Almagate: A clinical and biochemical review
Mahadeo Garale1, Kavita Joshi2, Vinod K Mishra3, Ulhas Ghotkar4
1 Department of Surgery, Seth G. S. Medical College & KEM Hospital, Mumbai, Maharashtra, India
2 Department of Medicine, Seth G. S. Medical College & KEM Hospital, Mumbai, Maharashtra, India
3 Department of Gastroenterology, The Gastro-Liver Hospital, Kanpur, Uttar Pradesh, India
4 Department of Pharmacology, Government Medical College, Nagpur, Maharashtra, India
|Date of Submission||21-Jan-2020|
|Date of Decision||06-Apr-2020|
|Date of Acceptance||16-Apr-2020|
|Date of Web Publication||23-Oct-2020|
Dr. Kavita Joshi
Department of Medicine, Seth G. S. Medical College & KEM Hospital, Parel, Mumbai, Maharashtra.
Source of Support: None, Conflict of Interest: None
Almagate is a crystalline hydrated aluminum-magnesium hydroxycarbonate containing antacid with a unique rigid lattice structure. The observations from preclinical and clinical studies have shown that almagate has a higher acid-neutralizing capacity (ANC) with a buffering capacity in pH 3–5 making it effective for longer duration compared to aluminum hydroxide, magnesium hydroxide, and magaldrate. Almagate achieves pH 4 within 2 min as reported by in vitro studies. It was reported to have longer Rossett–Rice time and buffering capacity with bile acid adsorption capacity at pH 3. It also has inhibition activity against pepsin. It does not cause overalkalization and the risk of rebound acidity is low. Almagate was found to have the lowest intrinsic sodium content of 25 ppm compared to aluminum hydroxide (1200 ppm), magnesium hydroxide (1100 ppm), and magaldrate (360 ppm). Unlike aluminum hydroxide, magnesium hydroxide, and magaldrate, almagate maintains capacity to dilute acid even at increasing gastric pH. This review presents the clinical, nonclinical, and biochemical properties of almagate.
Almagate is a crystalline hydrated aluminum-magnesium hydroxycarbonate. The empirical formula of almagate is Al2Mg6 (OH)14(CO3)2 X 4 H2O. The crystal structure has brucite layers where magnesium is replaced by aluminum (3:1) interposed with negatively charged layers, making it unique compared to other related antacids. Its molecular weight is 314.984 g/mol and molecular formula is CH11AlMg3O12.[Figure 1] shows chemical structure of almagate.
Almagate has a rigid crystal lattice structure, which provides the ability for optimal acid neutralization and long-term stability.
Evaluation of thermal profile of almagate reveals that it is stable at different temperatures. In addition, antacid activity assessment showed that almagate has a rapid neutralization velocity and a high acid-consuming capacity.
As almagate does not get absorbed, it is not possible to determine all the other pharmacokinetic parameters. Almagate is a nonsystemic antacid as serum levels of magnesium or aluminum do not increase above the basal level even after repeated administration of high doses of almagate up to 4 g/kg. A nonsignificant increase in aluminum and magnesium ion has been reported after administration of a dose of 0.27 g/kg, but not 0.135 g/kg, in dogs.
| Pharmacological Properties|| |
Pharmacological in vitro, nonclinical, and clinical studies carried out with almagate have confirmed its utility as an effective antacid.
Almagate was observed to have the capacity to act rapidly to neutralize a high proportion of acid and to control the gastric pH in the acidic range of 3–5 for long-term duration in comparison to other crystalline aluminum magnesium hydroxide derivatives such as hydrotalcite and magaldrate. It also has an inhibition activity against pepsin with the ability to adsorb bile acids and low sodium content. It has a better neutralization velocity and acid-consuming capacity than the amorphous gels and co-gels of aluminum and magnesium hydroxides or hydroxycarbonate. Furthermore, almagate has been shown to maintain its antacid activity in spite of increase in the pH.
Total acid-consuming capacity
ANC is the amount of acid that can be neutralized. Higher the ANC value more would be the capacity of an antacid to dilute the acid. ANC is estimated by back titration method through in vitro experiments.
As per the standard United States Pharmacopeia (USP) test, almagate has been shown to have an ANC value of 28.3 mEq HCl/g, which is higher than that of magaldrate (24 mEq HCl/g) [Table 1].
|Table 1: Comparison of acid-neutralizing capacities of different antacids|
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Dynamic test, which is preferred over the static USP method to estimate the ANC value, mimics the changing pH of the stomach and the ANC of antacids in this changing pH. All antacids maintain a significant ANC value at pH 2, but as pH progresses to pH 4, aluminum hydroxide and magaldrate lose the ANC significantly; however, almagate retains the ANC of 17.3 mEq HCl/g [Table 2].
|Table 2: Acid-neutralizing capacities of different antacids at different pH|
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The reaction times t90 and t50 indicate the time to dilute 90% and 50% of the acid at pH 2, pH 3, and pH 4. To be effective for longer duration, the reaction time should not increase as pH increases. For magaldrate, magnesium hydroxide, and aluminum-magnesium trisilicate, t90 increases significantly at pH 2, pH 3, and pH 4. However, for almagate, t90 remains stable at pH 2 and pH 3, whereas it increases significantly at pH 4 [Table 3].
pH profile test
Magnesium hydroxide and magnesium hydroxycarbonate causes over alkalization and raises the pH above 5. In addition, Rossett–Rice time, a length of time during which the antacid products maintain the pH of a simulated gastric solution between 3 and 5, is short. Overalkalization and shorter Rossett–Rice time increases the risk of rebound acidity.
Almagate and magaldrate are reported to have a longer Rossett–Rice time and buffering capacity. Almagate has higher ANC values compared to magaldrate, aluminum hydroxide, and magnesium hydroxide [Table 4].
Time/pH profile of almagate (Holbert’s test)
Almagate increases the pH to 4 within 2 min and maintains the pH in the range of 3–5 for a longer duration [Figure 2].
Action on pepsin
Almagate reduces the activity of pepsin to 5% within 10 min, and after 80 min, 90% pepsin is reactivated.
Almagate has been shown to have lowest sodium content (<25 ppm) as compared to aluminum hydroxide (1200 ppm), magnesium hydroxide (1100 ppm), and magaldrate (360 ppm) [Table 5].
In rats with pyloric ligatures, superiority of almagate (125–500 mg/kg) over aluminum hydroxide to raise the pH and to decrease the total acidity of the gastric juice produced, without affecting the volume secreted was established. In a study by Esplugues et al., almagate was shown to prevent ethanol-induced gastric mucosal damage in the rat model of gastric injury.
In a study by Nagy et al., almagate was shown to have a potent gastroprotective effect on rat gastric mucosa by mucosal generation of prostaglandins (PGs) and free radical scavenging. Another study in rats highlighted that the antiulcer activity of almagate may be responsible for its ability to seize and inactivate bile acids at the pH of the stomach contents, and this effect can be beneficial for its acid-neutralizing property in the treatment of gastritis, peptic ulcer, and associated conditions. A study conducted to compare the ANC of almagate and aluminum hydroxide in histamine-induced acid secretion rat model showed that in comparison to aluminum hydroxide, almagate has eight times higher ANC. Furthermore, this study revealed that the almagate more rapidly neutralized to pH 4 at the beginning of the experiment. Therefore, almagate is a potent drug with rapid activity to reduce acidity of the gastric contents during conditions of acid hypersecretion. Beckett et al. showed that almagate is significantly more potent than aluminum hydroxide in raising the pH in rats with pyloric ligatures and unlike aluminum hydroxide, almagate inhibited pepsin activity even at pH 2.
| Clinical Studies|| |
In a study that included healthy human volunteers in whom hyperactivity was induced using pentagastrin, the potency of almagate has been compared with that of aluminum hydroxide in neutralizing the hyperacidity. The titratable acid content of gastric aspirates reduction was significantly higher in almagate (1 g) (87.5%) than an identical dose of aluminum hydroxide (87.5% vs. 45.1%, P < 0.01). Similarly, almagate was able to reduce the pepsin proteolytic activity in the samples of gastric juice by 58.9%, whereas aluminum hydroxide reduced only by 27.5%. Furthermore, the neutralizing effect of almagate was more prolonged (90 min) than that of the standard antacid (30 min) and these studies in humans have thus confirmed the findings of in vitro and in vivo preclinical experiments.
A single-blind, prospective, randomized, parallel multicenter clinical trial evaluated the clinical efficacy and possible side effects of almagate in 332 patients with active duodenal ulcers. The findings revealed that the cumulative healing rate of ulcers and the decrease of complaints can be achieved equally by relatively low doses (3 g/day vs. 6 g/day) of almagate monotherapy and cimetidine alone. Almagate tablet and suspension showed comparable clinical potency and side effects. Human tolerability and pharmacodynamic study of almagate tablet in patients with duodenal ulcer showed that depending on the dose, it rapidly and permanently reduces the acidity of the gastric content and increases the serum gastrin concentration only moderately and for a short time. Benefits of using almagate in combination with cimetidine include promoting the healing of duodenal ulcer and the cessation of complaints. In addition, it helps to prevent elevation of the aluminum and magnesium concentrations of the plasma, even if given for long duration.
Observations of a multicenter clinical trial involving 169 patients with and without endoscopically demonstrable duodenal ulcer receiving almagate for the treatment of gastric pyrosis suggested overall good tolerance with few transient side effects (diarrhea, nausea, and constipation) and preference by 84.2% of the patients for almagate over their previous antacid treatment.
In healthy volunteers, almagate has been shown to have greater reduction (87.5%) in the titratable acid content compared with aluminum hydroxide (45.1%) and more prolonged neutralizing effect (90 min) as compared to the standard antacid (30 min). More pronounced decrease in the pepsin proteolytic activity is reported by almagate compared with aluminum hydroxide. These observations corroborate the similar observations from in vitro and in vivo preclinical experiments.
Almagate showed more acid neutralizing activity in the presence of polypeptides such as pepsin, as compared to other crystalline antacids (magaldrate) and aluminum-magnesium hydroxide co-gel.
In vivo study showed no effect of almagate in oral doses up to 3 g/kg on the central, autonomic, and somatic nervous systems. Similarly, a dose of 500 mg/kg did not influence the cardiovascular system or blood pressure responses to agonist drugs in anaesthetized cats . Almagate has side effects when used in patients with severe renal function impairment due to increased danger of occurrence of hypermagnesemia. In patients with low-phosphate diets, excessive doses, or even normal doses may lead to phosphate depletion accompanied by increased bone resorption and hypercalciuria with a risk of osteomalacia. No clinical trial data are available for dosage adjustment in patients with impaired hepatic function. Almagate can be used in pregnancy, if needed, under medical supervision. In clinical studies, almagate treatment resulted in common side effects such as diarrhea, nausea, and constipation. Almagate may interfere with drugs by increasing the gastric pH, altering disintegration, dissolution, solubility, ionization, and gastric emptying time.
| Dosage and Administration|| |
Tablets and suspension are available in European countries. The recommended dose for adults is one tablespoon of 7.5mL (1 g) three times a day, preferably from half to 1 h after meals, administered directly or diluted in half a glass of water. For children of 6–12 years age, half of the dose prescribed for adults should be administered.
It was approved in India in 2015. Fixed dose combination with simethicone and oxetacaine is approved in India. Internationally almagate is approved in South Korea, Spain, and Hungary.
| Summary|| |
Antacids have a definite place in the management of dyspepsia and other gastrointestinal symptoms. Despite their properties such as rapid action and proven safety for longer duration, an ideal antacid with clinically important properties would be required for efficient management of dyspepsia. Almagate, a lattice structured antacid, has a high ANC and can rapidly dilute acid. The risk of over alkalization and rebound acidity is low with Almagate owing to higher Rossett–Rice time and the ability to act for longer duration at pH 3–5 is reported in in vitro studies. Its action is not influenced by the presence of pepsin and polypeptides. It significantly reduces the activity of pepsin at pH 4–5. Enterohepatic circulation of bile gets affected, as almagate does not adsorb the bile acid in alkaline state. Almagate is considered to be the lowest intrinsic sodium containing antacid. Almagate has been used as an antacid in European and Korean countries for more than 3 decades. It could a useful antacid; however, controlled comparative clinical studies with other antacids may be needed.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]