Drug interactions with diosmectite: a study using the artificial stomach-duodenum model.

Drug interactions with diosmectite, a gastric-protective drug, were studied in vitro using an artificial stomach-duodenum model. The behavior of neutral and ionisable drugs with pKa values ranging between 2 and 8 was monitored to determine the physicochemical characteristics of the interactions. The main neutral (digoxin) and acid (valproic acid) drug substances were moderately fixed by clay (<27%), in a pH-independent manner. Basic compounds with a pKa<7 (dapsone, metronidazole, cimetidine) were strongly fixed in acid medium (?62%), and fully released under neutral conditions. Amphoteric (fluoroquinolones) and basic compounds with a pKa>/=7 (ranitidine, pyrimethamine) were adsorbed by more than 81% by diosmectite in gastric and duodenal compartments. In the part of the model representing the distal duodenum, the potential site for drug absorption, only the active substances which remained positively charged (amphoteric and basic compounds) showed a large reduction (>/=80%) in their available free fraction. Ionisation of drug substances administered per os concomitantly with diosmectite plays a crucial role in these interactions.

Interests of the 'artificial stomach' techniques to study antacid formulations: comparison with in vivo evaluation.

In this overview, the methods for assessing antacid activity in vitro are surveyed, and the problems of their comparison with in vivo methods of evaluation are discussed. In vitro assessment is based on two types of method: static and dynamic. The static method of titration, with end-of-titration pH values ranging between 3.0 and 1.0, has been used to quantify the number of sites capable of binding H+ ions at each end-of-titration pH, and to identify certain chemical mechanisms involved in this binding; in other words, this approach provides the pharmacological characteristics of the drugs tested. In contrast, it does not take into account physiological factors modulating antacid activity, such as gastroduodenal fluxes (including gastric emptying), drug adherence to the mucosa, and acid secretion. The dynamic method was initially based on an artificial stomach model, which has gradually been upgraded to a computer-controlled artificial stomach-duodenum model. This model overcomes certain weaknesses of the static method by simulating flux and pH conditions in the gastroduodenal tract, by taking into account interactions with the gastric mucosa and thereby reproducing the in vivo medium encountered by antacids. It is therefore capable of reflecting the characteristics of antacids, namely their effect on gastric pH and resistance to acidification, at the same time helping to identify the underlying chemicophysical mechanisms. In vivo, the antacid effect can be assessed qualitatively by means of pH-meter studies in healthy volunteers, both in baseline conditions and during secretory stimulation, and also quantitatively by methods based on intragastric titration in response to a liquid meal (IGT). pH-meter studies in baseline conditions come up against the variability of the basal pH and antacid homogenization with gastric contents, which results in a wide range of individual values. This variability is found in pH-meter studies during pentagastrin infusion and, to a lesser degree, in response to a meal. Close correlations have, however, been established between results obtained with the artificial stomach model and in healthy volunteers submitted to pH-metric or IGT studies, with several antacids. It seems that the artificial stomach method is sufficiently reproducible to make it the method of choice for investigating the antacid activity of all drugs aimed at treating acid hypersecretion disorders. In contrast, in vivo studies may be warranted for precise therapeutic indications, such as treatment of duodenal ulcer or gastro-esophageal reflux, in which the therapeutic effect is judged on the basis of an improvement in symptoms and endoscopic criteria, without the need to demonstrate the antacid effect itself.

In vitro assessment of antacid efficacy using a computer-controlled 'artificial stomach-duodenum' model reproducing gastroduodenal flux regulation.

We have developed an artificial stomach-duodenum model made up of three compartments representing the stomach, (including a fragment of hog gastric mucosa), the proximal duodenum, and the distal duodenum. Gastroduodenal flow rates are controlled by a microcomputer capable of (1) adjusting gastric emptying and alkaline secretion in the proximal duodenum according to intragastric pH; (2) adjusting pancreatic alkaline secretion according to proximal duodenum pH; and (3) simulating acid response to food ingestion. Antacid drugs were added 90 min after simulated food ingestion in near-physiological or duodenal ulcer conditions. Aluminum phosphate-containing antacids resulted in a persistent antacid effect, due to their adsorption to the gastric mucosa; this prolonged the buffering capacity at pH 2.4 to 120 min. Aluminum+magnesium hydroxides and calcium+magnesium carbonate combinations mainly exerted neutralizing activity, inducing an increase in the gastric emptying rate. In the duodenal ulcer simulation, the pH of the gastric contents was lower and the antacid effect was shorter than in the 'physiological' simulation.

[Antacid activity of citrate-bicarbonate complex of effervescent formulations of ranitidine. In vitro analysis using 'artificial stomach-duodenum' model]. / Activité antiacide du couple citrate-bicarbonate des formes effervescentes de ranitidine. Analyse in vitro à l'aide du modèle de 'l'estomac-duodénum artificiels'.

Antacid activity supported by citrate-bicarbonate complex of four effervescent ranitidine forms has been assessed in vitro using an 'artificial stomach-duodenum' model controlled by microcomputer. This model allows (i) maintenance of constant the rates of the fluxes throughout the experiments or (ii) simulation of gastroduodenal flux regulation, in the normal subject (NS) or in the duodenal ulcer patient (DU) situation. The four forms developed a theoretical maximal antacid capacity between 61 and 81 mmol with a maximum intragastric pH between 3.2 and 4.8. In the gastroduodenal flux regulation simulation, antacid activity duration was rapid and included between 85 and 118 min in NS situation (50 to 56 mmol H+ consumed) and between 75 and 93 min in DU situation (43 to 47 mmol H+ consumed). The reduction of acid load penetrating into the duodenum was contained between 36 and 50 per cent. Effervescent compounds exerted a neutralising activity and a buffering capacity close to pH 6.0 (5 per cent of total antacid capacity), related to antacid potency.

Effect on gastric secretion, gastrin and histamine release during and after long-term treatment by pirenzepine in dogs.

We assessed the effects of pirenzepine (2 mg/kg per os) on gastric secretion and gastrin and histamine release in response to food and histamine dihydrochloride infusion in four dogs during 24 weeks of treatment and for 15 weeks after the end of treatment. The results were compared to those obtained in the same animals in control experiments, before treatment, and in four untreated dogs. Pirenzepine absorption was checked by measuring plasma concentrations. Pirenzepine led to a significant reduction in acid and pepsin secretion in response to histamine. In response to food, the reduction in secretion was concomitant with a reduction in gastrin and histamine release. Baseline concentrations of gastrin were reduced, while those of histamine were unchanged. No side effects were observed. After treatment, a long time lapse (about 15 weeks) was required for acid and pepsin secretion and gastrinemia to return to control levels, while histamine release in response to food normalized rapidly. Pirenzepine fixes selectively to M1 muscarinic receptors of the synaptic ganglion, thus inhibiting the effect of vagal stimulation, especially on pepsin secretion. Our data suggest that it might also fix to M1 receptors located on ECL cells, thereby reducing histamine release. In addition, pirenzepine probably fixes to other muscarinic receptors inhibiting gastrin release and resulting in a G and secretory cell mass reduction, probably by increasing somatostatin release.

[Factors of gastroesophageal acid reflux in severe obesity]. / Facteurs de reflux gastro-oesophagien acide dans l'obésité sévère.

OBJECTIVE: To study in morbid obesity the relationship between the degree of gastro-oesophageal reflux (GER) and the excess of body weight, or the related factors such as the energy intake or the fat distribution (waist-hip ratio). METHODS: In 20 morbid obese subjects (body weight: 125 +/- 32 kg) consulting in a weight-loss programme, anthropometric measurements, 3-hr oesophageal pHmetry, double isotope labelled meal for studying gastric emptying, study of gastric acid and pepsin secretions using PEG 4,000 as marker, and upper endoscopy were performed. RESULTS: Nine out of the 20 patients had more than 10 GER per 3-hr period. Seven patients had at least one GER symptom per day. In 6 patients, pH was under 4 for more than 10% of the time. The total number of GER and the number of GER of more than 5 min duration were correlated to the body mass index (P = 0.016 and P < 0.05 respectively). The number of GER was also correlated to the android type of overweight (P < 0.03). These relationships persisted when sex, age, smoking, and obesity complications (such as diabetes) were taken into account. There was a positive correlation between the number of GER and energy and lipid intake (energy intake: 3,119 +/- 1,082 kcal/day; P < 0.003 for both). The degree of GER was positively related to basal acid output (P = 0.049), and to sham feeding-stimulated acid output (P = 0.05); it was negatively related to gastric emptying half time, but was not correlated with basal or stimulated pepsin output. A relationship was found between body mass index (BMI) and gastric emptying half time for solid (P = 0.002) and liquid phases (P = 0.001). CONCLUSION: GER seems to be common in long lasting morbid obesity. The number of refluxes increased with waist/hip ratio, BMI and energy or fat intake. GER was also increased by decreased gastric emptying rate, which was in part determined by BMI. The real prevalence of GER in morbid obeses must be determined by a large prospective study.

Characteristics and consequences of duodenogastric reflux in children on total parenteral nutrition (TPN) for severe gastrointestinal disorders.

This study was carried out to determine the frequency and composition (biliary and/or pancreactic) of duodenogastric reflux (DGR) in children with severe gastro-intestinal disorders on total parenteral nutrition (TPN), and to assess its consequences in terms of gastric histology (gastric per endoscopic biopsies) and secretion (acid, pepsin and sialic acid output). Sixteen children (mean age: 20 months) with severe gastro-intestinal disorders requiring TPN (mean duration: 9.5 months) were studied. DGR was demonstrated by measuring gastric choline and trypsin outputs. Serum gastrin levels were measured in all patients. Seven children (44%) had a DGR, with a significant increase in choline output (p < 0.02). Trypsin output was elevated in one patient only. Exudative gastritis and increased sialic acid output occurred in the presence and in the absence of DGR. DGR did not alter the basal acid and pepsin secretions. The serum gastrin levels were normal except in one case. These results show that DGR occurs frequently in children suffering from severe gastro-intestinal disorders on TPN, that it is mainly of biliary origin and that exudative gastritis is very frequent but not correlated with DGR. It suggests that DGR causes little injury in children on TPN, perhaps because of their decreased pancreatic secretion.

Interactions of cimetidine and ranitidine with aluminum-containing antacids and a clay-containing gastric-protective drug in an "artificial stomach-duodenum" model.

Interactions of cimetidine and ranitidine with aluminum-containing antacids and clay-containing gastric-protective drugs were analyzed in vitro by using an artificial stomach-duodenum model. The model reproduced near-physiologic conditions, taking into account gastric and duodenal flux variations and interactions between gastric mucosa and drugs added to the gastric content. Clay bound cimetidine in acid medium, but the drug was released when the pH increased, resulting in cimetidine amounts in the duodenal site close to those in controls. In contrast, clay bound ranitidine in acid medium and did not release it in the duodenal site. Aluminum-containing antacids did not significantly modify the amount of cimetidine or ranitidine available for absorption. Several factors play a role in the interactions of cimetidine and ranitidine with aluminum-containing antacids and clay-containing gastric-protective drugs: the structure of the antisecretory drugs, gastroduodenal pH, interactions of the antacid and clay with the gastric mucosa, and release of aluminum that could adsorb the drugs or prevent their adsorption by the mucosa. These phenomena are intricate and difficult to analyze without using a physicochemical approach.

Antacid activity of calcium carbonate and hydrotalcite tablets. Comparison between in vitro evaluation using the "artificial stomach-duodenum" model and in vivo pH-metry in healthy volunteers.

Antacid activity of calcium carbonate (CAM, Rennie) and of hydrotalcite (HYD) containing tablets has been assessed in vitro using computer-controlled "artificial stomach-duodenum" model, including or not a piece of hog gastric mucosa in the gastric reservoir, and simulating the constant flux system or the normal gastroduodenal flux regulation. The data obtained under the latter condition were compared to those obtained in vivo by pH-metry in 12 healthy volunteers, in response to one administration of 2 tablets. The theoretical maximal capacity was similar when 1 tablet of CAM or of HYD was added to the gastric contents, including or not a piece of gastric mucosa, close to 95 H+ mmol. The reduction of acid load penetrating into the duodenum and the duodenal pH were of the same magnitude in response to both antacids. When normal gastroduodenal flux regulation was simulated, a dose-response curve, constructed by 1, 2 or 3 tablets, resulted in the same antacid characteristics in response to both antacids. The maximal gastric and the mean duodenal pH values obtained with CAM were, however, higher than with HYD, corresponding to a greater neutralizing activity developed by CAM than by HYD. The comparison between in vivo administration of two tablets of each antacid and the in vitro model simulating normal gastroduodenal flux regulation in response to the addition of two tablets resulted in similar data. The maximal pH values obtained in in vivo assays were slightly lower than in vitro, depending on the ratio of antacid amount to gastric acid content, well established in in vitro conditions and unknown in in vivo situations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Dose-response effect of lansoprazole in patients with Zollinger-Ellison syndrome]. / Effet dose-réponse du lansoprazole chez des malades atteints d'un syndrome de Zollinger-Ellison.

Lansoprazole, a new substituted benzimidazole, is an effective acid proton pump inhibitor acting by inhibiting selectively H+/K+ ATPase of the gastric parietal cell. This study was performed to assess the effect of successive 30, 60, 90 and 120 mg dosages of lansoprazole in 4 patients suffering from Zollinger-Ellison syndrome. The basal gastric acid output was markedly inhibited in comparison with baseline values (mean maximal reduction: 87%; extremes: 75-99%) and was dose-related. Lansoprazole inhibited pepsin output globally with a dose range effect between 30 and 90 mg/day. The treatment induced a rapid relief of clinical symptoms. No biological abnormality was noted. These data proved that lansoprazole is efficient for treating gastric acid hypersecretion in patients suffering from ZES.

[Cephalic phase of gastric secretion in dogs. Effect of palatability and caloric intake]. / Phase céphalique de la sécrétion gastrique chez le chien. Influence de la palatabilité et de l'ingestion calorique.

The purpose of this study was to analyze the relative part of the cephalic phase in the gastric secretory and circulating gastrin responses to meals of variable composition and palatability in dogs. Meal palatability was quantified by measuring the ingestion rate of a fixed amount of food. By progressively increasing the amount of carbohydrates or lipids added to a normal meat meal, it was possible to obtain eleven meals of progressively decreasing ingestion rate. When were offered as sham-feeding these eleven meals in dogs fitted with a cervical esophagostomy and a gastric fistula, gastric acid response decreased only after meals of very small ingestion rates. Moreover, neither gastrin, nor gastric pepsin responses changed significantly with ingestion rate of the sham-fed meals. By subtracting the response to sham-fed meals from the response to real meals of identical composition, it was possible to calculate the non-cephalic part of gastric responses. The non-cephalic part of gastric acid secretion and of circulating gastrin was significantly correlated to calorie intake; the slope of the best fitting regression line was greater after lipid meals than after carbohydrate meals. The non-cephalic part of pepsin secretion was very small, if any, and its level was not correlated to the amount of ingested calories. This work suggests that palatability has very little influence on gastric secretion control in dogs.

[The observance of Ramadan and its repercussion on gastric secretion]. / L'observance du Ramadan et son retentissement sur la sécrétion gastrique.

The influence of the Ramadan on the gastric secretion has been assessed in 13 volunteers. Their basal and pentagastrin-stimulated secretion has been collected before, during and one month after the Ramadan. Gastric activity, pepsin activity, sialic acid bound to glycoprotein, choline and gastrinaemia have been measured. During Ramadan, acid secretion was increased (+ 159%; P = 0.02) and it recovered the pre-Ramadan level, one month later. Pepsin secretion was also increased during the Ramadan (+ 133%; P = 0.05) and it was significantly reduced after Ramadan. The secretion before the Ramadan was related to vagal hypertony, decreased during Ramadan and was substituted by a gastrinic stimulation after the Ramadan. Mucolysis and gastrinaemia were not modified and no duodenogastric reflux was observed during and after the Ramadan. The Ramadan induces an increase of acid and pepsin secretion. This increase was reversed when Ramadan stopped. These gastric secretion modifications are likely involved in the increase of dyspeptic symptoms observed during the Ramadan.

Gastric secretion of platelet activating factor and precursors in healthy humans: effect of pentagastrin.

The release of platelet activating factor (PAF-ACETHER or PAF) and its precursors in the gastric lumen was assessed in 13 normal subjects in basal condition and after stimulation by gastrin. Acid, pepsin, and sialic acid outputs were determined under the same conditions. Gastric juice was collected using a nasogastric tube after overnight fast in basal condition for 60 minutes, then under pentagastrin infusion (6 micrograms/kg/hr for 60 minutes). Platelet activating factor was detected at low concentration in 4/13 subjects under basal condition (mean (SEM) 1.2 (0.6) pg/hr) while high concentrations of lyso platelet activating factor (6.1 (1.8) microgram/hr) and of alkyl-acyl-glycerophosphocholine (AAGPC) (11.5 (3) micrograms/hr) were found in 13 and 11 subjects, respectively. Platelet activating factor was not detected during pentagastrin infusion, while lyso platelet activating factor and alkyl-acyl-glycerophosphocholine were detected in 13 and in 12 subjects, respectively. Compared with the basal condition these platelet activating factor precursors increased significantly (p < 0.001) going up to fivefold baseline (31.8 (6.8) micrograms/hr and 53 (9.3) micrograms/hr respectively) in response to pentagastrin. There was a positive correlation between platelet activating factor precursors and acid or pepsin output but not between platelet activating factor precursors and sialic acid. As sialic acid may be considered an index of mucus glycoprotein degradation, it seems that gastrin stimulation of gastric epithelial cells results in a concomittant secretion of platelet activating factor precursors, acid, and pepsin irrespective of mucus glycoprotein degradation.

Molecular fractionation of gastric mucus component by high-performance liquid chromatography: application to pig gastric mucus in vitro and to human gastric mucus collected by aspiration during gastric endoscopy.

The glycoprotein molecular composition of antral and fundic adherent mucus has been studied by high-performance liquid chromatography on a silica gel column. Preliminary assays with pig gastric mucus allowed us to demonstrate the reproducibility of the method. The mucolytic activity of pepsin on this mucus demonstrates its ability to detect degradation of its glycoprotein components. This method was applied to control the state of pig antral mucosa that has previously been used in an in vitro antacid evaluation procedure, and also study human fundic and antral mucus collected by aspiration from normal and diseased stomachs during upper gastrointestinal endoscopy. Different elution profiles were obtained with these samples, depending on the presence of non-degraded or degraded mucus or due to the lack of mucus on the mucosa.

Treatment of patients with Zollinger-Ellison syndrome.

In the treatment of Zollinger-Ellison syndrome patients with severe disease and acid hypersecretion, proton pump inhibitors are the drugs of choice. Data have now been accumulated on lansoprazole treatment of 41 patients (21 treated at the National Institutes of Health [NIH], Bethesda, Maryland, USA, and 20 treated at the Bichat-Claude Bernard Hospital, Paris, France). Short-term studies of the inhibitory action of lansoprazole on acid secretion have been carried out in both institutions. Our group first performed a dose-response analysis of the efficacy of lansoprazole in reducing basal acid output (BAO) in four patients with severe Zollinger-Ellison syndrome (mean BAO 52 +/- 9 [SD] mmol H+/h) who had previously been treated with a mean omeprazole dosage of 75 mg/day. The maximum acid inhibitory effect was obtained with lansoprazole 60-90 mg/day. The 40-hour duration of action of lansoprazole appears equivalent to that of omeprazole. In a second study at the Bichat-Claude Bernard Hospital, nine Zollinger-Ellison syndrome patients underwent 24-hour intragastric pH monitoring while receiving lansoprazole (mean dosage 80 mg/day, range 30-165 mg/day) or omeprazole (mean dosage 75 mg/day, range 20-180 mg/day). The acid inhibitory activity of the two drugs was comparable. Those patients are currently receiving long-term maintenance treatment with lansoprazole, and satisfactory clinical and biological secretory control has been achieved. The long-term safety and efficacy of lansoprazole administration were studied in the 21 patients followed at the NIH. In those patients the initial maintenance dose was determined using acid inhibition studies; in all patients lansoprazole controlled gastric acid hypersecretion and peptic symptoms in both the short and long term. The mean initial maintenance dose was 60 mg QID, except for two patients who required 60 mg BID. During long-term treatment (mean duration 31 months, range 1-43 months), six patients required a dosage increase within the first year, while the lansoprazole dose could be reduced in six others. The safety profile of lansoprazole has been excellent. Comparable results have been noted in nine Zollinger-Ellison syndrome patients during an ongoing evaluation in our institution. These studies indicate that lansoprazole is an efficacious, well-tolerated antisecretory agent in patients with Zollinger-Ellison syndrome.

Evidence for the interaction between antacid and gastric mucosa using an "artificial stomach" model including gastric mucosa.

In light of evidence that certain aluminum-based antacids adhere to the gastric mucosa, we modified our previously described "artificial stomach" (AS) model by including a piece of hog stomach and compared the antacid activity of six aluminum-containing antacid products in the model with and without gastric mucosa. The activity of three of these, Maalox, Riopan and Supralox, was not significantly different in the two systems. In contrast, the activity of the other three, Aludrox, Phosphalugel and Simeco, was significantly greater with mucosa. Antacid activity of one product from each set (Supralox, Phosphalugel) was evaluated in two in vivo methods in human volunteers. For both antacids, results in vivo were similar to those obtained with the AS-containing mucosa. Without mucosa, in vivo and in vitro results were dissimilar for Phosphalugel, thus validating the modified AS. The difference between the two sets of antacids can be explained by 1) the fact that the Al:Mg ratio in the set affected by mucosa is greater than that of unaffected antacids, and 2) a weaker antacid load than in unaffected Supralox. We suggest that in an acid milieu, aluminum ions in antacids like Aludrox, Phosphalugel and Simeco are bound to sialic acid residues in mucus glycoproteins, thus retarding the transit of these antacids through both the AS and the real stomach and prolonging their activity in both situations. When the Al:Mg ratio is low or when the amount of antacid salts is large, aluminum ions tend to be buried in complexes, giving them less chance to interact with gastric mucus, so they transit the stomach more quickly.

Significance and regulation of gastric secretion of platelet-activating factor (PAF-acether) in man.

Platelet-activating factor (PAF) has been implicated in the pathogenesis of acute inflammatory and ulcerative diseases of the upper gastrointestinal tract. In the present study, we compared the gastric output of PAF and its precursors with gastric acid output, in patients with various upper gastrointestinal tract diseases and healthy controls. PAF and precursors were also extracted from gastric biopsies from subjects with chronic gastritis and/or gastric colonization by Helicobacter pylori. Under basal conditions, hourly gastric PAF output increased in esophagitis and erosive gastritis, but not in duodenal ulcer or Zollinger-Ellison syndrome. In the gastric juice of duodenal ulcer patients, PAF output rose after secretin, but in patients with Zollinger-Ellison syndrome, PAF was only detected when gastric acid secretion had been reduced by antisecretory drugs and no concurrent changes were observed in serum gastrin levels. After pentagastrin, patients and controls exhibited a significant decrease in PAF output and a negative correlation was found between PAF and acid outputs (r = -0.57, p < 0.01). When PAF was incubated with gastric juice in vitro, it underwent degradation irrespective of the medium pH. We found no relation between the outputs of PAF and precursors and the severity of gastritis or gastric colonization by H. pylori. Overall, these results suggest that PAF might be released in the stomach by gastric epithelial cells and could be responsible for mucosal injury of the upper gastrointestinal tract.

An artificial stomach-duodenum model for the in-vitro evaluation of antacids.

To improve the dynamic in-vitro evaluation of the effects of antacids, we have developed the 'artificial stomach' model by adding a 'duodenal reservoir' to receive the gastric emptying flux and simulated bicarbonate secretion, thus constituting an 'artificial stomach-duodenum' model. With this model we measured antacid-induced resistance to gastric acidification, and simultaneously evaluated the effect of antacid activity on the duodenal milieu. The model also permitted evaluation of the antacid effects of proteins (as natural antacids), and of drugs containing aluminium phosphate, alone or combined with magnesium oxide, or aluminium and magnesium hydroxides. At the gastric site, these drugs, as well as the proteins (that is, meat extract), induced a strong resistance to acidification due to the gastric emptying flux and to antacid composition. At the duodenal site, the decrease of the acid load penetrating into the duodenum varied, depending on the efficacy of gastric antacid activity. Duodenal pH was related to the equilibrium between bicarbonate secretion and the emptying of acid load. Proteins and aluminium phosphate induced the same duodenal pH as in the control tests without antacids, but magnesium-containing antacids increased it, thus decreasing bicarbonate consumption. The antacid mechanisms within the stomach, and the fate of antacids in the duodenal milieu, might explain the variation in duodenal pH in response to antacid administration.