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.

Failure of a 1-day high-dose quadruple therapy for cure of Helicobacter pylori infection.

BACKGROUND: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1-day high-dose quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt and a proton pump inhibitor has led to eradication rates of 57-77%. In view of the high frequency of metronidazole-resistant strains of H. pylori in Europe, we hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a 1-day high-dose quadruple therapy could be improved. METHODS: Patients were randomized to receive either amoxycillin 1000 mg b.d., clarithromycin 500 mg b.d. and lansoprazole 30 mg b.d. for 7 days, or amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s. and bismuth subcitrate 240 mg q.d.s. for 1 day. RESULTS: It was originally intended to include 100 patients. The first planned interim analysis performed after follow-up was completed for 30 patients revealed H. pylori eradication rates of 80% (12/15) in the 7-day triple therapy group and 20% (3/15) in the 1-day quadruple therapy group, the difference being highly significant (P = 0.003). Because the efficacy of the 1-day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1-day treatment were re-treated with the 7-day triple therapy: the eradication rate was 91% (10/11). CONCLUSIONS: One-day high-dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole and bismuth subcitrate is dramatically less effective than the classic 7-day triple therapy with the same antibiotics.

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.

[Laparoscopic Toupet partial fundoplication as general surgical therapy of gastroesophageal reflux. 1-year results of a 5-year prospective long-term study]. / Laparoskopische partielle Fundoplicatio nach Toupet als generelle chirurgische Therapieform der gastrooesophagealen Refluxkrankheit. 1-Jahresresultate einer auf 5 Jahre ausgelegten prospektiven Langzeitstudie.

INTRODUCTION: A variety of laparoscopic antireflux operations exist for patients with gastroesophageal reflux diseases (GERD). Most surgeons operate using the concept of "tailored approach", which depends on esophageal motility. We have abandoned this concept because of the relatively high incidence of wrap-related complications in patients treated with laparoscopic Nissen fundoplication compared with patients treated with partial fundoplication. It is our policy to perform laparoscopic Toupet partial fundoplication in all patients suffering from GERD, independent of their esophageal motility. METHODS: In a prospective trial we have assessed and evaluated our 1-year results of the first 100 consecutive patients treated with Toupet partial fundoplication. All patients underwent esophagogastroscopy and 24-h pH manometry before operation. One third of patients (n = 34) underwent control manometry 8 weeks postoperatively. The patients were followed up clinically 1, 2, 6 and 12 months postoperatively. RESULTS: In this study group we achieved a healing rate in GERD of 97%. In 3% of patients GERD recurred. The median clinical DeMeester score decreased from 4.27 +/- 1.5 points preoperatively to 0.25 +/- 0.5 points 1 year postoperatively (P < 0.0005). The median fractional time with pH < 4 decreased from 17.8% +/- 12.5% preoperatively to 0.9% +/- 1.2% 8 weeks postoperatively (P < 0.0005). Because of persistent dysphagia 5% of our patients required postoperative dilatation therapy. The rate of reoperation and mortality was 0%. The total morbidity rate was 18%. In 50% of patients with preoperatively recorded esophageal motility disorder, an improvement of esophageal motility was found postoperatively. CONCLUSIONS: Our 1-year results encourage us to continue to perform laparoscopic Toupet partial fundoplication as the primary repair in all GERD patients, independent of their esophageal motility. Laparoscopic Toupet partial fundoplication has proven to be a safe and highly successful therapeutic option in these patients.

[Diagnosis of peptic ulcer disease]. / Diagnostik beim peptischen Ulkusleiden.

Today the upper gastrointestinal endoscopy is the diagnostic tool of choice to detect peptic gastroduodenal lesions. In case of substantial gastric outlet obstruction or strong suspicion of perforated ulcer, an upper gi-transit with barium or water soluble contrast medium in suspected perforated ulcers may be useful. Gastric ulcers are endoscopically controlled up to their complete healing and biopsies taken at each endoscopy in order to rule out gastric cancer. In contrast, duodenal ulcers are rarely malignant and uncomplicated duodenal ulcers, correctly treated with omeprazole over 8 weeks do not necessarily need a final endoscopic control. Since about 5% of duodenal ulcers treated with H2 blockers or mucosal protective agents do not heal within 8 weeks however, an endoscopic control of the healing is recommended. In peptic ulcer patients tests for detection of helicobacter pylori are only needed in presence of a hard indication for immediate eradication: Frequent ulcer recurrencies, complicated ulcer disease or very painful ulcer relapses, because the eradication therapy is often not well tolerated and the patient compliance therefore compromised. 30% of helicobacter infected patients have antibiotic resistant strains and there is no sufficient longterm experience with the eradication therapy available (4) to 8 weeks after treatment of the helicobacter pylori infection the effect on ulcer healing and infection should be verified. Determinations of plasma gastrin levels in peptic ulcer patients are mandatory in patients with suspected Zollinger-Ellison syndrome or patients with treatment resistant ulcers or recurrent ulcers after vagotomy or partial gastric resection.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

[Colonic motility]. / Dickdarmmotilität.

Colonic motility is provided by contraction of intramural smooth muscle under the control of the enteric and the extrinsic nervous system and humoral connections. In vivo measurement of colonic motility remains difficult because of the complexity of these interactions and anatomical considerations. The possibility that symptoms are due to colonic dysmotility should be considered in patients with normal barium enema and colonoscopy. Examples of this are patients with chronic constipation, irritable bowel syndrome or colonic symptoms associated with diabetes mellitus or diseases of the nervous system. A number of techniques have been developed to assess colonic motility. The simplest is to assess colonic transient with a single abdominal x-ray following ingestion of radio-opaque markers. This is cheap, reproducible and easy to perform. Normal values for age and sex are available. Colonic transit of both liquid and solid can be determined by scintigraphic measurement. This technique provides information about regional variations in colonic function; it is however relatively demanding and requires access to a gamma camera. Manometry provides a more direct assessment of colonic motor activity. Changes in the electrical potential of the colonic smooth muscle can be determined by electromyography. Both techniques are however difficult to perform, and are currently only used for research purposes. It is likely that the combination of techniques that examine transit with more direct measurement of motor function will provide further insights into the mechanisms responsible for colonic dysmotility.

Prophylactic endoscopic sclerotherapy of oesophageal varices. A prospective controlled study.

Of 109 patients with cirrhosis and endoscopically demonstrated oesophageal varices who had not bled, 56 were treated by sclerotherapy and 53 were treated conservatively. Patients were assigned to one of three categories according to varix size and Child's classification of severity of liver disease. Severity of liver disease increased with varix size. Frequency of haemorrhage in the control group also increased with varix size: haemorrhage occurred from small varices in 35% of patients, from medium varices in 53%, and from large varices in 83%. Prophylactic sclerotherapy diminished the frequency of variceal bleeding and overall mortality: over 25 months, frequency of bleeding was 9% in the therapy group and 57% in the controls, with mortality rates of 23% and 55%, respectively.

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.

[Endoscopic findings in volunteers and dyspeptic patients]. / Endoskopische Befunde bei freiwilligen und dyspeptischen Patienten.

Although more than a fourth of the adult population reports dyspeptic complaints, little is known about the prevalence of clinically relevant UGI endoscopic findings in these patients in comparison with asymptomatic volunteers. This type of information is required in order to assess the relative risks of organic dyspepsia and the sensitivity and specificity of dyspeptic complaints for peptic lesions. In an attempt to fill this gap, the authors compared two trials carried out in the German-speaking part of Switzerland: (a.) 172 adult asymptomatic volunteers (age 20-78 years, 74 females, 98 males) participated in an epidemiological trial to measure the prevalence of positive CLO-urease tests and of upper GI-tract lesions. (b.) 119 patients (age 18-84 years; 68 females, 51 males) consulting their family doctor because of upper digestive symptoms of at least 1 month's duration (epigastric pain or discomfort, heartburn, acid regurgitation, early satiety, bloating, etc.) were referred for UGI endoscopy as a screening procedure; functional dyspeptics were thereafter randomized to a double blind drug trial (not reported here). In both trials the gastric presence of Helicobacter pylori was measured by means of the CLO-urease test. Prevalences of lesions and of positive urease-tests in the dyspeptic population were compared with the sex and age adjusted prevalences registered in the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

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.