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.

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.

[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.