patterns of gastric acidity and tolerance during prolonged dosing was assessed. METHODS: Eleven healthy subjects were randomized to receive ranitidine infusions of up to 600 mg/24 hours by a pH feedback-regulated pump before and after 9 days of oral dosing with ranitidine, 300 mg four times daily, beginning either in the evening or in the morning in a cross-over, third party-blinded and placebo-controlled study design. RESULTS: Mean 24-hour intravenous ranitidine doses given to attain the target pH of 4 were greater after 9 days of treatment with oral ranitidine than before in the morning and evening studies (P < 0.01). The median 24-hour pH decreased from 5.1 before to 3.6 after oral dosing in the morning study (P < 0.001) and from 4.4 to 2.8 in the evening study (P < 0.001). Before oral dosing of ranitidine, the time of pH > 4 in the evening and morning fasting periods was 71% and 84%, respectively (P < 0.05). After 9 days oral ranitidine, the respective results were 20% and 53% (P < 0.05). CONCLUSIONS: The reduced responsiveness to ranitidine in the evening and the tolerance to ranitidine with repeated dosing were not overcome by individually titrated, high intravenous doses of ranitidine.

Gastrospirillum hominis in asymptomatic, healthy individuals.

Gastrospirillum hominis is a spiral-shaped bacterium found in the stomach. It has been implicated as a possible cause of chronic gastritis. We report two cases of G. hominis colonization observed in a series of 175 healthy, asymptomatic volunteers investigated for Helicobacter pylori. None of the volunteers had symptoms or a history of gastrointestinal disease. Both carriers of G. hominis had histological signs of chronic, active antral gastritis. Multiple tests for H. pylori were negative. The prevalence of this spiral bacterium in healthy, asymptomatic individuals may be as low as in symptomatic persons.

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.

Individual and group dose-responses to intravenous omeprazole in the first 24 h: pH-feedback-controlled and fixed-dose infusions.

1. Individual responses to intravenous boli of omeprazole have shown considerable variability. Data on the individual responses to the new omeprazole infusion formulation are lacking. 2. Individual dose-responses in the first 24 h of fixed-dose and pH-feedback-controlled infusions of omeprazole were assessed in two randomised, third-party blinded, cross-over studies, using two separate groups of eight healthy subjects. In study A, feedback-controlled infusions of omeprazole (target pH 5, dose range 0-12 mg h-1) and fixed-dose infusions (8 mg h-1) were compared, both with an initial bolus of 80 mg. Omeprazole plasma concentrations were measured. Study B assessed the effect on individual pH-control of a loading bolus of either 40 mg or 80 mg omeprazole, followed by feedback-controlled infusions. 3. Study A: the median % time of pH > 5 was 71.2 (total range: 48.9-83.2) with feedback infusions and 57.9 (28.0-95.3) with fixed-dose infusions (P = 0.06). The mean 24 h infusion doses were 173.1 mg (44.5-253.1) in the feedback group and 192 mg in the fixed-dose group. The AUC of omeprazole plasma concentrations ranged widely, but correlated with the % time of pH > 5 during fixed-dose infusions. Study B: initial boli of 40 mg and 80 mg of omeprazole resulted in similar 24 h median % of time with pH > 5, 69.2 (49.9-78.8) and 69.6 (44.4-87.7), respectively. Mean omeprazole doses infused by feedback pump were 187.6 mg (83.1-253.6) after 40 mg boli and 159.9 mg (61.8-227.0) after 80 mg boli.(ABSTRACT TRUNCATED AT 250 WORDS)

Is a fluoroscopic verification of the electrode position necessary in ambulatory intragastric pH monitoring?

To assess whether a fluoroscopic verification of the electrode position is necessary before and whether electrode displacement occurs during intragastric pH measurements, a crossover study was performed in 20 healthy male volunteers. The pH electrode was initially placed in the gastric corpus using pH readings and catheter length only, and the electrode tip was fluoroscopically located before and after the 24-hour study. Only in one study arm was an adjustment of the electrode position allowed, if fluoroscopy showed a position outside the gastric body. Thirty-seven (92%) of all 40 electrodes were in the corpus when placed by pH-metric methods alone. With fluoroscopic guidance, 2 of the 3 electrodes lying outside the corpus could be repositioned as desired. The median night, day or 24-hour gastric pHs measured in the groups with or without replacement of the electrode tip were identical. Displacement after 24-hour measurements did not occur with initially correctly positioned electrodes. Fluoroscopy is not necessary for the verification of the position of electrodes placed by pH-metric techniques in individuals with residual acid secretion, and electrode displacement is rare.

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.

Long-acting somatostatin analog controls acid and gastrin secretion in benign, not in malignant, Zollinger-Ellison syndrome.

The long-acting somatostatin (SMS) analog, SMS 201-995 has beneficial effects on APUDomas. In two Zollinger-Ellison syndrome (ZES) patients we assessed basal acid output (BAO) and 24-h pH under SMS and compared them to controls. We also assessed total gastrin, gastrin 17, insulin, glucagon, C-peptide, and SMS by radioimmunoassay. In the benign gastrinoma, an acid-controlling action of SMS was shown, elevating the 24-h pH threshold over the pH range 1.5-5 of 55-10% compared with control. A parallel inhibition of the gastrins greater than 90% was apparent. We found no beneficial effect on gastric acid secretion and on tumor gastrin in the malignant gastrinoma despite a fourfold higher plasma SMS level. Non-tumor-related peptides were suppressed by approximately 50% and in contrast to gastrin they again reached pre-SMS levels before the next dose of the drug. We conclude that SMS is more effective in benign than in malignant gastrinomas, and may be exclusively so.

pH-feedback controlled infusions of ranitidine are no more effective than fixed-dose infusions in reducing gastric acidity and variability in antisecretory responses.

1. The antisecretory responses to pH-feedback controlled (maximum dose 800 mg 24 h-1) and fixed-dose (0.25 mg kg-1 h-1) continuous infusions of ranitidine were compared in a randomised, placebo-controlled, cross-over study in 10 healthy male volunteers. 2. To assess tolerance during repeated dosing with ranitidine, the same infusion regimens were given before and after 6 days oral dosing with ranitidine 300 mg four times daily. 3. With the pH-feedback controlled infusion of ranitidine the median % time (interquartile range) with pH greater than 4 in the 24 h period was 57% (45-76) before and 23% (17-34) after 6 days oral dosing (P less than 0.001). The respective values with fixed-dose infusion were 51% (38-63) and 26% (15-32) (P less than 0.002). 4. The median 24 h doses (interquartile range) of ranitidine given by feedback-controlled infusion before and after 6 days oral dosing were 675 mg (542-728) and 749 mg (709-760), respectively (P less than 0.01). The dose of ranitidine given by fixed-rate infusion was 423 mg (393-502) on both study days (P less than 0.001 vs feedback infusion). 5. Plasma gastrin concentrations remained slightly elevated after 6 days of oral ranitidine dosing, whereas pancreatic polypeptide plasma levels remained unchanged. 6. The antisecretory efficacy of infusions of ranitidine is significantly decreased by circadian stimuli and tolerance. Individually-adapted infusions of high doses of ranitidine were not superior to fixed-dose infusion of 0.25 mg kg-1 h-1 in overcoming this variability.

Influence of Helicobacter pylori, sex, and age on serum gastrin and pepsinogen concentrations in subjects without symptoms and patients with duodenal ulcers.

The relation between Helicobacter pylori (H pylori) infection and fasting gastrin and pepsinogen-I and -II concentrations was evaluated in 278 volunteers without symptoms and the results were compared with the values obtained in 35 patients with duodenal ulcers. H pylori infection was determined with the 13C-urea breath test in subjects without symptoms and with endoscopy, biopsy (histology and culture), and quick urease test (CLO-test) in patients with duodenal ulcers. Gastrin and pepsinogen-I and -II concentrations were assayed with specific radioimmunoassay systems. The results clearly indicate that fasting gastrin and pepsinogen-I and -II concentrations were significantly higher in H pylori positive compared with H pylori negative subjects. Neither age nor sex affected basal gastrin and pepsinogen concentrations in H pylori negative subjects. Fasting gastrin, pepsinogen-I and -II concentrations in serum samples were similar in H pylori positive persons with no symptoms and those with duodenal ulcers suggesting that similar mechanisms are involved in increasing plasma concentrations of these variables in both populations. Hypergastrinaemia and hyperpepsinogenaemia are therefore probably secondary to active H pylori infection.