Licorice

FAMILY: Fabaceae.

HABITAT: Mediterranean basin, Middle East, China, Australia.

USED PARTS: rhizomes, roots and juice.

RECOMMENDED PHARMACEUTICAL PREPARATION: the nebulised dry extract titrated in glycyrrhizic acid (min.4%) (Italian Pharmacopoeia X). The daily dosage used in studies published in the literature is 6-8 mg/kg/day, divided into two doses, one between 7am and 8am and the other between 4pm and 5pm. As these studies were conducted with different extracts with different titres, the above posological value represents an indicative average value.

CHEMICAL COMPOSITION: contains 25 to 30% starch, 3 to 10% D-glucose and sucrose, and also coumarins, triterpenoids, sterols and flavonoids, especially flavanones, chalcones, isoflavones and isoflavonols. There is also a polysaccharide called glycyrrhizane and two other polysaccharides consisting of polygalacturonans and simple and complex sugars. The main ingredients are saponosides represented mainly by glycyrrhizin (3 to 5% of the dry drug). It is a monodesmoside which, by hydrolysis, releases two molecules of D-glycuronic acid and one molecule of glycyrrhetinic acid. A derivative of glycyrrhizic acid, called gliderinin, has also been recognised as having significant antiphlogistic activity.

THERAPEUTIC PROPERTIES:
Antigastric and anti-ulcerous action: is mainly related to glycyrrhetinic acid but also to flavonoids. This action is due both to an increase in the secretion of the mucipar cells of the gastric wall and to direct activity on the inflammatory and/or ulcerated mucosa, and results in a rapid improvement in the patient's symptoms and also in the radiological and endoscopic picture.
Liquorice given with aspirin halves the incidence of gastric ulcer induced by this drug in rats, and also tends to reduce the production of gastrin and thus hydrochloric acid by the stomach mucosa.
The anti-ulcer action of this drug is largely due to inhibition of the enzymes 15-OH-prostaglandin dehydrogenase and delta 13 prostaglandin reductase. The former converts prostaglandins E2 and F2 to 15 ketoprostaglandins, which are practically inactive, while the latter metabolises the inactive delta 13 prostaglandins, which are thus eliminated with the urine. In this way, Liquorice increases the levels of active prostaglandins in the gastric mucosa.
12-keto-triterpensaponins with antiphlogistic action are present in the aqueous liquorice extract. In this in vitro study, the effect of this aqueous extract on the adhesiveness of Helicobacter pylori to gastric mucosa and Porphyromonas gengivalis to periodontal tissue was investigated. It was noted that the extract in question inhibited the adhesion of Helicobacter to human gastric mucosa cells, and that this action depended mainly on the polysaccharides present in the extract. The latter had no direct cytotoxic action against Helicobacter and did not influence haemagglutination. These polysaccharides also had a valuable anti-adhesive action on Porphyromonas gengivalis. The study indicates that an aqueous liquorice extract hinders the adhesion of Helicobacter pylori and Porphyromonas gengivalis to target cells.

Antiphlogistic action: Glycyrrhetinic acid has been shown to inhibit the transformation of cortisol to cortisone by 11 beta-hydroxysteroid dehydrogenase. It has been shown that the most active substance in this respect is 3-monoglycuronyl glycyrrhetinic acid, which is significantly more potent than glycyrrhizic acid. Inhibition of this enzyme is dose-dependent, as demonstrated in a study in healthy volunteers. In fact, a dose of 500 mg/day of glycyrrhizin per os inhibits the enzyme for about 12 hours, whereas a dose of 1000 mg/day causes enzyme inhibition for about 24 hours.
Recent data indicate that glycyrrhetinic acid hampers beta glucuronidase activity in the liver, with reduced excretion of glucuronate compounds, including the steroids themselves. These actions are mainly exerted at the hepatic and renal levels.
Recently, another mechanism responsible for the antiphlogistic action of this drug has been identified, namely glycyrrhizin's ability to inhibit the production of free radicals, which are a class of potent inflammatory agents, by neutrophil granulocytes. The drug also seems incapable of appreciably interfering with phagocytosis and chemotaxis of these cells.
Also important is glycyrrhizin's ability to hinder tissue damage resulting from the ischaemia-reperfusion phenomenon, consisting essentially of an increase in lipid peroxidation with a consequent increase in malondialdehyde in both brain and peripheral plasma, and a decrease in superoxide dismutase (SOD) activity in the same districts. These effects are antagonised by glycyrrhizin at 100 mg/kg given for three consecutive days.
Interestingly, free radicals produced by leucocytes are one of the main causes of follicular epithelium damage in acne and rosacea.
Significant levels of 11 beta-hydroxysteroid dehydrogenase have recently been demonstrated in the central nervous system, particularly in the cerebellum, hippocampus, cortex and pituitary gland. Messenger RNA encoding the synthesis of the above-mentioned enzyme was also found. This fact could be important because 11 beta-hydroxysteroid dehydrogenase would be crucial in controlling glucocorticoid activity on the central nervous system, in particular by protecting brain structures from the deleterious effects caused by excess glycocorticoids.
The accumulation of hydrophobic bile acids causes cholestatic hepatopathy by strongly increasing oxidative stress, mitochondrial dysfunction and activation of cellular signals. The aim of this study was to evaluate the effect of liquorice on cholestatic hepatopathy in the rat. Rat hepatocytes were incubated with liquorice extract (GL) or 18-beta glycyrrhetinic acid (GA), which resulted in a clear and significant decrease in free radical generation, with GA being more effective. It was also seen that GA reduced both apoptosis and cell necrosis, while GA increased apoptosis. Bile acids promoted the activation of JNK and caspases 3, 9 and 10 and the cleavage of PARP, and these phenomena were antagonised by GA but not by GL. At the mitochondrial level, both GL and GA were potent inhibitors of mitochondrial membrane permeability modification, free radical generation and cytochrome c release. The data from this study indicate that GA is a potent inhibitor of bile acid accumulation hepatotoxicity in rat hepatocytes.

Clinical Trials
A clinical study evaluated the effect of hydrogel patches in the treatment of aphthous stomatitis. Fifteen patients were enrolled, who had to rate pain intensity on an analogue scale and who had to apply the above-mentioned patches for five consecutive days. The number and extent of ulcers and the time for their complete healing were also evaluated. It was noted that the application of the patches caused a significant reduction in pain after 3, 4 and 5 days (p<0.001) and also a significant reduction in the size of the ulcers and their necrotic phenomena always versus placebo (p<0.03). The study indicates that these patches may be useful in the treatment of aphthous stomatitis in humans.
Action on the skin: it is useful in contact dermatitis, eczema, some neurodermatitis and partially in psoriasis, with an efficacy comparable to that of medium-strength corticosteroids. In part, the skin-protective action of Liquorice may be due to the stimulation of anti type 2T lymphocyte production, which counteracts the activity of CD 8 type 2T lymphocytes induced by burns and pronounced inflammation.
Exposing rat skin to burn lesions makes it much more susceptible (up to about 50 times) to Candida albicans infections. Pretreatment of animals with dry liquorice extract per os significantly reduced the number and severity of these infections. These results suggest that glycyrrhizin, by inducing the proliferation and activity of CD4+T cells, which in turn suppress the type 2 cytokines produced by type 2T cells after burns, increases the resistance of burned skin to Candida albicans infections.

Anti-allergic action: Liquorice also inhibits the release of histamine, leukotrienes in particular leukotriene C, prostaglandin E2 and bradykinin. Beta glycyrrhetinic acid has been shown to be a potent inhibitor of the classical complement pathway, while it does not act on the alternative pathway. This action is due to inhibition of the C2 ingredient of complement. It also counteracts the radiation-induced decrease in the number of leucocytes and their mitotic processes in the rat.
An in vitro and in vivo study examined the anti-allergic action of the main liquorice ingredients (glycyrrhizin, 18-beta-glycyrrhetinic acid, isoliquiritin and liquiritigenin). It was seen that 18-beta glycyrrhetinic acid and liquiritigenin potently inhibited the passive anaphylactic skin reaction and treatment induced in the rat by compound 40/80 and also the production of IgE in asthma caused by ovalbumin, but in the latter case liquiritigenin was less active.
Airway inflammation is very important in the pathogenesis of acute respiratory failure, asthma and chronic obstructive pulmonary disease. In this study, the effect of liquorice flavonoids on acute pulmonary inflammation induced by intratracheally instilled LPS at doses of 3 or 10 or 30 mg/kg in the rat was investigated. LPS caused a marked increase in the infiltration of neutrophils, macrophages and lymphocytes and their subsequent increase in the broncho-alveolar lavage fluid. The above flavonoids inhibited neutrophil infiltration with optimal effect at a dose of 30 mg/kg, with an effect similar to that of dexamethasone at a dose of 1 mg/kg. Furthermore, these flavonoids increased SOD activity and reduced myeloperoxidase activity, and also decreased the expression in lung tissue of mRNA specific for TNF alpha and IL1 beta 6 and 24 hours after instillation. Liquorice flavonoids not only significantly reduced the increase in fluid in the lungs but also markedly attenuated the lung histological changes caused by LPS. The study indicates that liquorice flavonoids reduce LPS-induced airway inflammation and exert antioxidant actions on the airways.

Anti-radical action: Seven substances capable of antiradical action have been identified in the liquorice phytocomplex. Three of these are isoflavans, two chalcones and one isoflavone. Isoflavans seem to have the most activity, being able to almost completely inhibit beta-carotene destruction and LDL oxidation, while chalcones are less active and formononetin is not very active. Isoflavans are particularly active against the oxidation of LDL, and since oxidation of these substances is a key event in the formation of atherosclerotic lesions, the use of these antioxidants may be helpful in reducing blood vessel atherosclerosis. This action is due to the ability of isoflavans to bind to circulating LDL particles, protecting them from oxidation, as evidenced by the significant reduction in the formation of lipoperoxides and oxysterols and the simultaneous protection of LDL-associated carotenoids such as beta carotene and lycopene.
In vitro studies have shown that the isoflavone glabridin inhibits copper-induced LDL oxidation, as evidenced by the conspicuous reduction in the formation of conjugated dienes, thiobarbituric acid and lipoperoxides.
A study in the rat investigated the protective action of glycyrrhizin and glycyrrhetinic acid on neurotoxicity induced by the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+) mainly at the mitochondrial level and the role of oxidative stress in it. MPP caused nuclear damage, altered mitochondrial membrane permeability, cytochrome c release from mitochondria, caspase 3 activation, ROS formation and GSH depletion. Glycyrrhizin at doses of 100 microM or more and glycyrrhetinic acid at doses of 10 microM attenuated the above damage. The study indicates that glycyrrhizin and glycyrrhetinic acid reduce MPP toxicity at the neuronal level, mainly due to their ability to protect in mitochondria.

Clinical Trials  A controlled clinical study was done to evaluate the effect of Liquorice against the development of atherosclerotic lesions. For this purpose, a group of moderately hypercholesterolaemic patients took 100 mg/day of dry liquorice extract per os or a placebo for 30 days. The evaluation was done by measuring a number of plasma parameters. It was seen that at the end of the trial, the levels of these parameters had improved by the following percentages: plasma antioxidant activity by 19%, LDL resistance to oxidation by 55%, aggregation by 28% and retention assessed as chondroitin sulphate binding capacity by 25%, total cholesterol by 5%, LDL cholesterol by 9%, plasma triacylglycerols by 14%.

Hypertensive action: Glycyrrhetinic acid can also cause symptoms similar to those of hyperaldosteronism such as sodium, chlorine and water retention, potassium loss, reduced diuresis and hypertension.
In addition, 18-beta-glycyrrhetinic acid also causes Ca++ loss, which is reversible with discontinuation of treatment. This is due to competitive inhibition of mineralocorticoid-degrading enzymes, although some affinity for aldosterone receptors has also been demonstrated.
It has been clarified that the liquorice phytocomplex binds to renal receptors that normally respond to aldosterone. The latter are also stimulated by cortisol accumulating due to the inhibition of the enzyme responsible for degrading it, which also causes a reduction in cortisone.
Licorice phytocomplex has recently been shown to reduce the activity of 11 beta-hydroxysteroid dehydrogenase present in the blood vessel wall. In fact, rat aorta sections incubated with corticosterone and liquorice extract showed a contractile response to phenylephrine and angiotensin II that was significantly greater than that of sections incubated only with corticosterone and then exposed to these substances. This means that this drug enhances the hypertensive effect of phenylephrine and angiotensin II, favouring their vasoconstrictive action.
The effect of administration of glycyrrhizin per os over a 12-week period in the rat on pulmonary arterial pressure, electrolytes and right atrium pressure was also evaluated. The results confirm an increase in pulmonary pressure, right atrium pressure and sodium, with a decrease in potassium. Histologically, thickening of the wall of the pulmonary arterioles is noted. This picture is typical of the early phase of pulmonary hypertension.
A study in animals examined the role of glycyrrhizin (GL), glycyrrhetinic acid (GA) and its metabolite monoglucuronyl glycyrrhetinic acid (MGA) on liquorice-induced hyperaldosteronism. It was noted that plasma levels of MGA were higher for prolonged administration of this drug than for short-term administration, but this was not the case for GL and GA. It was also seen that MGA reduced plasma potassium levels and increased the potassium-dispersing action of furosemide. The study indicates that MGA also plays a role in the hypertensive and potassium-dispersing action of liquorice.

Clinical Trials
By administering glycyrrhizin at a dose of 546 mg/day for one month to a group of patients suffering from chronic hepatitis, it was noted that only 60 per cent of them developed hypertension with hypersodiukaemia and hypokalemia. These so-called responders had a pre-treatment plasma renin activity above 1.5 ng./ml, whereas in non-responders this parameter was below 1.5 ng./ml. This could mean that only subjects with plasma renin activity already above normal would be sensitive to the hypertensive action of glycyrrhizin.
A controlled clinical trial assessed whether hypertensive patients are more sensitive than normotensive patients to liquorice-induced 11 beta-hydroxysteroid dehydrogenase inhibition. For this purpose, hypertensive patients with essential hypertension and healthy volunteers were recruited, who took 100 g/day of liquorice root per os, corresponding to 150 mg/day of glycyrrhetinic acid. Blood pressure was measured every day for the entire four weeks of the study. The effects on cortisol metabolism were investigated by measuring total cortisol metabolites and the free cortisol/free cortisone quotient in urine. The average increase in systolic blood pressure was 3.5 mm/Hg in the normotensive and 15.3 mm/Hg in the hypertensive, while the average increase in diastolic blood pressure was 3.6 mm/Hg in the normotensive and 9.3 mm/Hg in the hypertensive. The typical symptoms of rising blood pressure were more pronounced in women than in men, although the difference in blood pressure between the two sexes was not statistically significant. These data confirm that the hypertensive effect of liquorice is more pronounced in hypertensive patients than in normotensive ones.
A controlled clinical study evaluated the effect of liquorice on sex steroids. A total of 15 women and 21 men, all healthy volunteers, were enrolled, taking 100 g/day of liquorice providing 150 mg of glycyrrhetinic acid, for 9 weeks. Sex steroids were measured in blood and urine pre-therapy, at the end of therapy and 1 month after its cessation. Liquorice was seen to cause a significant decrease (p<0.002) in dehydroepiandrosterone sulphate in men, with no effect on plasma and urinary levels of testosterone and other measured androgens. There were no appreciable effects on hormone levels in women. The study indicates that liquorice may only marginally affect sex steroid levels in men but not in women.
A clinical study evaluated the hypokalemic action of liquorice alone (32 g/day of dried root) and of the combination liquorice + hydrochlorothiazide (25 mg/day) for 2 weeks. It was seen that liquorice alone did not change plasma values of sodium, potassium, chlorine, renin activity and aldosterone, nor did blood pressure and heart rate. By adding hydrochlorothiazide, potassium was reduced by 0.32 mmol/l (p<0.0015), renin activity increased (p<0.0064) and body weight was reduced by 0.9 kg (p<0.0065). Twenty per cent of the participants became hypokalaemic during liquorice + hydrochlorothiazide combination therapy. The study indicates that this combination can induce hypokalaemia in healthy volunteers.

Pharmacokinetics When glycyrrhizin is administered per os in the rat, glycyrrhetinic acid appears in the plasma in an amount proportional to the glycyrrhizin administered, whereas the latter is not dosed. This means that there is a complete biotransformation of glycyrrhizin to glycyrrhetinic acid by the intestinal bacterial flora, and that this substance shows good absorption by the intestinal mucosa.
After oral administration, the blood peak is reached after 6 hours, then there is a plateau until the 12th hour and finally a slow descent begins, with almost complete disappearance after 24 hours. Once in the blood stream, glycyrrhizic acid binds to albumin.
Most glycyrrhetinic acid is eliminated with the bile in a glucuronated or sulphated form, while glycyrrhizin is not metabolised and is subject to enterohepatic circulation. It has been noted that both liquorice and glycyrrhizin alone consistently stimulate glucuronidation mechanisms in the liver in the rat.
Furthermore, this drug appears to be able to increase the activity of cytochrome P 450 and its dependent enzyme activities in the rat liver, thereby increasing the hepatic metabolism of many pharmacologically active substances.

Main indications: inflammatory-degenerative diseases of the osteoarticular system and skin, allergy, arterial hypotension.

Prevalent action: antiphlogistic, anti-allergic action.

Other actions:  Gastroprotective, antioxidant, hypertensive.

SIDE EFFECTS: none worth mentioning.

CONTRAINDICATIONS: is absolutely contraindicated in the hypertensive patient, particularly in subjects with suspected hyperaldosteronism or pheochromocytoma.
It should never be combined with steroid treatment, unless the dosage of the latter is substantially reduced, as it enhances its pharmacological action.
It can cause hypokalemia, hydrosaline retention, reduced muscle strength and even electrocardiographic disturbances typical of hypokalemia, so it is contraindicated in patients with hypokalemia of any cause.
It should not be used in individuals under 12 years of age, particularly females, pregnant women and lactating women.
It can worsen metabolic control and can easily induce hypokalaemia in diabetic patients.
It should be used with some caution in nephropathic patients.
It is incompatible with cinchona extracts and calcium compounds.
Rhabdomyolysis with severe myoadenylate deaminase deficiency has also been described in patients abusing liquorice, which, however, gradually regressed with drug withdrawal.
The case of a 93-year-old hypertensive woman with severe hypokalaemia and muscular paralysis associated with metabolic alkalosis, hypoxaemia, hypercapnia, high levels of alkaline phosphatase, myoglobin and myoglobinuria compatible with a picture of rhabdomyolysis is described. Plasma levels of aldosterone and renin were below normal. The woman had been taking liquorice extracts for seven years. Discontinuation of liquorice and administration of spironolactone and potassium brought the clinical picture back to normal within 2 weeks.

DRUG INTERACTIONS: It may significantly reduce the serum albumin binding of ibuprofen, warfarin, salicylates and deoxycholic acid, and thus may interfere with and potentiate the activity of these drugs.
Oral contraceptives enhance their hypertensive effect and vice versa.
Liquorice hinders the pharmacological action of spironolactone.
Liquorice reduces the action of acetaminophen as it increases its excretion in the liver.
It may increase sodium retention and potassium excretion induced by grapefruit juice.
It may potentiate that of digitalis, and may in some cases distort the results of digoxinemia.
It may potentiate the hypertensive effect of MAO drugs and tyramine, although there are no sufficiently clear data on this in the literature. However, it is prudent for patients taking these drugs to take Liquorice, if necessary, only under strict medical supervision.
Glycyrrhetinic acid appears capable of increasing the body's demand for thyroid hormones, which could reduce the efficacy of thyroid hormones administered in patients with hypothyroidism.

TOXICOLOGY: Glycyrrhizin and its derivatives are known to inhibit 11 beta OH-dehydrogenase, which converts cortisol to cortisone, resulting in an increase in this hormone in the blood and also in some mineralcorticoids, with hypertensive effects in both animals and humans. These effects are reversible with discontinuation of treatment. Genotoxicity and mutagenesis studies indicate that liquorice does not appear to be toxic and indeed may exert some anti-genotoxic action. Based on the studies published so far (August 2006), it is considered that a daily content of between 0.015 and 0.229 mg/kg/day of glycyrrhizin should not be exceeded.

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