Minophagen C

Glycyrrhizic acid, glycine, L-cysteine hydrochloride.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Physicochemical Properties of Active Ingredients: 1. Non-proprietary name: Monoammonium Glycyrrhizinate.
Chemical name: Monoammonium of 20β-carboxy-11-oxo-30-norolean-12-en-3β-yl-2-O-β-_D-glucopyranuronosyl-β-_D-glucopyranosiduronic acid.
Molecular formula: C₄₂H₆₅NO₁₆.
Molecular weight: 839.96.
Melting point: 208 °C to 214 °C (decomposition).
Description: Monoammonium Glycyrrhizinate occurs as a white crystal or crystalline powder, and has a strongly sweet taste. It is freely soluble in ammonia solution, sparingly soluble in dilute ethanol, slightly soluble in water and acetic acid (100), and very slightly soluble in ethanol (99.5). It is hygroscopic.
2. Non-proprietary name: Glycine [JAN].
Chemical name: Aminoacetic acid.
Molecular formula: C₂H₅NO₂.
Molecular weight: 75.07.
3. Non-proprietary name: L-Cysteine Hydrochloride Hydrate [JAN].
Chemical name: (2R)-2-Amino-3-sulfanylpropanoic acid monohydrochloride monohydrate.
Molecular formula: C₃H₇NO₂S•HCl•H₂O.
Molecular weight: 175.63.

Pharmacology: Pharmacodynamics: Anti-inflammatory effect: Inhibition of enzymes in arachidonic acid metabolic system: Glycyrrhizic acid directly binds to phospholipase A₂, the initial enzyme in the arachidonic acid metabolic system, and lipoxygenase, an enzyme to produce the inflammatory chemical mediators. Glycyrrhizic acid selectively inhibits the activation by phosphorylation of these enzymes.
Anti-allergic effect: This product has antiallergic activities as shown by the inhibition of Arthus reaction and Shwartzman reaction both in rabbits. Against the activities of cortisone, this product increases the stress reaction inhibitory effect, antagonizes the anti-granulation effect and thymic atrophy inducing effect, but does not affect the anti-exudation effect.
Immuno-response modulating effect: In an in vitro experimental system, glycyrrhizic acid has proved to exhibit: i) T-cell activation controlling effect, ii) Interferon-γ inducing effect, iii) NK-cell activating effect and iv) Extrathymic T lymphatic cell differentiation potentiating effect, etc.
Experimentally-induced hepatocytes injury inhibiting effect: In an in vitro experimental system using the primary culture of rat hepatocytes, glycyrrhizic acid has proved to inhibit hepatocyte injury induced by carbon tetrachloride.
Hepatocyte proliferative effect: In an in vitro experimental system using the primary culture of rat hepatocytes, glycyrrhizic acid and glycyrrhetinic acid have proved to promote proliferation of primary cultured rat hepatocytes.
Viral growth inhibiting or inactivating effect: In MHV (mouse hepatitis virus) infection experiments in mice, prolongation of the survivable days was observed after administration of this product. In an experiment to inhibit the vaccinia virus infection in rabbits, eruption of papules was inhibited. Also in vitro experimental systems, growth inhibition and inactivation have been shown in herpes virus etc.
Others: Glycine and L-Cysteine hydrochloride have an inhibitory or suppressive activity against manifestation of pseudoaldosteronism which is caused by abnormal electrolyte metabolism after long-term administration of glycyrrhizic acid in large amount.
Clinical Studies: Double-blind Comparative Trial in Chronic Hepatitis: At 36 institutions in Japan, a double-blind comparative trial was conducted in 133 chronic hepatitis patients, where a daily dose of 40 mL of this product was intravenously administered consecutively for one month.
The results were as follows.
The medicated group was superior in efficacy to the placebo group and in the biochemical parameters of liver function tests, AST (GOT), ALT (GPT) and γ-GTP levels improved with statistical significance. (See Table 3.)

Click on icon to see table/diagram/image

Comparative Studies with Different Doses on Chronic Hepatitis and Hepatic Cirrhosis: At 11 institutions in Japan, 178 chronic hepatitis and hepatic cirrhosis patients received intravenous administration of 40 mL/day of this product for 3 weeks. 93 patients without improvement of ALT (GPT) levels down to <1.5 times upper limit of normal at 2-week point were enrolled into a comparative dose study and allocated to a group with continuous dose of 40 mL and another group with increased dose of 100 mL. The results showed that the ALT (GPT) levels of 100 mL-dose group improved significantly compared to the 40 mL-dose group. Thus, the administration of increased dose of 100 mL was recognized to be effective in case where 40 mL was insufficient to lower ALT (GPT) levels. (See Table 4.)

Click on icon to see table/diagram/image

General Clinical Studies: Table 5 summarizes the efficacy data of clinical trials on 59 chronic hepatitis patients who received 60 mL of this product for 4 weeks. (See Table 5.)

Click on icon to see table/diagram/image

In another trial where 100 mL of this product was administered for 8 weeks in chronic hepatitis patients, good correlation was observed between the improvement of hepatic function and that of liver histology.
Pharmacokinetics: Pharmacokinetics in humans: Blood concentration: Following intravenous injection of 40 mL of this product (containing 80 mg of glycyrrhizic acid) to healthy adults, blood glycyrrhizic acid concentration decreased rapidly up to 10 hours after administration, then decreased gradually. Glycyrrhetinic acid, a hydrolysis metabolite of glycyrrhizic acid appeared 6 hours after administration, reached the maximum 24 hours after administration and almost disappeared 48 hours after administration.
Urinary excretion: Following intravenous injection of this product to healthy adults, glycyrrhizic acid in urine decreased with time. The urinary recovery rate within 27 hours was 1.2% of the administered dose. Glycyrrhetinic acid appeared at 6 hours after administration and reached the maximum at 22 to 27 hours after administration.
Pharmacokinetics in animals (Supplementary information): Distribution: Following intravenous injection of ³H-glycyrrhizin to mice, its distribution was observed in all organs collected in 10 minutes post-dose. Liver showed the highest distribution rate 62% of the administered ³H-glycyrrhizin, followed by kidney, lung, heart and adrenals in this order.

Improvement of abnormal hepatic function in chronic liver diseases.

For chronic liver diseases, the daily dosage is from 40 to 60 mL once a day by intravenous injection or intravenous drip infusion. The dosage may be adjusted depending on the patient's age and symptoms. If an increased dosage is required, the daily dosage should be kept within the limit of 100 mL.

This product is contraindicated in the following patients.
Patients with a history of hypersensitivity to any of the ingredients of this product.
Patients with aldosteronism, myopathy and hypokalaemia. [There is a concern about aggravation of hypokalaemia, hypertension or the like.]

Careful Administration: This product should be administered with caution to the following patients.
The elderly. [There is a higher incidence of hypokalaemia or the like.] (See "Use in the Elderly" as follows.)
Important Precautions: Patients should be carefully interviewed to assess the risk of shock and the like.
Emergency treatment should be ready for the occurrence of shock.
After administration, patients should be kept rested and observed carefully.
Since concomitant use with any other preparations containing Glycyrrhizae Radix brings about overlapping effect with glycyrrhizic acid contained in this product and is liable to cause pseudoaldosteronism, appropriate care should be taken.
Other Precautions: Rhabdomyolysis has been reported to occur by oral administration of preparations containing glycyrrhizic acid or Glycyrrhizae Radix.
Use in the Elderly: In the experience in the clinical use, the incidence of the adverse reactions such as hypokalaemia tended to be higher in the elderly patients. Administration should be made carefully while observing patient's conditions.

Safety in the administration to pregnant or lactating women has not been established. Administration to these patients should be considered only if the expected therapeutic effect is judged to outweigh any possible risk. [In an animal (rats) study where a large dose of monoammonium glycyrrhizinate was administered there were findings of kidney malformation and the like.]

Adverse reactions were observed in 27 (0.61%) out of 4,451 cases included in the double-blind studies conducted for the indication (improvement of abnormal hepatic function in chronic liver diseases), the dose comparison study and the post-marketing surveillance conducted for the use in chronic liver diseases. Notable ones were serum potassium decreased in 13 cases (0.29%), blood pressure increased in 5 cases (0.11%) and upper abdominal discomfort in 3 cases (0.07%).
Clinically significant adverse reactions: Shock and Anaphylactic shock (frequency unknown): Since shock and anaphylactic shock (blood pressure decreased, loss of consciousness, dyspnoea, cardio-respiratory arrest, flushing, face oedema, etc.) may occur, patients should be carefully observed. In the event of any abnormality, administration should be discontinued immediately and appropriate measures should be taken.
Anaphylactoid reaction (frequency unknown): Since anaphylactoid reaction (dyspnoea, flushing, face oedema, etc.) may occur, patients should be carefully observed. In the event of any abnormality, administration should be discontinued immediately and appropriate measures should be taken.
Pseudoaldosteronism (frequency unknown): Since after increased dosage or long-term administration, there is a concern about occurrence of pseudoaldosteronism such as severe hypokalaemia, high incidence of hypokalaemia, increased blood pressure, sodium retention, fluid retention, oedema, increased weight and the like, patients should be carefully observed (including determination of serum potassium level). In the event of any abnormality, administration should be discontinued.
Feelings of weakness and muscular weakness might be caused by hypokalaemia.
Other adverse reactions: The symptoms indicated as follows may appear. Along with increase in dose, decrease in serum potassium level and increasing tendency of elevation in blood pressure are observed. (See Table 6.)

Click on icon to see table/diagram/image

This product should be administered with care when coadministered with the following drugs. (See Table 7.)

Click on icon to see table/diagram/image

Precautions concerning Use: Injection rate: Under observation of patient's conditions, intravenous administration should be conducted at a controlled slow rate.
Precautions for Handling: Deoxidation agents are included in the package to maintain the stability of this product. Therefore, the package of ampoules should be opened immediately before use, and the product should be used immediately after opening.
The product should not be used when there is condensation on the inside of the package or when pigmentation, turbidity, or crystallization in the content solution is noted.

Store at temperatures not exceeding 30°C.

Cholagogues, Cholelitholytics & Hepatic Protectors

A05BA - Liver therapy ; Used in liver therapy.

Rx