Hydroxide-containing Antacids Research Articles

Results From Phase I Studies Investigating the Dose Linearity of Finerenone Tablets and the Influence of Food or pH-Modifying Comedications on its Pharmacokinetics in Healthy Male Volunteers

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that reduces the risk of adverse kidney and cardiovascular outcomes in patients with chronic kidney disease associated with type 2 diabetesmellitus. Clinical phase I studies with finerenone were carried out to assess its pharmacokinetics and the influence of common covariables on its absorption after oral administration. Three crossover studies in healthy male volunteers with single-dose administration of finerenone investigated the dose linearity of a film-coated tablet (1.25-10 mg [n = 24] and 10-20 mg [n = 18]), the effect of food on the 20 mg tablet (n = 18), and the effects of the proton-pump inhibitor omeprazole (4 days pre-treatment and co-administration 2 h before finerenone) and an aluminum/magnesium hydroxide-containing antacid (10 mL [Maalox®] 70 mVal, simultaneous intake) on the 10mg tablet (n = 10 and n = 11, respectively). Finerenone was rapidly absorbed (time to reach maximum plasma concentration [tmax] was 0.50-0.75 h). Area under the curve from zero to infinity (AUC∞) and the maximum concentration (Cmax) increased in proportion to dose in the range investigated in clinical phase II and phase III studies (1.25-20mg), with point estimates for the ratio of dose-normalized AUC∞ and Cmax (20 mg/10 mg, approved therapeutic doses) of 0.9943 and 0.9301. After the administration of finerenone 20mg with a high-fat, high-calorie meal, AUC∞ increased (+21%), Cmax decreased (-19%), and tmax was prolonged (2.47vs. 0.75 h) when compared with the fasting state. Omeprazole had no effect on finerenone AUC∞ and Cmax. Maalox had no effect on finerenone AUC∞ and led to a non-clinically-relevant decrease in Cmax (-19%). The pharmacokinetics of the finerenone film-coated tablet were linear. High-fat, high-calorie food had no clinically relevant effect on the pharmacokinetics of finerenone. In addition, pH-modifying comedications were not found to alter the pharmacokinetics of finerenone and were deemed safe for co-administration.

Effects of a Magnesium/Aluminium Hydroxide-Containing Antacid, Cimetidine or Ranitidine on the Pharmacokinetics of Metrifonate and its Metabolite DDVP

Objective: Metrifonate — via its pharmacologically active metabolite 2,2-dichlorovinyl dimethylphosphate (DDVP) — is an inhibitor of acetylcholinesterase effective in the treatment of Alzheimer’s disease. Two studies were performed to investigate the influence of potentially frequent co-medications on the pharmacokinetics of metrifonate and DDVP.

Clinically significant drug interactions with new immunosuppressive agents.

Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).

Cholesterol Lowering with Antacid

In vitro studies suggest that aluminum hydroxide has a strong affinity for bile acids similar to that of cholestyramine. This study evaluated the efficacy of an aluminum hydroxide-containing antacid in reducing serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL- C) in hypercholesterolemic adults.

Is there a place for antacids in the treatment of Helicobacter pylori infection?

Two pilot studies were performed to determine whether aluminium-containing antacids may have a place in the treatment of Helicobacter pylori infection. The urease activity of H. pylori is cytopathic to gastric epithelium, and inhibition of this enzyme may have therapeutic potential. In the first study 24 subjects, 12 of which were infected with H. pylori, were given 1 tablet of chewable aluminium hydroxide-containing antacids 10 min before a 14C-urea breath test. Gastric urease activity was suppressed by 33.3% (p = 0.02) in the H. pylori-positive subjects (none became negative) within 40 min after administration of the tablet. Gastric H. pylori infection can be effectively eradicated by triple regimens containing bismuth salts, tetracycline, and metronidazole. Owing to adverse effects of this treatment and concern for possible neurotoxicity of bismuth, a bismuth substitute is warranted. Hence, in the second study, 20 subjects infected with H. pylori were treated with 1 antacid tablet 4 times daily between meals, plus 500 mg oxytetracycline and 200 mg metronidazole 4 times daily with meals for 2 weeks. Individual H. pylori status was assessed by the 14C-urea breath test. Four weeks after cessation of treatment, H. pylori was eradicated in 45% (9 of 20) of the subjects (95% confidence interval, 23.1-68.5%). Thirty per cent (6 of 20) observed one or more adverse effect regarded as moderate or severe, of which loose stools and headache were the most common.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for Interference With the Intestinal Absorption of Levothyroxine Sodium by Aluminum Hydroxide

A patient with hypothyroidism who was euthyroid on a fixed-dosage, long-term maintenance regimen of levothyroxine sodium developed persistently elevated serum thyrotropin levels while receiving an aluminum hydroxide-containing antacid. The thyrotropin levels returned to normal shortly after cessation of the antacid therapy. These observations indicate that aluminum hydroxide may interfere with the bioavailability of thyroxine. The thyroid function of patients who are receiving replacement or suppressive thyroxine therapy should be monitored following the commencement of concurrent treatment with medications containing aluminum hydroxide.

The hypocholesterolemic effect of an antacid containing aluminum hydroxide

study objective: To evaluate the efficacy, safety, and hypocholesterolemic effect of an aluminum hydroxide-containing antacid in hypercholesterolemic individuals. design: A prospective, randomized, double-masked, placebo-controlled phase of 2 months' duration, followed by an open-design treatment phase of 2 months' duration and a washout phase of 2 months' duration. setting: Family practice clinics of two rural communities (kibbutzim) in Israel. patients: Fifty-six men and women with hypercholesterolemia (type IIa or IIb). Fifty individuals completed the study. intervention: After 2 months of dietary modification (low-fat, low-cholesterol diet), the participants were randomized into two matched groups. Group 1 (28 participants) was treated for 2 months with a chewable antacid tablet containing simethicone, magnesium hydroxide, and 113 mg of aluminum hydroxide per tablet, at a dose of two tablets four times daily. Group 2 (22 participants) was given a similar number of placebo tablets for 2 months. During the following 2 months, both groups received the antacid at the above dose. measurements and main results: Lipoprotein levels were evaluated at baseline and every 2 months thereafter for 6 months. Compared with pretreatment levels, Group 1 experienced a decrease in low-density lipoprotein cholesterol (LDL-C) of 9.8% after 2 months (p <0.001) and 18.5% after 4 months (p <0.001). Compared with Group 2, the decrease in LDL-C in Group 1 was 6.2% at the end of the 2-month double-masked placebo phase. Although the high-density lipoprotein cholesterol (HDL-C) was also reduced in Group 1 at the end of 4 months of therapy (10.2%), the HDL-C/LDL-C ratio increased by 13% during the same interval (p <0.05). The treatment was well tolerated, with minimal side effects. conclusions: An aluminum hydroxide-containing antacid reduces LDL-C in hypercholesterolemic individuals. Although HDL-C was also reduced to a lesser extent, the overall atherogenic index was improved. Further studies should be conducted to evaluate the long-term safety and efficacy of antacids containing aluminum hydroxide in hypercholesterolemic patients.

Effects of Antacids on the Clinical Pharmacokinetics of Drugs

Since a previous review by Hurwitz was published in 1977 a large number of reports on drug interactions with antacids have appeared, few of which are of clinical relevance. Tetracyclines form insoluble complex molecules by metal ion chelation with various antacids; tetracycline absorption may be decreased by more than 90% by this interaction. Of the new class of quinolone antibiotics, the absorption of ciprofloxacin and ofloxacin is reduced by 50 to 90% in the presence of aluminium- and magnesium hydroxide-containing antacids. In contrast to early work showing inhibition of the absorption of beta-adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid. The bioavailability of captopril was significantly reduced in the presence of an antacid, and lower plasma concentrations of this angiotensin-converting enzyme inhibitor were accompanied by a reduction of its effect on the systolic blood pressure of the patients. The absorption of the cardiac glycosides digoxin and digitoxin is not inhibited by antacids to a significant degree, although earlier studies had shown a positive effect when the dissolution of the glycoside preparations was relatively poor. Antacids reduce the bioavailability of the H2-receptor antagonists cimetidine and ranitidine only when high antacid doses are used and when the drugs are administered simultaneously. The bioavailability of famotidine was not significantly altered by a potent antacid preparation, although a trend towards reduced absorption was observed. Iron absorption is significantly decreased in the presence of sodium bicarbonate and calcium carbonate, but is nearly complete when coadministered with aluminium-magnesium hydroxide. Nonsteroidal anti-inflammatory drugs such as naproxen, tenoxicam, ketoprofen, ibuprofen and piroxicam are not affected in their absorption by antacid treatment. Theophylline bioavailability is unchanged when the drug is given together with antacids, although its rate of absorption may be altered, leading to a reduction or an increase in the time of the occurrence of peak plasma drug concentrations.

Gastroprotection by an aluminium- and magnesium hydroxide-containing antacid in rats. Role of endogenous prostanoids.

This study was designed to determine the gastroprotective actions of an antacid (Maalox 70) and its components, Al(OH)3 and Mg(OH)2, against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. Given orally, the antacid prevented dose-dependently the formation of gastric lesions by all three ulcerogens, and these effects were similar to those obtained with a methylated prostaglandin E2 (PGE2) analog. Active Al(OH)3 gel was equipotent with Maalox, whereas Mg(OH)2 was significantly less effective in gastroprotection than Maalox 70. Chemically inactive Al(OH)3 wet gel showed only small and insignificant protective properties. Since the gastroprotective activities of Maalox 70 against ethanol lesions cannot be reversed by pretreatment with indomethacin, and since neither Maalox 70 nor its active components affected the mucosal generation of PGE2 and leukotriene C4, we postulate that mucosal prostanoids are not the primary mediators in the mechanism of their protective action on the gastric mucosa.

Possible role of sulfhydryls in mucosal protection induced by aluminum hydroxide.

The involvement of sulfhydryl-containing compounds was investigated in the cytoprotective effect of certain antacids against ethanol-induced gastric mucosal damage in the rat. Not only the protective effect of a sulfhydryl containing compound, N-acetylcysteine, was abolished after pretreatment with N-ethylmaleimide, but also the adaptive cytoprotection induced by 20% ethanol. Pretreatment of the animals with the cyclooxygenase inhibitor indomethacin or with the thiol reagent N-ethylmaleimide significantly diminished the cytoprotection evoked by aluminum hydroxide. However, the protective effect of aluminium hydroxide could only be totally abolished by pretreatment with the combination of indomethacin and N-ethylmaleimide. The present results suggest the additional role of sulfhydryl-containing compounds localized in the gastric mucosa in the cytoprotection induced by a mild irritant or by aluminium hydroxide and aluminium hydroxide-containing antacids as well.

Antacids and gastric mucosal protection.

Aluminum hydroxide-containing antacids have a protective effect on the stomach in that they prevent grossly visible mucosal necrosis and hemorrhages produced by noxious agents, such as aspirin or absolute ethanol. Histologically, this protective effect is mainly confined to the tissue located deep in the gastric mucosa, essentially comprising gastric glands, while the damage to the surface epithelium is not significantly lessened. Accordingly, integrity parameters of the superficial epithelial layer (potential difference, mucous secretion, cell desquamation) do not indicate a protective action of antacids against damage by necrotizing agents. By contrast, significantly diminished microbleeding rates do suggest that protection by antacids works at a deeper level within the mucosa. The protective action of antacids may be mediated, at least partly, by endogenous prostaglandins, which were found to be elevated in this context.

Osteomalacia and Weakness From Excessive Antacid Ingestion

A 60-year-old woman was evaluated for bone pain and incapacitating weakness. Initial laboratory studies showed a serum calcium level of 10.1 mg/dL, severe hypophosphatemia (1.1 mg/dL), and an elevated alkaline phosphatase level. X-ray films showed changes consistent with osteomalacia. Further studies revealed hypercalciuria (448 mg/24 hr) but absent urinary phosphorus. These data indicated phosphate malabsorption. Excessive use of an aluminum hydroxide-containing antacid was the cause of this patient's failure to absorb dietary phosphate. The features of this syndrome are reviewed to increase physicians' awareness of this illness, which occurs particularly in the elderly and is easily treated.

Rapid fall of serum phosphorus secondary to antacid therapy

Two patients with marked hypophosphatemia secondary to antacid therapy are described, 1 asymptomatic and the other symptomatic. In contrast to previous reports, these 2 patients were on aluminum hydroxide-containing antacids for relatively short periods of time before the hypophosphatemia occurred. Hypophosphatemia developed after only moderate doses of antacid in the symptomatic patient who was on a low phosphorus diet. An adequate intake of dietary phosphorus or phosphorus-containing antacids may be necessary to avoid a low serum phosphorus in patients taking aluminum hydroxide antacids even when the duration of therapy is as short as 2 weeks and the dose of antacids is not large.

Alkalosis resulting from combined administration of a “nonsystemic” antacid and a cation-exchange resin

Summary The effect upon acid base balance of combined oral administration of cation exchange resins and nonabsorbable antacids was studied. The combination of a sodium polystyrene sulfonate resin with a magnesium hydroxide-containing antacid consistently produced systemic alkalinization. Substitution of calcium phase resin for sodium phase resin resulted in loss of the alkalinizing effect of the regimen. The alkalinization resulted from systemic base accumulation; this effect is probably dependent upon cation exchange properties of the resin altering the usual chemical reactions of magnesium hydroxide in the duodenum and upper jejunum. Systemic alkalinization was also demonstrated when the resin was given with calcium carbonate. It is suggested that reactions similar to those with magnesium hydroxide are involved. These findings support a proposed mechanism explaining the nonsystemic nature of certain antacids. They also help to explain certain relations between calcium carbonate ingestion and systemic alkalosis.