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Radix Glycyrrhizae

Definition.
Radix Glycyrrhizae consists of the dried roots and rhizomes of Glycyrrhiza glabra L. and its varieties or of Gycyrrhiza uralensis Fisch. (Fabaceae).

Synonyms
Liquiritae officinalis Moench is a synonym of Glyeyrrhiza glabra L.

Selected vernacular names
Clycyrrhiza glabra L. and its varieties

Adimaduram, akarmanis, asloosoos, aslussos, athimaduram, athimaduramu, athimathuram,bekh-e-mahak, bois doux, cha em thet, estamee, gancao, glycyrrhiza, herbe aux tanneurs, hsi-pan-ya-kan-tsao, irk al hiel, irk al hilou, irksos, jakyakgamcho-tang, jashtimadhu, jethimadh, jethimadha, kanpo, kanzo, kan-ts'ao, kum cho, Lakritzenwurzel, licorice, licorice root, liquiritiae radix, liquorice, liquorice root, madhuyashti, madhuyashti rasayama, mulathee, muleti, mulhatti, neekhiyu, persian licorice, racine de reglisse, racine douce, reglisse, reglisse officinalis, rhizoma glycyrrhizae, Russian licorice, Russian liquorice, Russisches Sussholz, si-pei, sinkiang licorice, Spanish licorice, Spanish liquorice, Spanisches Sussholz, Sussholzwurzel, sweet root, sweetwoof, ud al sus, velmi, walmee, welmii, xi-bei, yashti, yashtimadhu, yashtimadhukam, yashtomadhu.

Glycyrrhiza uralensis Fisch.
Chinese licorice, Chinese liquorice, gancao, kan-ts'ao, kanzo, kanzoh, licorice root, liquiritiae radix, north-eastern Chinese licorice, saihokukanzoh, tohoku kanzo, tongpei licorice, tung-pei-kan-tsao, Ural liquorice, uraru-kanzo.

Description
Glycyrrhiza glabra L. and it varieties

A perennial plant, up to more than 1m in height, erect, with highly developed stoloniferous roots.  Leaves compound, 9-17 aternate impairpinnate leafltes, oblong to elliptical-lanceolate, acute or obtuse; racemes loose, shorter than the leaves or a little longer.  Flowers 1cm long.  Flapods oblong to linear, 1-3 cm long by 6mm wide, more or less densely echinate glandular, many-seeded or abbreviated, 2 or 3 seeded.

Glycyrrhiza uralensis Fisch.
A perennial glandular herb, 30-100cm high.  Stem erect, with short whitish hairs and echinate glandular hairs; the lower part of the stem is woody.  Leaves alternate, imparipinnate; leaflets, ovate-celliptical, 2-55cm long by 1-3 cm wide; apex obtuse-rounded; base rounded; both surfaces covered with glandular hairs and short hairs.   Stipules lanceolate.  Inflorescence an axillary cluster.  Flowers purplish, pailionaceous; calyx villous.  Fruit a flat pod, oblong, sometimes falcate, 6-9mm wide, densely covered with brownish echinate glandular hairs.  Seeds 2-8.   The root is cylindrical, fibrous, flexible, 20-22cm long and 15mm in diameter, with or without cork, cork reddish, furrowed, light yellow inside.

Plant material of interest: dried root and rhizome
General appearance
Glycyrrhiza glabra L. and its varieties

The commercial variety, G. glabra var. typica Regel & Herd, known as Spanish liquorice, consists generally of roots and rhizomes in nearly cylindrical pieces, up to 1 m long and 5-20 mm in diameter; externally, the bark is brownish grey to dark brown, longitudinally wrinkled, occasionally bearing small dark buds in rhizomes or small circular or transverse rootlet-scars in roots. The peeled root is yellow, smooth, fibrous, finely striated; fracture, fibrous in the bark and splintery in the wood; internally, brigh.t yellow: A distinct cambium ring separates the yellowish grey bark from the finely radiate yellow wood; central pIth, only in rhizomes.

The commercial variety, G. glabra var. glandulifera (Wald et Kit) Regel & Herd, known as Russian liquorice, consists mainly of roots, in cylindrical pieces somewhat tapering and sometimes longitudinally split; 15-40cm long. 1-5cm in diameter. The enlarged crown of the root may attain up to 10cm in diameter; externally, the unpeeled root purplish brown, somewhat scaly, with stem scars at the top; the peeled root yellowish, coarsely striated; fracture as for Spanish type; internally, yellow, radiating .

Glycyrrhiza uralensis Fisch.
The roots and rhizomes are cylindrical, fibrous, flexible, 20-100cm long. 0.6- 3.5 cm in diameter, with or without cork. Externally reddish brown or greyish brown, longitudinally wrinkled, furrowed, lenticellate, and with sparse rootlct scars. Texture compact, fracture slightly fibrous, yellowish white, starchy; cambium ring distinct, rays radiate, some with clefts. Rhizomes cylindrical. externally with bud scars, pith present in the centre of fracture.

Organoleptic properties
Odour slight and characteristic; taste, very sweet.

Microscopic characteristics
In transverse section the cork is thick, brown or purplish brown, formed of several layers of flattened polygonal thin-walled cells; cortex of phelloderm in root somewhat narrow, yellow fibres of parenchyma cells contain isolated prisms of calcium oxalate; phloem, wide, yellow, traversed by numerous wavy parenchymatous medullary rays, 1-8 cells wide and consisting of numerous radial groups of fibres, each surrounded bya crystal sheath of parenchyma cells. Each cell usually contains a prism of calcium oxalate and Jayers of parenchyma alternating with sieve tissue, the latter occasionally obliterated, arpearing as .. refractive irregular structures; phloem fibres, very long, with very narrow lumen ; and strongly thickened stratified walls which are cellulosic in the inner part of the phloem and slightly lignified in the outer; xylem, yellow, distinctly radiate; xylem rays, consisting of small pale yellow parenchyma. groups of fibres similar to those of the phloem but more lignified, and surrounded by crystal-sheath. tracheids, and large wide lumen vessels, 80-200Ám in diameter, with thick yellow reticulate walls or with numerous oval bordered pits with slit-shaped openings. Other parenchyma cells contain small round or oval starch granules. Pith, only in rhizome, dark yellow, parenchymatous. Root, with 4-arch primary xylem, no pith and shows 4 broad primary medullary rays, radiating from thc centre at right angles to one another. In peeled liquorice, the cork, cortex, and sometimes part of the phloem are absent.

Powdered plant material
Light yellow in the peeled or brownish yellow or purplish brown in thc unpeeled root. Characterized by the numerous fragments of the fibres accompanied by crystal-sheath, the fibres 8-25Ám. mostly 10-15Ám, in diameter; dark yellow fragments of vessels, 80-200Ám in diameter, containing solitary prismatic crystals of calcium oxalate, free or in cells 10-35Ám (mostly 15-25Ám) long; numerous simple oval, round or fusiform starch granules, frec or in parenchyma cells, with no striation but occasionally -showing hilum. 2-20Ám (mostly about 10Ám) in diameter: cork may be present.

Geographical distribution
Glycyrrhiza glabra

Native to central and south-western Asia and the Mediterrancan region. It is cultivated in the Mediterranean basin of Africa, in southern Europe, and in India.

Glycyrrhiza uralensis
Northern China Mongolia, and Siberia.

General identity tests
Macroscopic, microscopic, and microchemical examinations; and thin-layer chromatographic analysis for the presence of glycyrrhizin.

Purity tests
Microbiology

The test for Salmonella spp. in Radix Glycyrrhizae products should be negative.  The maximum acceptable limits of other microorganisms are as follows. For preparation of decoction: acrobic bacteria-not more than 10 2/g; fungi-not more than.10 5 /g;Escherichia coli-not more than 10 2/g. Preparations for internal use: aerobic bacteria-not more than 10 5 g or ml; fungi-not more 10 4/g or ml; fungi--not more than 10 4/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 10 3/g or ml; Escherichia coli --0/g or ml.

Total ash
Not more than 7%.

Acid-insoluble ash
Not more than 2%.

Sulfated ash
Not more than 10%

Water-soluble extractive
Not less than 20%.

Dilute alcohol-soluble extractive
Not less than 25%.

Pesticide residues
To be established in accordance with national requirements.  Normally, the maximum residue limit of aldrin and dieldrin for Radix Glycyrrhizae is not more than 0.05mg/kg.   For other pesticides, see WHO guidelines on quality control methods for medicinal plants guidelines for predicting dietary intake of pesticide residues.

Heavy metals
Recommended lead and cadmium levels are no more than 10 and 0.3mg/kg. respectively, in the final dosage form of the plant material.

Radioactive residues
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants.

Other purity tests
Alcohol-soluble extractive, chemical, and foreign organic matter tests to be established in accordance with national requirements.

Chemical assays
Assay for glycyrrhizin (glycyrrhizic acid, glycyrrhizinic acid) content (at least 4%) by means of spectrophotometric, thin-layer chromatographic densitometric or high-performance liquid chromatographic methods.

Major chemical constituents
The major constituents are triterpene saponins.  Glycyrrhizin (glycyrrhizic acid, glycyrrhizinic acid) is the major component (2-9%); minor components occur in proportions that vary depending on the specides and geographical location.  Glycyrrhizin occurs as a mixture of potassium and calcium salts.  It is a monodesmoside, which on hydrolysis releases two molecules of  D-glucuronic acid and the aglycone glycyrrhetic (glycyrrhetinic) acid (enoxolone).  Glycyrrhizin is generally regarded as the active principle of Radix Glycyrrhizae and is responsible for its sweetness, which is 50 times that of sucrose.  Flavonoid constituents include liquiritigenin and isoliquiritigenin.

Dosage forms
Crude plant material, dried extract and liquid extract.  Store in a well-closed container, protected from light and moisture.

Medicinal uses
Uses supported by clinical data

None.

Uses described in pharmacopoeias and in traditional systems of medicine.
As a demulcent in the treatment of sore throats, and as an expectorant in the treatment of coughs and bronchial catarrh.  Also in the prophylaxis and treatment of gastric and duodenal ulcers, and dysppsia.  As an anti-inflammatory agent in the treatment of allergic reactions, rheumatism and arthritis, to prevent liver toxicity, and to treat tuberculosis and adrenocrticoid insufficiency.

Uses described in folk medicine, not supported by experimental or clinical data
As a laxative, emmenagogue, contraceptive, galactagogue, antiasthmatic drug, and antiviral agent.  In the treatment of dental caries, kidney stones, heart disease, "consumption", epilepsy, loss of appetite, appendicitis, dissniness, tetanus, diphtheria, snake bite, and haemorrhoids.

Pharmacology
Experimental pharmacology

The demulcent action of the drug is due primarily to glycyrrhizin.  The antitussive and expectorant properties of the drug have also been attributed to glycyrrhizin, which accelerates tracheal mucus secretion.

The antiulcer activity of Radix Glycyrrhizae has been demonstrated both experimentally and clinically.  Intraperitoneal, intraduodenal, or oral administration of aqueous or alcoholic extracts of Radix Glycyrrhizae reduced gastric secretions in rats, and it inhibited the formation of gastric ulcers induced by pyloric ligation, aspirin, and ibunprofen.  Glycyrrhizin and its aglycone (glycyrrhetic acid, enoxolone), two of the active constituents of Radix Glycyrrhizae, both have antiphlogistic activity and increase the rate of mucus secretion by the gastric mucosa.   Deglycyrrhizinated liquorice (97% of glycyrrhizin is removed) effectively treated stress-induced ulcers in animal models.  The mechanism of antiulcer activity involves acceleration of mucin excretion through increasing they synthesis of glycoprotein at the gastric mucosa, prolonging the life of the epithelial cells, and antipepsin activity.  

The spasmolytic activity of Radix Glycyrrhizae has been demonstrated in vivo (guinea-pig, rabbit, and dog), and appears to be due to the flavonoids liquiritigenin and isoliquiritigenin.

Glycyrrhizin reduces the toxic action of carbon tetrachloride- and galactosamine-induced cytotoxicity in cultured rat hepatocytes, through its f antioxidant activity. Glycyrrhizin inhibited histamine rclease from rat mast cells and prevented carbon tetrachloride-induced liver lesions and macrophage-mediated cytotoxicity. Intragastric administration of a flavonoid fraction isolated from Radix Glycyrrhizae to mice protected against carbon tetrachloride hepatotoxicity. Glycyrrhizin protected the liver apparently through its membrane stabilization effects.

The anti-inflammatory and antiallergic actions of the dru,g have been attributed to the corticosteroid-like activity of glycyrrhizin and glycyrrhetic acid (enoxolone). These compounds act indirectly by potentiating the activity of corticosteroids. In vitro, glycyrrhetic acid inhibits ▀reductase, an enzyme that competitively inactivates steroid hormones, and 11▀-hydroxysteroid dehydrogenase, the enzyme that deactivates cortisol. Glycyrrhizin given intraperitoneally suppressed contact dermatitis in mice, and was more effective than prednisolone, but no effects were observed after oral administration.

In vitro, the drug inhibits the growth of Bacillus subtilis, Mycobacterium tuberculosis, Aspergillus spp., Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.

Clinical pharmacology
Oral administration of Radix Glycyrrhizae to 15 patients with peptic ulcer reduced symptoms and improved healing in 75% of the cases. Glycyrrhetic acid (enoxolone), the active constituent, produced its antiulcer activity inhibiting 15-hydroxyprostaglandin dehydrogenase and -prostaglandin reductase. Inhibition of these two enzymes stimulated an increase in the concentration of prostaglandins E and F 2 , in the stomach, which promoted the healing of peptic ulcers owing to a cytoprotective effect on the gastric mucosa. Carbenoxolone, a derivative of glycyrrhetic acid, has been used clinically for years in the treatment of gastric and duodenal ulcers.

Oral administration of deglycyrrhizinated liquorice (380 mg, 3 times daily) to 169 patients with chronic duodenal ulcers was as effective as antacid or cimetidine treatments. These results indicate that, in addition to g]ycyrrhetic acid, other unidentified constituents of Radix Glycyrrhizae contribute to its antiulcer activity.

Reports on the usefulness of liquorice extracts on body fluid homeostasis in patients with Addison disease are contradictory. One study found no positive effects, while three other studies noted an increase in weight gain and sodium retention.

Contraindications
Radix Glycyrrhizae is contraindicated in patients with hypertension, cholestatic disorders or cirrhosis of the liver, hypokalaemia, or chronic renal insufficiency, and during pregnancy.

Warnings
Prolonged use of large doses (>50 g/day) of the drug for extended periods (>6 weeks) may increase water accumulation, causing swelling of the hands and feet. Sodium excretion is reduced and potassium excretion is increased. Blood pressure may rise.

Precautions
General

Radix Glycyrrhizae should not be taken concurrently with corticosteroid treatment. If sore throat or cough persists for more than 3 days, the patient should consult a physician.

Drug interactions
Because it increases potassium loss, Radix Glycyrrhizae should not be administered for prolonged use with thiazide and loop diuretics or cardiac glycosides. Because it reduccs sodium and water excretion, the effectiveness of drugs used in the treatment of hypertension may be reduced. Radix Glycyrrhizae should not be administered in conjunction with spironolactone or amiloride.

Carcinogenesis, mutagenesis, impairment of fertility
Radix Glycyrrhizae is not mutagenic in vitro.

Pregnancy: teratogenic effects
The drug is not teratogenic in animal models.

Pregnancy: non-teratogenic effects
The safety of Radix Glycyrrhizae preparations during pregnancy has not been established. As a precautionary measure the drug should not be used during pregnancy.

Nursing mothers
The safety of Radix Glycyrrhizae preparations during lactation has not been   established. As a precautionary measure the drug should not be used during lactation except on medical advice.

Paediatric use
The safety and effectiveness of the drug in children have not been established.

Other precautions
No information available about drug and laboratory test interactions.

Adverse reactions
No adverse reactions have been associated with the drug when used within the recommended dosage and treatment period.

Prolonged use (>6 weeks) of excessive doses (>50 g/day) can lead to pseudoaldosteronism, which includes potassium depletion, sodium retention, oedema, hypertension, and weight gain. In rare cases, myoglobinuria and myopathy can occur.

Posology
Unless otherwise prescribed, average daily dose of crude plant material, 5-15g, corresponding to 200-800 mg of glycyrrhizin. Doses of other preparations should be calculated accordingly. Radix Glycyrrhizae should not be used for longer than 4-6 weeks without medical advice.