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)

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.

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.

[In vitro evaluation of antacid activity in gastric acid secretion in static and dynamic systems]. / Evaluation in vitro de l'activité antiacide dans les conditions de la sécrétion acide gastrique en systèmes statique et dynamique.

A valid in vitro evaluation of antacid capacity should consider: 1) the intragastric pH-range; 2) the antacid mechanism; 3) the dependence of antacid activity from intraluminal flux variations; 4) the interaction between proteins and antacids. Pharmacologically, a static method allows 1) to quantify H+ binding sites at different pH-end points of the titration: pH 3.0, 2.0 and 1.0 and 2) to characterize the antacid mechanism, neutralizing activity and/or buffering capacity. In dynamic conditions, using the "artificial stomach-duodenum" model the antacid-induced resistance to acidification was measured, the antacid mechanisms were characterized in regard to intraluminal gastroduodenal flux variations and the incidence of antacid activity on duodenal pH was evaluated. These procedures were applied to antacid evaluation of proteins, as natural antacids, and of drugs containing aluminium salts alone or combined with magnesium salts. Pharmacologically, antacid drugs exhibited a greater amount of H+ binding sites when titration end-point was pH 1.0 than pH 3.0 corresponding to the development of neutralizing activity and/or buffering capacity. In dynamic conditions, the drugs, like proteins, induced a potent resistance to acidification related to gastric emptying fluxes. Antacid effect was supported by neutralizing activity and/or by buffering capacity. It was prolonged by removal of H+ ions since lagtimes for recovering initial pH were longer than antacid total emptying, the dilution of intragastric content by H+ impoverished secretory flux contributing thus to prevent gastric acidification. At duodenal site, proteins and aluminium-containing antacids induced the same duodenal pH as controls, without antacids, while magnesium-containing antacids increased it.

[Gastric functional exploration. Comparison between secretory results in 72 non-ulcer dyspeptic patients and 289 non-operated duodenal ulcer patients. Predictive criteria for the efficacy of fundus vagotomy in duodenal ulcer]. / L'exploration fonctionnelle gastrique. Comparaison des résultats sécrétoires chez 72 dyspeptiques non ulcéreux et 289 ulcéreux duodénaux non opérés. Critères prédictifs de l'efficacité de la vagotomie fundique chez l'ulcéreux duodénal.

Basal and pentagastrin- or insulin- stimulated secretion was studied in 72 non ulcer dyspectic patients (NUD), in 289 non operated duodenal ulcer patients (DU), and in 30 DU, before and after highly selective vagotomy (HSV). Acidity, proteolytic activity, choline indicating the presence of duodenogastric refluxed material and sialic acid bound to mucus glycoprotein, marker of mucus erosion, were measured. Basal and pentagastrin-stimulated acid and pepsin secretions in NUD were significantly reduced with regard to those in DU. Sialic acid content was weak in basal secretion and markedly increased in response to pentagastrin reaching the values observed in DU. DU basal secretions of acid and of pepsin were modulated according to the stimulating secretory mechanism. Mucus glycoprotein erosion was related to pepsin mucolytic activity and/or to the presence in gastric juice of refluxed material. In DU the increase of peptic mucolysis corresponded to a biological signal of the ulcer attack when no duodenogastric reflux was identified. High values pepsin output in basal secretion and in response to insulin and of basal sialic acid content combined with a pepsin/acid basal output ratio higher than 80 were biological arguments anticipating the efficacy of HSV in DU. Multiparametric analysis of gastric secretion allows to evaluate the ratio between aggressive factors and mucosal defense corresponding to an equilibrium in NUD and to greater aggressivity in DU whose intensity is related to the course of disease.

New approach for the in vitro evaluation of antacids.

Evidence is given that the in vitro evaluation of antacids has been incomplete, not regarding physiopathological conditions. As a consequence arbitrary antacid potency classifications were introduced and in clinical practice high dosages of antacid drugs were prescribed. The main reason is that the in vitro evaluation procedures used did not take into account the actual conditions of gastric acid secretion. The proposed methods allow to assess antacid activity under conditions similar to those during gastric secretion. "Pharmacologically", the capacity of binding H+ ions in acid milieu can be quantified and the antacid mechanism can be characterized. "Therapeutical efficacy" might be analysed under acid conditions taking into account gastric intraluminal flux variations by using the "artificial stomach" model. This procedure also allows to evaluate the influence of gastric protein content on antacid activity and to simulate the actual gastric conditions by using human gastric juice as gastric content and as simulated "secretion". The antacid-induced resistance to acidification largely corresponds to the therapeutical antacid activity. Data obtained with aluminum containing antacids are presented.

[pH gradient support and antacid action of gastroesophageal coating agents. In vitro pharmacologic study using a model of "the artificial stomach"]. / Capacité d'induction d'un gradient de pH et activité anti-acide des pansements gastro-oesophagiens. Etude pharmacologique in vitro en utilisant le modèle de "l'estomac artificiel".

The effects of gastroesophageal mucosal coating agents could be related to a) the decrease of aggressive contents of gastric juice and/or b) the presence of a pH gradient between intraluminal (IL) contents and mucosa. Antacid capacities of Gaviscon and Topaal, containing sodium alginate or alginic acid, respectively, were measured using the "artificial stomach" model. This model, reproducing two major gastric dynamic functions, secretion and gastric emptying, allows to evaluate the pH variations in the IL contents and at its surface, by a double pH metric recording. Experiments were performed when drugs to be tested were added either to 100 ml of human gastric juice (100 mmol/l or 88 mmol/l with biliary reflux) or to 100 ml of 0.1 N HCl, without and with 1 percent meat extract. Simulated secretion was represented by a 3 ml/min flux of either 0.1 N HCl or gastric juice and "gastric emptying" fluxes varied from 1.5, 3.0 to 4.5 ml/min. When 0.1 N HCl solution was used, the pH levels at the surface of IL contents were close to pH 3.0 when intragastric pH reached pH 1.0 independently of "gastric" emptying flux variations. In the presence of proteins or biliary reflux material, these pH levels were higher, close to pH 4.5 and persisted for a longer time. Antacid activity was calculated as the resistance to acidification of the IL contents, as the amount of H+ ions consumed after addition of antacid to recover initial pH, i.e. 37 and 22 mmol in human gastric juice, between 37 and 17.5 mmol in 0.1 N HCl for Gaviscon and Topaal, according to emptying fluxes.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of antacid characteristics of drugs containing a combination of aluminium and magnesium salts using the "artificial stomach" model.

Antacid characteristics of three drugs containing aluminium and magnesium salts (combination of clay with aluminium and magnesium hydroxides, aluminium and magnesium hydroxide mixture and hydrotalcite) have been studied in a dynamic situation simulated by the "artificial stomach" model, simultaneously taking into account both gastric fluxes, a constant secretory flux and variable emptying fluxes. Therapeutic doses of the drugs were added 1. to 100 ml of 0.1 N HCl, without or with 1% or 5% meat extract, and 2. 100 ml of pooled human gastric juice (96 mmol/l, pH 1.1). In addition, antacid activity of 0.5 g aluminium and magnesium hydroxides, taken alone or in combination, were evaluated when added to 100 ml of 0.1 N HCl. In aqueous HCl solution or in human gastric juice, the three antacid drugs exhibited 1. a neutralising activity characterised by pH-rise and 2. a buffering capacity close to pH 3.8. In addition, hydrotalcite exhibited also buffering capacity at pH 1.2. The antacid-induced capacity, expressed as H+ mmol, to recover initial pH were very similar, indicating that antacid physiochemical properties are similar in HCl solution or in gastric juice. H+ consumption depended upon emptying fluxes. The same antacid characteristics were observed when antacids were mixed with 1% meat extract while 5% meat extract resulted in a modification of antacid characteristics. Therefore the antacid capacities of respective mixtures were of smaller magnitude (50-60%) than the sum of the activities of antacids plus meat extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

[Influence of pH in the adsorption capacity of bile salts and lysolecithins in vitro by antacids containing clay and/or aluminum]. / Influence du pH dans la capacité d'adsorption des sels biliaires et des lysolécithines in vitro par les antiacides contenant de l'argile et/ou de l'aluminium.

In vitro binding properties of eight clay and/or aluminium-containing antacids for bile salts and lysolecithin were measured in comparison with cholestyramine binding capacity, taking into account the final medium pH. Dihydroxy-bile salt adsorption was greater when the initial pH was 1.8 and the intensity varied according to the drugs. Trihydroxybile salts were less bound and the binding was less related to the medium pH. Lysolecithins were bound by clay-containing antacids with the same intensity as cholestyramine, while the binding capacity of aluminium-containing antacids was weaker and related to the final pH. There were close relationships between binding capacities and the final pH so that bile salts are bound by antacids with a great intensity in acid medium and released by alkalinisation in contrary to the binding capacity of cholestyramine. Lysolecithins should be also bound more intensively in acid medium by aluminium-containing antacids. Binding capacities of the antacids were related to their composition, their antacid effect and to the final pH.

[Evaluation of the antacid properties of Gelox in a dynamic milieu using the artificial stomach apparatus]. / Evaluation des propriétés antiacides de Gelox en milieu dynamique par le dispositif de "l'estomac artificiel".

Gelox antacid activity has been evaluated in a dynamic procedure by using the "artificial stomach" model that mimics both gastric fluxes, gastric secretion and gastric emptying. At time 0, the gastric reservoir has been filled by 100 ml of 0.1 N hydrochloric acid solution without or with protein, or by 100 ml of human gastric juice (pH 1.1). Gastric secretion was simulated by a constant 3 ml/min flux of HCl solution or of human gastric juice. Gastric emptying fluxes varied from 1.5 to 4.5 ml/min. Gelox addition to 100 ml of 0.1 N HCl or of human gastric juice induced 1) a pH-rise from 1.0 to 4.5-5.8, 2) a buffering capacity close to pH 3.6-4.0 and 3) the consumption of an acid amount between 25 and 50 mmol according to emptying fluxes, for recovering initial pH. In a mixture of HCl 0.1 N and protein extract 1 or 5%, Gelox induced 1) a pH-rise related to the protein concentrations, 2) a buffering capacity close to pH 3.2-3.9 when 1% protein extract has been used, and close to pH 5.0-5.9 with 5% protein extract and 3) a greater acid consumption with 1% than with 5% protein extract. For both protein concentrations, the resistance for recovering the initial pH, expressed as the amount of consumed mmol H+, was therefore less than the sum of individual capacities of proteins and Gelox.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of an 'artificial stomach' for assessing the characteristics of an antacid.

A model of an 'artificial stomach' has been constructed in order to take into account some of the parameters lacking in conventional in vitro antacid evaluation, namely the interaction between secretory flux and variation in emptying fluxes, the presence of proteins, and the use of human gastric juice instead of an aqueous solution of hydrochloric acid. The 'artificial stomach' has two elements, the 'stomach' and the pH recording system. The 'stomach' includes a 'gastric' reservoir receiving secretory flux and is emptied by variable fluxes. Aluminium phosphate gel has been studied in 100 ml of 0.1 N HCl, without and with 1 or 5% meat extracts and also in 100 ml of human gastric juice. The antacid effect of 1 or 5% meat extracts has also been assessed. The antacid effect of aluminium phosphate was characterized by the pH rise of the 'gastric' contents, the buffering capacity, and the dilution of gastric contents. These factors were modulated by emptying fluxes. The same characteristics were found when antacid was studied in gastric juice. Proteins exerted a neutralizing effect and modified aluminium phosphate's antacid capacity. A mechanism for buffering capacity by cation aluminium is suggested.

The somatostatin/histaminic pathway balance on gastric secretion could be based on a competitive antagonism.

Measurements of acid and pepsin secretions and of histamine release in response to food alone or in combination with graded doses of antramine (AH), a molecular form of histamine isolated from antral mucosa, with or without somatostatin were performed simultaneously in dogs equipped with a denervated pouch. AH restored somatostatin-inhibited acid and pepsin secretions but with different intensities in regard to the different inhibitory levels induced by somatostatin. AH competitively antagonized somatostatin (1 microgram/kg/h) inhibition of acid secretion, but when stronger levels of inhibition were achieved, AH restored weakly acid secretion. Recovery of pepsin secretion occurred through a competitive mechanism between AH and somatostatin (1 and 2 micrograms/kg/h). There was a close relationship between the secretory outputs and the integrated histamine responses; the slopes of the regression lines might be considered as reflecting the stimulatory activity of blood histamine on secreting cells. For acid secretion, this activity is similar in control and somatostatin (1 microgram/kg/h) tests, while for pepsin secretion it is identical in control and 1 or 2 micrograms/kg/h somatostatin tests. One can speculate that the suppression of the somatostatin inhibitory effects by antramine, within the limits of physiological conditions, results from a competitive mechanism.

[Characterization and evaluation of the pathogenic nature of duodenogastric reflux by measurement of intragastric choline and sialic acid in normal subjects and in patients with duodenal ulcer]. / Caractérisation et évaluation du caractère pathogène du reflux duodénogastrique par la mesure de la choline et de l'acide sialique intragastriques chez le sujet normal et l'ulcéreux duodénal.

The high choline content in pancreatic juice and bile-contaminated gastric juice samples suggested that intragastric choline content could be related to duodenogastric reflux (DGR). In 308 secretory tests in normal subjects (38) and in duodenal ulcer patients (DU) (270), acid, pepsin, sialic acid and choline outputs were measured in basal secretion and after pentagastrin, insulin or secretin modulation. The distribution of choline output values in basal secretion showed that 77% subjects had no or small choline amounts (less than 10 mumol/h) and another population had high output values (greater than or equal to 10 mumol/h). Choline hourly outputs greater than or equal to 10 mumol/h could be related with positive DGR. DGR did not seem to modify acid or pepsin secretion except if acid outputs were low: in these cases the neutralizing activity reduced acid outputs and resulted in a pepsin inactivation. DGR by itself increased sialic acid outputs as evidenced by mucus erosion. In normal subjects, weak mucus erosion might be due to proteolytic activity. In DU patients without DGR, erosion was increased but was due to the same mechanism. In DU patients with DGR, erosion was stronger and no relationship with proteolytic activity could be established because of the introduction of eroded duodenal glycoprotein into the stomach. Pentagastrin, insulin and secretin were able to induce DGR. Reflux could contribute to mucus erosion either by its detersive properties or by the proteolytic material coming from the pancreas.

[Antacid action of the aluminum cation: comparison of the in vitro effect of hydroxide and phosphate in open and closed systems]. / Activité antiacide du cation aluminium: comparaison de l'effet de l'hydroxyde et du phosphate "in vitro" en systèmes fermés et ouverts.

Antacid capacity of two aluminium containing-antacid drugs was evaluated in vitro; the first drug contained aluminium hydroxide (Alternagel), the second, aluminium phosphate (Phosphalugel). The antacid evaluation was performed 1) in a closed system by measuring antacid activity by down titration, 2) by a dynamic evaluation simulating acid secretion and gastric emptying. The results were reported both to the recommended therapeutical dose and to 100 mg aluminium. In static conditions, without gastric emptying, it was shown that aluminium hydroxide and phosphate acted by their buffer capacity in pH range less than or equal to pH 1.5. The therapeutical dose of aluminium phosphate displayed greater antacid activity than aluminium hydroxide, this fact being due to the empiric choice of the doses. With regard to aluminium content, aluminium phosphate activity remained greater than that of aluminium hydroxide although the difference decreased with decreasing pH values. The antacid capacities were related to the emptying outputs. Antacid activity corresponding to 100 mg aluminium was similar in both antacids less than pH 1.5. This effect was dependent on emptying rates. It can be suggested that Al was responsible for antacid activity in both preparations, and that the buffering capacity was supported by the change of aluminium cation in hydrolysis intermediary compounds.

The antigastrinic effect of a phenothiazine (LM 24056) prevents gastric secretory activity of histamine.

Gastric antisecretory phenothiazine LM 24056 inhibited acid and pepsin responses to feeding in dogs. Administered perorally two hours before feeding, LM 24056 reduced significantly the secretory responses to combinations of feeding either with antramine, a natural histamine derivate, or with synthetic histamine. LM 24056 reduced circulating gastrin levels (p less than 0.01 and p less than 0.001) and gastrin responses to feeding (p less than 0.01) without modifying neither circulating histamine concentrations nor histamine responses to feeding. The residual acid and pepsin secretions were closely related to gastrin reduction and endogenous or exogenous histamine, by themselves, seemed to be unable to recover the levels of secretory responses observed in response to feeding alone or in combination with antramine or histamine. These data favour a new scheme of gastric secretion regulation where gastrin would be the last step for stimulating parietal and chief cells. LM 24056 by reducing circulating gastrin prevents stimulatory effect of exogenous or feeding-released endogenous histamine. Histamine would not be thus the final common mediator for gastric secretion.

Gastric acid secretion results from antagonistic effects of antral histamine (Antramine) and somatostatin on gastrin.

Gastric acid secretion, whole blood histamine concentration and serum gastrin were measured in dogs, equipped with Heidenhain pouch, in response to feeding alone and in combination with antral histamine (AH)--Antramine--or with somatostatin. Feeding stimulated acid secretion, histamine and gastrin responses in a dose-related manner. Addition of antramine to feeding resulted in a potentiated acid and gastrin responses while histamine response corresponded to sum of individual responses to antramine and to feeding. Somatostatin reduced markedly acid and histamine responses, while gastrin response was unchanged. Serum gastrin and whole blood histamine appear to be agonistic factors responsible together for acid secretion. Somatostatin suppresses histamine response and would inhibit gastrin activity on acid secreting cells by this mean. Somatostatin and histamine might act antagonistically on gastrin which would be their common substrate, and thus they could intervene in a regulation process of acid secretion. In regard to synthetic histamine, native antral histamine--antramine--appears to be a better candidate for a physiological histamine regulation of acid secretion.