Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori-positive healthy subjects.

BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection. It was speculated that omeprazole-induced hypoacidity enhances the antibacterial activity of amoxycillin. Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy. No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole. METHODS: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline intragastric pH-metry, 24 H. pylori-positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d. + placebo, amoxycillin 750 mg b.d. + omeprazole 40 mg b.d. and omeprazole 40 mg b.d. + placebo for 5 days. On the last day of each regimen intragastric pH-metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles. RESULTS: Amoxycillin monotherapy had no acid-inhibiting effect. Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01). Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different. CONCLUSIONS: High-dose omeprazole does not alter the pharmacokinetics of amoxycillin. The significantly lower intragastric pH during combination therapy might be due to the H. pylori-suppressive effect of this treatment.

Dose-response of omeprazole combined with amoxycillin on duodenal ulcer healing and eradication of Helicobacter pylori.

BACKGROUND: Combination therapy using omeprazole and amoxycillin can cure Helicobacter pylori infection, but data are controversial concerning the efficacy of this regimen. The present study investigated varying doses of omeprazole combined with a standard amoxycillin dose on duodenal ulcer healing and eradication of H. pylori, in order to find an optimal dose regimen. METHODS: H. pylori-positive out-patients (n = 231) with duodenal ulcers were treated randomly and double-blind with either omeprazole 20, 40 or 80 mg b.d. plus amoxycillin 1 g b.d. for 14 days. Patients with an unhealed ulcer after this therapy took omeprazole 20 mg o.m. for another month. RESULTS: After 2 weeks, ulcer healing rates in the three treatment groups were not statistically different (85, 82 and 93%, respectively). Treatment with omeprazole 80 mg b.d. was significantly better in curing H. pylori infection (eradication rate 69%) than treatment with omeprazole 20 and 40 mg b.d. (47 and 53%). CONCLUSIONS: Combination of either omeprazole 20 or 40 mg b.d. plus amoxycillin 1 g b.d., is not sufficiently effective to be recommended as an anti-H. pylori therapy. Omeprazole 80 mg b.d. combined with amoxycillin is more efficient and well tolerated, but better treatment options now exist to cure H. pylori infection.

Effect of pantoprazole on 24-h intragastric pH and serum gastrin in humans.

Pantoprazole, a novel proton pump inhibitor, is a potent inhibitor of gastric acid secretion. In this review, data are presented from nine controlled, prospective, clinical pharmacodynamic investigations. The effects of oral and intravenous doses of pantoprazole (administered for 5-7 days) on continuously monitored 24-h intragastric pH and serum gastrin are discussed: oral pantoprazole 20 to 80 mg/day (given in the morning before breakfast) induced a dose-related increase in both the 24-h intragastric pH and the serum gastrin profile. The effects of pantoprazole doses of 60 and 80 mg were not significantly different from those of the 40 mg dose. It was concluded that oral pantoprazole at 40 mg/day is the optimal antisecretory dose for the treatment of acid-related diseases. In two comparative studies, this dose of pantoprazole (administered before breakfast) proved to be significantly more effective than ranitidine 300 mg (given in the evening) and omeprazole 20 mg (given in the morning). Administration of oral and intravenous pantoprazole (40 mg) was found to be equipotent at increasing 24-h intragastric pH, but this finding requires further evaluation. The approximately 2-4-fold rise in median serum gastrin concentrations following several days' administration of pantoprazole 40 mg is of a comparable magnitude to that of other proton pump inhibitors. It seems unlikely that this moderate hypergastrinaemia during pantoprazole treatment should influence the human enterochromaffin-like (ECL) cell density in a clinically relevant way, but data during long-term therapy are necessary to confirm this conclusion.

Modern approach to the evaluation of combined effects of single-dose trials and clinical time-course studies, exemplified by combinations of pirenzepine and H2-receptor antagonists.

A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern understanding of actions and interactions of drugs which act at distinct molecular sites. It rests on a comparison of observed combined effects with calculated effects of independent action of A plus B--greater than independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of the antisecretory action of pirenzepine and H2-receptor antagonists (cimetidine, ranitidine). Briefly, peptone-stimulated acid output was measured in 15 min periods over 3 h after the injection of drugs in three trials, one with five duodenal ulcer patients, two of them with 8 healthy volunteers each. The doses of pirenzepine and H2-blockers were fixed in each trial. The results were either expressed by the total acid output (single-dose analysis) or by the acid secretion over 15 min as time course. The results with the drug combination show greater reduction in acid secretion in all three trials with respect to independent effects. The time-course studies more clearly showed greater reduction in acid output than the analysis of total acid output, not the least with respect to p-values of differences between observed combined effects and calculated independent effects. They were obtained by the chi-square (chi 2) goodness-of-fit test, recently applied for the evaluation of dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagitis.

The combination of a histamine H2-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades I-III). After four weeks of treatment, healing rates were 32/75 (43%) in the combined treatment group and 34/76 (45%) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69% vs. 52%, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.

Three year follow up of patients with gastrooesophageal reflux disease.

Data on the natural course of gastrooesophageal reflux disease are sparse. One hundred and sixty six patients with typical reflux symptoms (heartburn and/or acid regurgitation) and pathologic pH monitoring (reflux time > 8.2% upright and/or > 3.0% supine) were studied. The patients were followed up by questionnaire and interview for a mean of 41 (seven to 86) months after diagnosis of reflux disease. Ten patients had died of diseases not reflux related. In 117 (75%) of the remaining 156 patients data on the course of gastrooesophageal reflux disease could be obtained. In 12 patients anti reflux surgery had been performed. Forty one (39%) of the remaining 105 patients have stopped taking medical therapy, in 13 of these patients symptoms had completely disappeared. Sixty four patients continued on medication (40 on demand, 24 regularly). When asked how their symptoms would be if they completely stopped medication, 71 patients considered their symptoms to be equal or worse and 21 patients to be improved as compared with the initial investigation. Patients with persisting symptoms at follow up had significantly more supine reflux (p < 0.05) at the initial pH monitoring as compared with patients with improved symptoms. The presence and grade of oesophageal erosions at initial endoscopy, duration of symptoms, age, sex, and smoking habits had no influence on the course of gastrooesophageal reflux disease. In conclusion, reflux symptoms disappear only in a minority of patients with proven gastrooesophageal reflux disease. More than half of all patients continue medication, either on demand or regularly. Severe supine reflux is an unfavourable prognostic factor.

Dose-related healing of duodenal ulcer with the proton pump inhibitor lansoprazole.

Lansoprazole (AG 1749) is a novel substituted benzimidazole which inhibits gastric acid secretion by blocking H+,K(+)-ATPase. This randomized, double-blind multicentre trial studied the dose-response relationship of lansoprazole on ulcer healing and compared it with ranitidine in 314 out-patients with endoscopically assessed, symptomatic duodenal ulcer. Cumulative healing rates with Lansoprazole 7.5, 15, and 30 mg o.m. were 48, 59, and 74% at 2 weeks and 75, 84, and 95% at 4 weeks, respectively (intention-to-treat); the difference of the healing rates between 7.5 and 30 mg groups was significant (P less than 0.001). Corresponding healing rates for 300 mg ranitidine nocte were 51 and 89%. Pain relief was similar in all treatment groups. Lansoprazole was well tolerated. During a follow-up of 6 months relapse rates after lansoprazole 7.5, 15, and 30 mg were 21, 29, and 22%, respectively; the relapse rate after ranitidine 300 mg was 20%. In conclusion, lansoprazole provides faster healing of duodenal ulcer than ranitidine and a similar relapse pattern. For further trials in peptic ulcer disease a daily dose of lansoprazole 30 mg o.m. is recommended.

Standardization of electrode positioning and composition of meals for long-term intragastric pH metry in man.

In these prospective studies the influence of two different intragastric positions of electrodes and of four different compositions of standardized meals on 24-hour ambulatory pH recording were compared intraindividually in healthy male subjects. Simultaneous pH monitoring in 12 subjects demonstrated a more pronounced postprandial pH elevation in the fundus body compared to the antral area. The intraindividual comparison of an identical diet given on two different days to 10 subjects revealed nearly identical pH profiles. Variations of carbohydrate, protein and fat content of isocaloric meals given in a randomized order did not significantly alter 24-hour intragastric pH profiles. It is concluded from these data that positioning of the pH electrode in the fundus body area is superior to an antral position. 24-hour ambulatory intragastric pH monitoring in man is well reproducible. A strict standardization of the composition of meals is mandatory only for scientific investigations.

Simultaneous comparison of 24-hour intragastric pH recording using glass and antimony electrodes in man.

Based upon the results of in vitro studies, antimony electrodes are generally considered to have inferior electrochemical properties when compared with glass electrodes. Since a direct comparison in man is lacking, a 24-hour ambulatory intragastric pH recording was performed in 10 healthy male subjects simultaneously using glass and antimony electrodes. In the first set of experiments (when both electrodes were calibrated in buffers of pH 7 and 1 at 37 degrees C: beaker calibration) significantly lower pH recordings during fasting periods were registered with the antimony electrode. This difference could be corrected by a modified calibration, using the external skin reference electrode of the antimony electrode (finger calibration). In the second series of experiments (performed after finger calibration) comparable recordings of 24-hour intragastric pH could be obtained with antimony and glass electrodes in the same subjects. The reason for statistically insignificant differences of pH recordings with both electrodes in the early hours of the morning remains uncertain. The drift of glass and antimony electrodes did not differ. It is concluded from these data that, after adequate calibration, inferior electrochemical properties of antimony electrodes do not influence intragastric pH recordings in man.

Diminishing efficacy of octreotide (SMS 201-995) on gastric functions of healthy subjects during one-week administration.

In this study, the pharmacokinetics, efficacy, and tolerability of 25 and 100 micrograms of octreotide given t.i.d. for 7 days subcutaneously were investigated in 12 healthy male subjects. Serum concentrations of the drug were well reproducible within 1 wk. Octreotide significantly raised 24-h median intragastric pH on day 1, but no longer on day 6. Peptone-stimulated gastric acid and volume secretion were markedly less suppressed by octreotide on day 7 compared with day 2. Peptone-stimulated gastrin release was abolished on days 2 and 7, as was peptone-stimulated insulin release. Blood glucose was altered in a biphasic pattern on days 2 and 7. All effects of octreotide were without clear-cut dose-response relationship. A mean half-life of 115 min was calculated. Dose-unrelated side effects (e.g., abdominal cramps, diarrhea, and fatty stools) were registered. In conclusion, octreotide is a powerful inhibitor of gastric acid and volume secretion during acute treatment. Its loss of efficacy during a 1-wk administration may be due to the adaptation of somatostatin receptors and hormonal counterregulation.

Pharmacokinetic and pharmacodynamic studies in man simulating acute and chronic treatment with oral pirenzepine.

Nine healthy, male subjects received controlled-rate i.v. infusions of a new formulation of pirenzepine to produce constant plasma levels of 40 ng/ml and 105 ng/ml. They also received stepped infusions resulting in plasma levels of 20, 40, 80 and 40 ng/ml for defined periods. Peptone-stimulated gastric acid and volume secretion and near point vision decreased dose dependently, whereas gastric acidity was unchanged. There was a significant correlation between inhibition of gastric acid secretion and the pirenzepine concentration in plasma and in gastric juice. During the stepped i.v. infusion, changes in near point vision were closely related to the plasma drug concentration. Antimuscarinic side-effects occurred more frequently when the plasma drug level was high. Overall, there was a close relationship between the plasma concentrations and the effects and side-effects of pirenzepine. Its gastric inhibitory action was characterized only by a reduction in gastric volume secretion. Increasing plasma concentrations during the first days of treatment may be essential for its efficacy as an antiulcer drug.

Protection against the staphylococcal enterotoxin-induced intestinal disorder in the monkey by anti-idiotypic antibodies.

The staphylococcal enterotoxin serotype B (SEB)-induced enteric intoxication and the immediate-type reaction in the skin of unsensitized monkeys was used to define whether agents competing with SEB for target cell receptors may inhibit pathophysiological effects. For this purpose a duodenal provocation test was developed by use of a pediatric gastroscope, allowing the evaluation of the influence of antagonists on the intestinal disorder upon SEB challenge at the same duodenal site. First, carboxymethylation of histidine residues of SEB caused a complete loss of emetic and skin-sensitizing activity without changing the immunological specificity. However, carboxymethylated SEB is a strong inhibitor of enteric intoxications and immediate-type skin reactions upon SEB challenge. Second, after immunization of BALB/c mice with monoclonal anti-SEB antibodies, monoclonal antiidiotypic antibodies (anti-Id) were obtained by the "hybridoma technique" and purification by idiotype-affinity chromatography. Anti-Id specifically inhibited the binding of horseradish peroxidase-labeled anti-SEB to the ligand, and SEB blocked as well the interaction of these two antibody species, indicating a high degree of binding-site selectivity. Anti-Id completely protected against emetic response and diarrhea upon duodenal provocation with SEB and inhibited immediate-type skin reactions as well. Further, anti-Id acted as an antagonist without triggering biologic functions themselves. This shows that anti-Id constitute a useful tool to protect against a bacterial toxin-induced intestinal disorder.

Telenzepine is at least 25 times more potent than pirenzepine--a dose response and comparative secretory study in man.

Telenzepine is an analogue of pirenzepine with a higher potency and similar selectivity for M1-receptors in animals. In this placebo controlled, double blind, randomised study mean peptone stimulated gastric acid secretion (mean +/- SEM) of 10 male healthy subjects (58 +/- 6 mmol H+/3 h for placebo) was significantly and dose dependently inhibited by oral telenzepine (2 mg: 31 +/- 5, 3 mg: 23 +/- 5, 5 mg: 21 +/- 4 mmol H+/3 h). Telenzepine 3 and 5 mg were significantly stronger than pirenzepine 50 mg orally (37 +/- 8 mmol H+/3 h). Mean percentage acid inhibition was 37% for pirenzepine, and 48, 61, and 64% for 2, 3, and 5 mg telenzepine, respectively. Basal and peptone stimulated gastrin release was unaffected. Mean salivary output per three hours declined moderately from 156 +/- 45 g (placebo) to 136 +/- 45 g with pirenzepine and significantly to 88 +/- 28 g, 95 +/- 39 g and 39 +/- 13 g with telenzepine 2, 3, and 5 mg, respectively. There was a parallel effect on Na+, K+, Ca++ and amylase output in saliva. Near point vision was not altered by either drug. Pulse rates were lowered by both substances. Complaints of dry mouth were more frequent with telenzepine 5 mg. On a molar basis telenzepine proved to be a 25 and 50 times more potent inhibitor of gastric and salivary secretion, respectively.

Pharmacological effects of secretin and somatostatin on gastric and renal function in man.

In this randomized, double-blind, placebo-controlled study therapeutic doses of synthetic secretin (0.5 CU/kg/h) and somatostatin (3.5 micrograms/kg/h) given an intravenous infusion suppressed significantly peptone-stimulated gastric acid output per 3 h in nine male healthy subjects from 59.2 +/- 7.4 mmol H+ (placebo) to 16.9 +/- 3.1 and 6.6 +/- 1.5 mmol H+, respectively. Peptone-stimulated gastrin release was reduced to basal concentrations by both hormones. In five subjects secretin raised serum lipase to pathological concentrations. Somatostatin diminished significantly mean blood glucose concentrations. Both had opposite renal effects; secretin showed diuretic and somatostatin antidiuretic properties. Secretin and somatostatin were well tolerated. It is concluded from these data that therapeutic doses of secretin and somatostatin are comparably effective on exocrine and endocrine gastric functions, but have opposite effects on renal functions in man.

Present status and future perspectives of muscarinic receptor antagonists.

Conventional anticholinergics (better called muscarinic antagonists) do not differentiate between subtypes of muscarinic receptors and cause unpleasant side-effects in peptic ulcer treatment. Pirenzepine, the first M1-receptor antagonist, has more selective inhibitory properties on oxyntic gastric glands and accelerates healing rates in peptic ulcer. Pirenzepine and H2-receptor antagonists interact synergistically on parietal cell function; their combination seems to be of therapeutic advantage in defined indications. Telenzepine, a pirenzepine analogue with a modified tricycle and M1-receptor selectivity, is about 10 to 25 times more potent than pirenzepine in reducing basal and stimulated gastric acid secretion in man. In patients with duodenal ulcer 3 mg telenzepine nocte seems to be as effective as 50 mg pirenzepine twice daily in regard to ulcer healing and pain relief. Another pirenzepine analogue with a modified side-chain (AF-DX 116) proved to be cardioselective in animal pharmacology, and was characterized as an M2-receptor antagonist. This might be an important step for a more profound understanding of structure-activity relationships of muscarinic receptor antagonists.

Anti-ulcer drugs in antisecretory doses for "cytoprotection" in arthritic patients?

Gastric injury and dyspepsia are major side-effects of acetylsalicylic acid (ASA) or most non-steroidal anti-inflammatory drugs (NSADs) which cause either gastric ulcerations or gastroduodenal erosions. There is only a limited number of trials in which the possibility of preventing or treating gastric lesions due to those drugs have been studied in man. This paper reviews trials in which H2-receptor antagonists, pirenzepine and prostaglandins have been investigated. - Pirenzepine given in antisecretory doses seems to improve gastrointestinal symptoms induced by ASA or NSADs. Cimetidine and misoprostol might prevent fecal blood loss. Gastroduodenal lesions might be prevented by pirenzepine, misoprostol and enprostil. It might be possible that cimetidine or ranitidine heal NSAD-induced peptic ulcers better than placebo in arthritic patients who stop the ingestion of NSADs. - All over the results of the cited trials are inconclusive, since the number of patients studied were too small and the design of almost all trials was incomparable. Furthermore, all cited studies do not correspond to Robert's concept of "cytoprotection", since H2-blockers, pirenzepine and prostaglandins have been applied in antisecretory doses in man.

Omeprazole heals duodenal, but not gastric ulcers more rapidly than ranitidine. Results of two German multicentre trials.

In two double-blind, randomized German multicentre trials the effects of omeprazole 20 mg mane and ranitidine 150 mg b.i.d. were compared for the first time in 334 outpatients with duodenal ulcer and 184 outpatients with gastric ulcer. In patients with duodenal ulcer endoscopically controlled healing rates after two weeks were 72% with omeprazole and 59% with ranitidine (p = 0.012); after 4 weeks 96 and 92%, resp. were healed (n.s.). In patients with gastric ulcer the healing rates after two, four, and eight weeks were 43, 81, and 95%, respectively, with omeprazole and 45, 80, and 90%, respectively, with ranitidine (n.s.). Smoking impaired healing in duodenal, but not in gastric ulcer. Symptom relief was comparable with both drugs. Serious side effects or clinically relevant changes in laboratory screening results were not detected. - Our results demonstrate for the first time that omeprazole 20 mg mane is superior to ranitidine 150 mg b.i.d. in the short-term treatment of duodenal, but not gastric ulcer.

Simple approach to assess potentiated drug combinations in clinical trials: studies with pirenzepine plus H2-receptor antagonists.

A simple approach to prove or disprove potentiation is described, which is based on the comparison of observed effects of reversibly acting drugs A plus B with effects of independently acting drugs in combination, since the latter already represent a special type of overadditive drug combination, i.e., potentiation. As an example, secretory studies in man using combinations of the antimuscarinic drug pirenzepine and the H2-receptor antagonists cimetidine or ranitidine were reevaluated. In these studies combined antisecretory effects were found which not only correspond to those of independently acting (i.e., functional) synergists, but even significantly exceed them. Pirenzepine caused 60 +/- 4.0%, and cimetidine 61 +/- 4.6% inhibition of peptone-stimulated acid secretion. In combination the effect amounted to 90 +/- 0.8% (n = 8) which is more pronounced than the calculated effect of functional synergists (83 +/- 3.1%). Similar results were obtained with pirenzepine plus ranitidine. Hence, a true interaction between antimuscarinic and H2-receptor antagonizing drugs to suppress gastric acid secretion can be assumed.

[Healing rates following omeprazole and ranitidine treatment of gastric ulcer. Results of a German multicenter study]. / Abheilungsraten nach Omeprazol- und Ranitidin-Behandlung des Ulcus ventriculi. Ergebnisse einer deutschen Multizenterstudie.

The effectiveness of omeprazole (20 mg orally each morning) or ranitidine (150 mg orally twice daily) in the treatment of gastric ulcer was compared in 184 out-patient in a randomized, endoscopically controlled multi-centre double-blind ("double dummy") trial. Healing rates with omeprazole after two, four and eight weeks were 43, 81 and 95%, respectively, those with ranitidine were 45, 80 and 90%, a statistically not significant difference. Independently of medication, small ulcers (less than 8 mm diameter) healed more quickly than larger ones. Ulcers in the body of the stomach responded poorest to both drugs. Smoking had no statistically significant effect on healing rate. Omeprazole and ranitidine had similarly favourable effects on symptoms. Neither side effects nor changes in biochemical parameters could be ascribed to omeprazole. Both drugs had equivalent effects on the healing of gastric ulcers in the stated dosages.

[Short-term therapy of duodenal ulcer with omeprazole and ranitidine. Results of a German multicenter study]. / Kurzzeit-Therapie des Ulcus duodeni mit Omeprazol und Ranitidin. Ergebnisse einer deutschen Multizenterstudie.

In a randomized, endoscopically controlled double-blind trial the effectiveness of a single oral, morning dose of 40 mg omeprazole was compared with a twice daily oral dose of 150 mg ranitidine given to 334 ambulatory patients with duodenal ulcers. Under omeprazole 105 of 146 duodenal ulcers were demonstrated to have healed within 14 days (72%), compared with 95 of 160 (59%) on ranitidine. The difference is statistically significant (P = 0.0121). After 14 days smaller ulcers healed more quickly than large ones, regardless of the drug used: 80 of 110 with diameter 3-5 mm (73%); 48 of 90 with diameter more than 8 mm (53%). Smoking delayed healing [healing rate among non-smokers, 87 of 117 (74%); among smokers, 113 of 189 (60%)]. Healing rates among smokers receiving omeprazole and non-smokers receiving ranitidine were nearly identical. After 4 weeks, at 96 and 92% respectively, there was no difference in regard to healing rate. Both drugs had a similar influence on the symptoms. Thus, for the first time it has been demonstrated that omeprazole is superior to ranitidine after 14-day treatment of duodenal ulcer.