The in vitro adsorption of some antibiotics on antacids.

The adsorption of oxytetracycline hydrochloride, tetracycline hydrochloride, doxycycline hyclate, triacetyloleandomycin, chloramphenicol, ampicillin, and cloxacillin sodium was studied on various antacids namely, magnesium trisilicate, magnesium oxide, calcium carbonate, bismuth oxycarbonate, aluminium hydroxide, and kaolin. The adsorption of the various antibiotics by milk was also tested as milk is frequently used as an antacid. Charcoal was included in the present study as a model adsorbent having a large hydrophobic surface. The adsorption of the various antibiotics on the different antacids and other adsorbents in most cases obeyed the Freundlich adsorption isotherm. Magnesium trisilicate and magnesium oxide showed the highest adsorptive capacity, relative to other antacids used, for most antibiotics. Calcium carbonate and aluminium hydroxide and intermediate power while kaolin and bismuth oxycarbonate had the least adsorptive power. Charcoal exhibited a marked adsorption for all antibiotics tested. Tetracyclines were found to be more highly adsorbed than other antibiotics studied. Triacetyloleandomycin and chloramphenicol had intermediate values. Ampicillin was only adsorbed to a slight extent while cloxacillin was not adsorbed on the antacids used. The extent of adsorption was correlated to the structure of both the adsorbent and adsorbate, the pH of the adsorbent suspension, and to the polarity of the antibiotic in such pH. The reversibility of the adsorption process was studied in different media and at pH values similar to those of the gastrointestinal tract. The extent of elution was found to be inversely proportional to the adsorptive capacity of the different adsorbents. In general, 0.0143 n NaHCO3 solution was found to possess higher eluting properties than 0.01 n HCl. An exception to this pattern was observed with tetracyclines adsorbed on aluminium hydroxide where the elution with acid resulted in a higher degree of desorption. Careful in vitro and in vivo testing of drug availability is advisable prior to the concomitant administration of antibiotics with antacids or other adsorbents.     

Adsorption of ketoprofen and bumadizone calcium on aluminium-containing antacids and its effect on ketoprofen bioavailability in man

The present study reports the adsorption of ketoprofen and bumadizone calcium, two non-steroidal anti-inflammatory drugs, on three aluminium-containing antacids. The type of aluminium antacid, the initial drug concentration and the pH of the medium were found to influence drug adsorption. At pH 3–4, binding of both drugs to aluminium hydroxide and dihydroxyaluminium sodium carbonate indicated co-operative adsorption, while adsorption profiles of bumadizone calcium on aluminium glycinate suggested a constant partitioning pattern. pH (1–8) adsorption profiles for ketoprofen and bumadizone calcium binding to aluminium hydroxide and dihydroxyaluminium sodium carbonate passed through a maximum in the pH range 3.5–4.5. Antacid dissolution during the adsorption runs was also investigated at different pH values. The effect of coadministration of ketoprofen and aluminium hydroxide on the bioavailability of ketoprofen was investigated in healthy volunteers. Urine was collected for 24 h following drug administration and samples were analyzed by HPLC for ketoprofen and its conjugates. The urinary excretion data indicated a decrease in drug bioavailability upon coadministration with aluminium hydroxide.     

Structural survey of carbonate-containing antacids

A series of carbonate-containing antacids was examined by IR and X-ray analysis to establish the role of carbonate and to compare the structure of the antacids to naturally occurring carbonate minerals. Based on IR analysis, the relative degree of perturbation of carbonate increases in the order calcium carbonate, carbonate-containing aluminum hydroxide gel, and dihydroxyaluminum sodium carbonate. The crystalline carbonate-containing antacids were poorly organized forms of the minerals calcite, CaCO3; dawsonite, NaAl(OH)2CO3; and hydrotalcite, Mg6Al2CO3(OH)16-4H2O. Amorphous carbonate-containing aluminum hydroxide gel can be classified mineralogically as amorphous aluminum hydroxycarbonate. IR and X-ray evidence indicates that magaldrate has a hydrotalcite-like structure with sulfate as the major interlayer anion and carbonate also present in the interlayer space.     

Biopharmaceutical properties of liquid and tablet antacids: in vivo studies using the intragastric pH-measurement technique.

Three types of liquid and tablet antacids have been studied in vitro and in vivo: aluminium hydroxide, aluminium hydroxide-magnesium carbonate and hydrotalcite. The effects on gastric pH of antacid suspensions and antacid chewing tablets having identical active ingredients have been studied in 36 volunteers, the sequence of both forms of administration being randomized. Gastric acid secretion was continuously stimulated during the experiment by a pentagastrin infusion. Antacid chewing tablets gave inferior results when compared with the same antacid in liquid. Antacid suspensions are therefore preferred in the treatment of acid-peptic disease.     

Biopharmaceutical properties of liquid and tablet antacids: in vivo studies using the intragastric pH-measurement technique

Three types of liquid and tablet antacids have been studied in vitro and in vivo: aluminium hydroxide, aluminium hydroxide-magnesium carbonate and hydrotalcite. The effects on gastric pH of antacid suspensions and antacid chewing tablets having identical active ingredients have been studied in 36 volunteers, the sequence of both forms of administration being randomized. Gastric acid secretion was continuously stimulated during the experiment by a pentagastrin infusion. Antacid chewing tablets gave inferior results when compared with the same antacid in liquid. Antacid suspensions are therefore preferred in the treatment of acid-peptic disease.     

Characterization of Antacid Compounds Containing Both Aluminum and Magnesium. I. Crystalline Powders

The composition and antacid properties of 10 samples of crystalline antacids containing both aluminum and magnesium were determined. The composition was found to vary significantly, even within the same type of antacid. For example, three of four hydrotalcite samples exhibit evidence of the presence of a minor phase of amorphous aluminum hydroxide. Almagate and almagcit, which are claimed to be unique compounds, were found to be composed of hydrotalcite, magnesium hydroxycarbonate, and/or magnesium carbonate and amorphous aluminum hydroxide. All three magaldrate samples examined contained a minor phase of amorphous aluminum hydroxide. All 10 samples passed the preliminary antacid test and had high acid neutralizing capacities. However, the rate of acid neutralization varied between samples. In some cases the rate of acid neutralization at a dose of 400 mg was too slow to raise the pH to 3.0 as required by the Rossett–Rice test.     

Characterization of Antacid Compounds Containing Both Aluminum and Magnesium. II. Codried Powders

The composition and antacid properties of six samples of codried antacids containing both aluminum and magnesium were determined. Aluminum hydroxide–magnesium carbonate codried gel and aluminum hydroxide–magnesium hydroxide codried gel were non-homogeneous, as the samples contained combinations of hydrotalcite, amorphous aluminum hydroxide, magnesium hydroxide, magnesium hydroxycarbonate, and magnesium carbonate. All samples passed the preliminary antacid test and had high acid neutralizing capacities. However, the rate of acid neutralization varied between samples. In some cases the rate of acid neutralization at a dose of 400 mg was too slow to raise the pH to 3.0 as required by the Rossett–Rice test.     

Effect of aluminium and calcium ions on survival and physiology of rainbow trout Salmo gairdneri (Richardson) eggs and larvae exposed to acid stress

Survival and different physiological parameters of developing rainbow trout were investigated during exposure to conditions of low pH, different calcium and aluminium ion levels. In fertilized non-hatched eggs from rainbow trout exposed to different low pH levels mortality occurred at regular intervals during development. Hatching rate was delayed at the lowest ambient pH levels and hatching success was reduced accordingly. The lethal concentration of aluminium ions (LC₅₀) was 3.8 mg Al/l in soft water and 71 mg Al/l in hard water, when determined on day 25 after hatching at pH 7. In general, exposure to aluminium reduced survival. However, the greatest reduction in survival was observed in relation to the calcium ion concentration of the ambient medium. Exposure to Al reduced dry weight by 9% and respiration rate by 13% in soft water at pH 5. Aluminium ions had only minor effects on the body concentration of Ca and on the cardiac rate. Respiration rate was reduced by 41% by a lowering of pH only, and low pH also had the greatest reducing effect on cardiac rate (32% at pH 5 in soft water). Previous exposure to low pH, low calcium and high aluminium ion concentrations had no significant effect on larval growth after transfer to hard water at pH 7.     

Rationale for ibuprofen co-administration with antacids: Potential interaction mechanisms affecting drug absorption

Ibuprofen is a widely used NSAID which is often co-administered with antacids because of its gastro-irritant effects. Literature data suggest that antacid interactions may increase or decrease the drug's absorption rate and onset of action and that the interaction may be formulation specific. In the present study, literature data on ibuprofen absorption were evaluated in order to gain insight into the nature of the in vivo effect. Solubility determinations in reactive media containing magnesium or aluminium and dissolution studies in the presence of antacid suspension were performed in an attempt to simulate in vitro the effects observed in vivo. The results obtained indicate that magnesium hydroxide enhances ibuprofen solubility, dissolution and bioavailability, while aluminium hydroxide has a retarding effect. Solubility studies indicated formation of a soluble solid ibuprofen phase in the presence of Mg2+, in contrast, an insoluble ibuprofen salt was formed with Al3+. The introduction of magnesium based antacid suspension into the dissolution media resulted in a formulation specific increase in drug dissolution rate with the most pronounced effect observed for the slowest release tablet formulation. The results obtained indicate the potential for in vitro studies to predict physicochemical interactions that are likely to influence drug absorption rate in vivo.     

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)     

Controlled Release of Ferric-Magnesium Ions From Chitosan/Polyethylene Vinyl Acetate Comatrix for Preventing Pericardial Calcification

Ferric and magnesium ions were embedded in chitosan/polyethylene vinyl acetate comatrix to develop a prolonged release form. The in vitro release profiles of these ions from the comatrix system were monitored in Tris-HCl buffer, pH 7.4, using an ultraviolet (UV) spectrophotometer. The amount of Fe3+ and Mg2+ ions released was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release was substantially modified with glutaraldehyde cross-linking of chitosan beads and subsequent styrene butadiene (SBR) coatings on the comatrix. Prostaglandin E was immobilized on this matrix via free1 radical mechanisms, using N plasma to improve their biocompat2 ibility. From scanning electron microscopy studies it appears that the Fe3+/Mg2+ ions diffuse out slowly to the dissolution medium through the micropores of the comatrix. The released Fe3+/Mg2+ ions from the comatrix system had substantially inhibited the pericardial tissue associated calcification, in an in vitro model system. The result proposes the possibility of delivering drug combinations having synergestic effects for therapeutic applications.     

Controlled Release of Ferric-Magnesium Ions From Chitosan/Polyethylene Vinyl Acetate Comatrix for Preventing Pericardial Calcification

Ferric and magnesium ions were embedded in chitosan/polyethylene vinyl acetate comatrix to develop a prolonged release form. The in vitro release profiles of these ions from the comatrix system were monitored in Tris-HCl buffer, pH 7.4, using an ultraviolet (UV) spectrophotometer. The amount of Fe3+ and Mg2+ ions released was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release was substantially modified with glutaraldehyde cross-linking of chitosan beads and subsequent styrene butadiene (SBR) coatings on the comatrix. Prostaglandin E was immobilized on this matrix via free1 radical mechanisms, using N plasma to improve their biocompat2 ibility. From scanning electron microscopy studies it appears that the Fe3+/Mg2+ ions diffuse out slowly to the dissolution medium through the micropores of the comatrix. The released Fe3+/Mg2+ ions from the comatrix system had substantially inhibited the pericardial tissue associated calcification, in an in vitro model system. The result proposes the possibility of delivering drug combinations having synergestic effects for therapeutic applications.     

In vitro and in vivo defoaming action of three antacid preparations

The defoaming activity of three tablet antacids (hydrotalcite, hydrotalcite/dimethicone and aluminium hydroxide/dimethicone) powdered to 60 mesh was measured in vitro using a new static/dynamic technique. Their antacid actions and that of aluminium hydroxide gel B.P.C. were also measured using a modified Fuch's test. Combination of dimethicone with hydrotalcite conferred good defoaming activity with little effect on pH profile whilst combination of aluminium hydroxide with dimethicone markedly altered both. Additionally, the defoaming actions of the three commercial antacids were assessed in vivo. Radiographs were taken after administration of antacid, a foaming mixture and a normal barium meal. The radiographs were then ranked blind by 5 radiologists. The rankings assigned the significantly greatest (Mann-Whitney U-test) defoaming effect to the hydrotalcite/dimethicone combination, there being no difference between the other two preparations. The in vitro results were thus confirmed.     

Protective effect of two antacids in acute acetylsalicylic acid-induced injuries to the human gastric mucosa

The present study deals with the protective effect of a pretreatment period with antacids (preparation A = gastropulgit) 50; 1 bag with suspension corresponding to 12.5 g contains: 1 g attapulgite, 1.8 g aluminium hydroxide-magnesium carbonate gel and 0.7 g sorbitol. Reference preparation B = commercial product; 1 bag with suspension corresponding to 10 ml contains: 600 mg magnesium hydroxide and 9 g aluminium hydroxide gel) on the acute acetylsalicylic acid (ASA)-induced lesions of gastric mucosa in man. 8 healthy volunteers received in a double-blind crossover design 1 or 2 bags of the antacids or placebo 15 min prior to 1500 mg p.o. of ASA. Endoscopy was performed 2 h later. In the placebo experiments ASA caused severe lesions in all volunteers (placebo values, study with preparation A: 2.9 +/- 0.1; study with preparation B: 2.8 +/- 0.2). Pretreatment with either one bag reduced the ASA-injuries to 2.2 +/- 0.3) (preparation A) and 2.1 +/- 0.3 (preparation B) (not significant compared with placebo). By contrast, a significant protection of human gastric mucosa against ASA could be achieved with 2 bags of preparation A, but not with 2 bags of preparation B (1.5 +/- 0.3, p less than 0.05; 1.9 +/- 0.3, p less than 0.05). The majority of the volunteers reported less discomfort evoked by ASA under the higher antacid doses.     

Aluminium hydroxide inhibits acetylsalicylic acid-induced gastric erosions in cats with Heidenhain-pouch

The effect of Al(OH)3 was investigated on the gastric bleeding induced by acetylsalicylic acid + HCl. Cats provided with Heidenhain pouches were used. The pouch had vascular connections to the main stomach. Instillation of acidified acetylsalicylic acid into the pouch caused a marked increase in its blood content indicating the development of hemorrhagic mucosal damages. The blood loss was totally abolished by administration of Al(OH)3 into the main stomach. We, therefore, conclude that Al(OH)3 induced an enhanced release of PGE2 into the submucosa. PGE2 reached the pouch via connecting vessels originated from the main stomach. The results indicate that certain antacids induce the release of prostaglandins not only into the gastric lumen but also in the submucosa.     

Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells

Exposure to fluorides has been associated with asthmatic symptoms among workers in the aluminium industry. In a recent experimental study hydrogen fluoride (HF) was found to induce a weak inflammatory response in humans. In the present study the potential of sodium fluoride (NaF) and HF to induce cytokine response was examined and how these responses are modulated by Al3+ in a human epithelial lung cell line (A549). Dose-response experiments showed a maximal release of IL-6 and IL-8 at a concentration of 5 mM NaF 24 h after addition. The responses to HF were of a similar magnitude as for NaF. Time-course experiments showed a NaF-induced IL-6 response at 5 h, whereas an IL-8 response was observed after 10 h. Cycloheximide treatment completely abolished the NaF-induced cytokine responses. A marked increase in the mRNA level for IL-6 was observed already 2 h after exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8 responses in A549 cells.     

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 adsorption of some corticosteroids on antacids

The adsorption of prednisone, prednisolone, fluprednisolone, betamethasone, triamcinolone, beta-methylprednisone acetate and hydrocortisone acetate on various antacids or adsorbents was studied at 37 degrees C. The antacids or adsorbents used were magnesium trisilicate, aluminum hydroxide, bismuth oxycarbonate, magnesium oxide, magnesium carbonate, calcium carbonate, talc, kaolin and charcoal. Magnesium trisilicate and charcoal had the highest adsorption capacity for the corticosteroids tested. Bismuth oxycarbonate and talc had intermediate adsorption properties while kaolin and aluminium hydroxide had lower effects. Other antacids were without any adsorption character. Results of the elution study confirmed the higher affinity of magnesium trisilicate over that of bismuth oxycarbonate and talc for the steroids tested. Further in vivo testings are still needed to assess the effect of antacids on the bioavailability of coadministered corticosteroids.     

Effect of magnesium hydroxide on the absorption of tolfenamic and mefenamic acids

Summary The effect of various antacids on the absorption of tolfenamic and mefenamic acids has been investigated in three separate crossover studies, each consisting of four phases. Single doses of magnesium hydroxide (85 mg, 425 mg and 1700 mg) or of water (150 ml) were given by mouth to 6 healthy volunteers immediately after tolfenamic acid 400 mg (Study 1), and, using an identical study design, after mefenamic acid 500 mg (Study 3). In Study 2 sodium bicarbonate 1 g, aluminium hydroxide 1 g, an antacid preparation containing both aluminium and magnesium hydroxides, or water alone were ingested with tolfenamic acid 400 mg. Plasma concentrations of tolfenamic and mefenamic acids and their cumulative excretion in urine were determined up to 24 h. Magnesium hydroxide greatly accelerated, in a dose-dependent manner the absorption of both tolfenamic and mefenamic acids. The peak times in plasma were shortened by about 1 h by 425 mg and 1700 mg magnesium hydroxide, and the peak plasma concentrations of both fenamates were elevated up to 3-fold. The area under the plasma concentration-time curve between 0 and 1 h of tolfenamic acid was increased up to 7-fold and that of mefenamic acid up to 3-fold. The total bioavailability of tolfenamic and mefenamic acids was only slightly increased. Aluminium hydroxide alone and in combination with magnesium hydroxide significantly retarded the absorption and lowered the peak plasma concentration of tolfenamic acid. Sodium bicarbonate had no significant effect on its absorption. The interaction with magnesium hydroxide leads to higher and earlier peak plasma concentrations of the fenamates. Aluminium hydroxide prevents this effect of magnesium hydroxide. If rapid onset of the analgesic effect of the fenamates is required, concomitant ingestion of the fenamates with an antacid containing magnesium but not aluminium hydroxide is recommended.     

Interactions between ciprofloxacin and antacids--dissolution and adsorption studies

Ciprofloxacin is a fluorinated quinolone antibacterial agent extensively used against both Gram-positive and Gram-negative microorganisms. In certain polytherapy programs, ciprofloxacin can be administered with some antacids that could modify its dissolution rate and reduce its absorption leading to therapeutic failure. The aim of this study was to evaluate the influence of some antacids on the availability of ciprofloxacin. The release of ciprofloxacin from tablets in the presence of antacids, such as sodium bicarbonate, calcium hydroxide, calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, magnesium trisilicate and magaldrate was studied on BP 2002 dissolution test apparatus. These studies were carried out in simulated gastric and intestinal juices for 3 hours at 37 degrees C. The results confirmed that the dissolution rate of tablets was markedly retarded in the presence of all the antacids studied. Magaldrate and calcium carbonate in simulated gastric juice exhibited relatively higher adsorption capacities, as did magnesium trisilicate and calcium hydroxide in simulated intestinal juice.