SRI NAL AGATHIYAR SIDDHA HOSPITAL: ATHIMATHURAM-CLINICAL EVIADNCE

Glycyrrhiza glabra Monograph

Page 230 Alternative Medicine Review u Volume 10, Number 3 u 2005

Glycyrrhiza

glabra

Introduction

Glycyrrhiza glabra, also known as licorice and sweetwood, is native to theMediterranean and certain areas

of Asia. Historically, the dried rhizome and root of this plant were employed medicinally by the Egyptian, Chinese,

Greek, Indian, and Roman civilizations as an expectorant and carminative. In modern medicine, licorice extracts

are often used as a flavoring agent to mask bitter taste in preparations, and as an expectorant in cough and cold

preparations. Licorice extracts have been used for more than 60 years in Japan to treat chronic hepatitis, and also

have therapeutic benefit against other viruses, including human immunodeficiency virus (HIV), cytomegalovirus

(CMV), and Herpes simplex. Deglycyrrhizinated licorice (DGL) preparations are useful in treating various types

of ulcers, while topical licorice preparations have been used to sooth and heal skin eruptions, such as psoriasis and

herpetic lesions.

Description

The licorice shrub is a member of the pea family and grows in subtropical climates in rich soil to a height

of four or five feet. It has oval leaflets, white to purplish flower clusters, and flat pods. Below ground, the licorice

plant has an extensive root system with a main taproot and numerous runners. The main taproot, which is harvested

for medicinal use, is soft, fibrous, and has a bright yellow interior.1 Glycyrrhiza is derived from the ancient Greek

term glykos, meaning sweet, and rhiza, meaning root.

Active Constituents

A number of components have been isolated from licorice, including a water-soluble, biologically active

complex that accounts for 40-50 percent of total dry material weight. This complex is composed of triterpene saponins,

flavonoids, polysaccharides, pectins, simple sugars, amino acids, mineral salts, and various other substances.2

Glycyrrhizin, a triterpenoid compound, accounts for the sweet taste of licorice root. This compound represents a

mixture of potassium-calcium-magnesium salts of glycyrrhizic acid that varies within a 2-25 percent range. Among

the natural saponins, glycyrrhizic acid is a molecule composed of a hydrophilic part, two molecules of glucuronic

acid, and a hydrophobic fragment, glycyrrhetic acid.2 The yellow color of licorice is due to the flavonoid content of

the plant, which includes liquiritin, isoliquiritin (a chalcone), and other compounds.3The isoflavones glabridin and

hispaglabridins A and B have significant antioxidant activity,4 and both glabridin and glabrene possess estrogen-like

activity.5

COOH

HO O

HO COOH

COOH

Glycyrrhizin

Monograph Glycyrrhiza glabra

Alternative Medicine Review u Volume 10, Number 3 u 2005 Page 231

Pharmacokinetics

After oral administration of licorice in humans,

the main constituent, glycyrrhizic acid, is hydrolyzed

to glycyrrhetic acid by intestinal bacteria

possessing a specialized ß-glucuronidase.6,7 Glycyrrhetic

acid is 200-1,000 times more potent an inhibitor

of 11-ß-hydroxysteroid dehydrogenase (involved

in corticosteroid metabolism) than glycyrrhizic acid;

therefore, its pharmacokinetics after oral intake are

more relevant. After oral dosing, glycyrrhetic acid

is rapidly absorbed and transported via carrier molecules

to the liver. In the liver it is metabolized to

glucuronide and sulfate conjugates, which are subsequently

rehydrolyzed to glycyrrhetic acid. Glycyrrhetic

acid is then reabsorbed, resulting in a significant

delay in terminal clearance from plasma.8 After

oral administration of 100 mg glycyrrhizin in healthy

volunteers, no glycyrrhizin was found in the plasma

but glycyrrhetic acid was found at < 200 ng/mL. In

the 24-hour period after oral administration, glycyrrhizin

was found in the urine, suggesting it is partly

absorbed as an intact molecule.3

Mechanisms of Action

The beneficial effects of licorice can be attributed

to a number of mechanisms. Glycyrrhizin

and glycyrrhizic acid have been shown to inhibit

growth and cytopathology of numerous RNA and

DNA viruses, including hepatitis A9 and C,10,11 herpes

zoster,12 HIV,13,14 Herpes simplex,15,16 and CMV.17

Glycyrrhizin and its metabolites inhibit hepatic

metabolism of aldosterone and suppress 5-ßreductase,

properties responsible for the well-documented

pseudoaldosterone syndrome. The similarity

in structure of glycyrrhetic acid to the structure of

hormones secreted by the adrenal cortex accounts for

the mineralocorticoid and glucocorticoid activity of

glycyrrhizic acid.18

Licorice constituents also exhibit steroidlike

anti-inflammatory activity, similar to the action

of hydrocortisone. This is due, in part, to inhibition

of phospholipase A2 activity, an enzyme critical to

numerous inflammatory processes.19 In vitro research

has also demonstrated glycyrrhizic acid inhibits cyclooxygenase

activity and prostaglandin formation

(specifically prostaglandin E2), as well as indirectly

inhibiting platelet aggregation, all factors in the

inflammatory

process.

19,20

Certain licorice constituents possess significant

antioxidant and hepatoprotective properties.

Glycyrrhizin and glabridin inhibit the generation of

reactive oxygen species (ROS) by neutrophils at the

site of inflammation.21,22 In vitro studies have demonstrated

licorice isoflavones, hispaglabridin A and B,

inhibit Fe3+-induced mitochondrial lipid peroxidation

in rat liver cells.23 Other research indicates glycyrrhizin

lowers lipid peroxide values in animal models of

liver injury caused by ischemia reperfusion.24 Licorice

constituents also exhibit hepatoprotective activity by

lowering serum liver enzyme levels and improving

tissue pathology in hepatitis patients.25

Glycyrrhizin and other licorice components

appear to possess anticarcinogenic properties as well.

Although the exact mechanisms are still under investigation,

research has demonstrated they inhibit abnormal

cell proliferation, as well as tumor formation

and growth in breast,26 liver,27 and skin28,29 cancer.

Deglycyrrhizinated licorice formulations

used in the treatment of ulcers do not suppress gastric

acid release like other anti-ulcer medications. Rather,

they promote healing by increasing mucous production

and blood supply to the damaged stomach mucosa,

thereby enhancing mucosal healing.30,31

Glycyrrhiza glabra Monograph

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Clinical Indications

Chronic Hepatitis

In Japan, glycyrrhizin has been used for more

than 60 years as a treatment for chronic hepatitis C.

Stronger Neo-Minophagen C (SNMC), a glycyrrhizin

preparation, has been extensively used with considerable

success. In two clinical trials, SNMC has

been shown to significantly lower aspartate transaminase

(AST), alanine transaminase (ALT), and gamma-

glutamyltransferase (GGT) concentrations, while

simultaneously ameliorating histologic evidence of

necrosis and inflammatory lesions in the liver.25,32 In

recent years, several studies have been performed

supporting this action.10,11 Presently, interferon (IFN)

therapy is a predominant treatment for chronic hepatitis.

Because its efficacy is limited, an alternative

treatment is desirable. SNMC has profound effects on

the suppression of liver inflammation and is effective

in improving chronic hepatitis and liver cirrhosis. It

also appears to have considerably fewer side effects

than IFN.33

In a double-blind, randomized, placebo-controlled

trial investigating IV infusions of SNMC,

short-term efficacy of licorice was confirmed with

regard to ALT levels. The study showed the need for

daily IV administration of SNMC, which may be impractical

for patients. The study also demonstrated

that after cessation of therapy the ALT-decreasing effect

of licorice disappeared, suggesting the need for

long-term administration.25

Oral Lichen Planus

Patients with chronic hepatitis C often experience

oral lichen planus, an inflammatory disease characterized

by lymphocytic hyperkeratosis of the oral

mucosa. It is rarely cured and effective treatments are

limited. In an open clinical trial, 17 hepatitis C-positive

patients with oral lichen planus were given either

routine dental care or 40 mL IV glycyrrhizin daily for

one month. Among nine patients taking glycyrrhizin,

six (66.7%) noted improved clinical symptoms, such

as decreased redness, fewer white papules, and less

erosion of the mucosa. In the non-glycyrrhizin group

of eight patients, only one (14.3%) reported any improvement.

Other Viral Illnesses

It has been reported that licorice inhibits

growth and cytopathology of many unrelated DNA

and RNA viruses, while not affecting cell activity or

cellular replication.15

Hepatitis A virus (HAV) causes acute hepatitis,

a major public health concern in numerous countries.

In vitro research with glycyrrhizin and a human

hepatoma cell line has demonstrated glycyrrhizin

completely suppresses the expression of the HAV antigen.

In comparison to ribavirin (an antiviral agent

used to treat hepatitis), glycyrrhizin proved to be 10

times more potent at reducing infectivity of HAV, as

measured by reduction in viral titres. Glycyrrhizin

also exhibited a five-fold greater cell selectivity than

ribavirin in that it was less cytotoxic to the hepatoma

cells. These results indicate glycyrrhizin may be a

potential therapeutic adjunct in fighting HAV infections.

Studies show licorice and its constituents,

specifically glycyrrhizin, have antiviral activity

against Herpes simplex and are capable of irreversibly

inactivating the virus.16,35,36 Glycyrrhizin has also

been shown to inhibit viral replication and infectivity

of HIV,14,36 herpes zoster,37 Varicella zoster,12 and

CMV.17,38,39

A case report demonstrated a two-percent topical

glycyrrhizic acid cream (carbenoxolone sodium)

applied six times daily in 12 patients with acute oral

herpetic (Herpes simplex) infections resolved pain

and dysphagia within 24-48 hours of beginning use.

Moreover, the accompanying ulceration and lymphadenopathy

gradually healed within 24-72 hours.16

A clinical study of three HIV patients with

hemophilia investigated the effect of glycyrrhizin on

HIV replication. Glycyrrhizin was administered IV at

400-1600 mg on six separate occasions over a onemonth

period. The HIV p24 antigen was detected in

all patients at the beginning of treatment courses. At

the end of one month, p24 antigen levels had either

decreased significantly or become negative. Tapering

of the glycyrrhizin dose resulted in an immediate elevation

in p24 antigen levels, suggesting the higher

doses of glycyrrhizin were responsible for decreased

antigen levels, probably via suppressed viral replication.

Monograph Glycyrrhiza glabra

Alternative Medicine Review u Volume 10, Number 3 u 2005 Page 233

In a clinical trial of 31 patients with severely

painful herpes zoster lesions, 12 patients were given

20 mg IV glycyrrhizin on six separate occasions. The

remaining 19 patients received either zoster immune

gamma-globulin, recombinant interferon-ß, or acyclovir.

Glycyrrhizin ranked next to acyclovir for pain

resolution at the end of one month.37

CMV is the most common cause of congenital

and perinatal viral infections throughout the world.

It manifests with profound liver dysfunction and poor

weight gain. In a series of studies, both oral and IV

preparations of licorice (SNMC) were administered

to infants with CMV. Liver dysfunction and weight

gain improved in nearly all cases compared to groups

without treatment.17,38,39

Hepatocellular Carcinoma

In a retrospective study, long-term licorice

administration for hepatitis C infection was effective

in preventing hepatocellular carcinoma (HCC). Four

hundred fifty-three patients diagnosed with hepatitis

C were divided into three groups and given either

licorice, in the form of SNMC at a dose of 100 mL

daily for two months, or other natural treatments,

such as vitamin K. The remaining group of patients

was treated with a wider number of agents, including

SNMC, corticosteroids, and immunosuppressive

agents; as a result of the mixed medication regimen,

this group was excluded from the study. After 10

years, analysis of the results showed 30/84 patients

(35.7%) employing SNMC had normalized AST levels,

compared with seven patients (6.4%) not treated

with IV SNMC. Moreover, the 10- and 15-year appearance

rate of HCC was 7 and 12 percent in the

treated group compared to 12 and 25 percent in the

untreated group, respectively.40 A summary of the literature

on HCC and the use of SNMC has confirmed

that IV glycyrrhizin not only decreases ALT levels

but also improves liver histology and decreases incidence

of hepatic cirrhosis.41

Aphthous Ulcers

In a double-blind, placebo-controlled trial,

24 patients with recurrent aphthous ulcers were randomly

allocated to consume 2 g glycyrrhizin (carbenoxolone

sodium) in 30 mL of warm water or a

placebo three times daily following meals for four

weeks. In contrast to the placebo group, the use of the

oral licorice mouthwash significantly reduced the average

number of ulcers per day, pain scores, and the

development of new ulcers.42 In a study of 20 patients

instructed to use a DGL mouthwash four times daily,

15 experienced 50-75 percent clinical improvement

after only one day, with complete healing of canker

sores after three days.43

Peptic Ulcer Disease

Licorice has been used as a demulcent and

emollient for 2,000 years to promote the healing of

ulcers by acting on the mucosal layer. Glycyrrhizin

(as carbenoxolone sodium) speeds healing of gastric

ulcers and protects against aspirin-induced damage to

the gastric mucosa. In a double-blind, placebo-controlled

study, 70 patients with endoscopically-confirmed

gastric or duodenal ulcers were given carbenoxolone

sodium 300 mg or placebo daily during the

first seven days, followed by 150 mg daily over the

next 3-5 weeks. The authors concluded the carbenoxolone

group had an increase in pH at the stomach

antrum from 1.1 to 6.0, and a reduction in basal and

histamine-induced gastric acid secretion at pH 3 and

5. Overall, 70 percent of ulcers in the glycyrrhizin

group healed within 3-5 weeks of beginning therapy,

compared to 36 percent employing placebo.44

Unfortunately, the side effects of licorice

limit its potential to be used on a long-term basis for

treatment of peptic ulcer disease. A processed form

of licorice, DGL (removal of the glycyrrhizin), was

produced to eliminate potential adverse effects, including

licorice-induced hypertension.45 In a double-

blind trial, 100 patients were randomly chosen

to chew Caved S (DGL plus antacid), 760 mg three

times daily, or take cimetidine (Tagamet®) 200 mg

three times daily and 400 mg at night for 12 weeks.

Endoscopy showed the healing rate between the two

regimens was comparable at six (63 percent) and 12

(91 percent) weeks. Although both therapies reduced

pain symptom scores in a comparable fashion during

the day, cimetidine was more effective during the first

two weeks at reducing nighttime pain.46 A two-year

follow-up trial comparing the two therapies in the

prevention of gastric ulcer recurrence noted the outCopyright

Glycyrrhiza glabra Monograph

Page 234 Alternative Medicine Review u Volume 10, Number 3 u 2005

comes were similar, with a reported relapse rate of 29

percent (9/31) in the Caved S group and 25 percent

(8/32) in the cimetidine group.47

Other clinical trials have demonstrated the

effectiveness of DGL for gastric ulcer.48,49 A fourweek

clinical trial by Turpie et al demonstrated a

statistically significant greater reduction in ulcer size

in patients receiving 760 mg of a DGL preparation

compared to placebo.48

Helicobacter pylori infection is prevalent in

individuals with peptic ulcer and is also a known risk

factor for gastric cancer.50,51 Consequently, an in vitro

study was performed to investigate the effects of licorice

flavonoids on the growth of H. pylori. These flavonoid

components showed promising anti-H. pylori

activity against clarithromycin- and amoxicillin-resistant

strains. As the antimicrobial property seems to

be attributed to the flavonoid constituents of licorice,

DGL preparations may provide therapeutic benefit

for H. pylori infection.52

Other studies have demonstrated DGL’s benefit

in healing duodenal ulcers. In a trial of 40 patients

receiving either 3.0 or 4.5 g DGL daily for eight

weeks, all patients showed significant improvement

after 5-7 days. Patients were assessed for relief from

epigastric pain, nausea, vomiting, x-ray of ulcer craters

to determine changes in size, and frequency of

relapse (return of ulcer pain for two days per week).

Patients receiving the higher DGL dose showed the

most improvement.53 In a large study of 874 patients

with chronic duodenal ulcers, patients received either

DGL, cimetidine, or antacids. Ninety-one percent of

all ulcers healed, regardless of treatment type. Differences

among treatment groups were not statistically

significant, but patients in the DGL group experienced

the fewest relapses.54

Other Therapeutic Considerations

In a trial of 15 normal-weight subjects (seven

males, eight females, ages 22-26), 3.5 mg of a commercial

licorice preparation daily for two months resulted

in a decrease in body fat mass. Plasma renin

activity and aldosterone were also suppressed. No

changes in body mass index were noted. These results

indicate licorice and its constituents can reduce

body fat by inhibiting 11-ß-hydroxysteroid dehydrogenase

in fat cells.55

Armanini et al investigated the effect of licorice

on serum testosterone in nine healthy women,

ages 22-26, using the same licorice preparation as

above, and found total serum testosterone decreased

from 27.8 (± 8.2) to 19.0 (± 9.4) ng/dL after one

month, and further decreased to 17.5 (± 6.4) ng/dL

after the second month of therapy. This is likely due

to inhibition of 17-hydroxysteroid dehydrogenase,

indicating

licorice may be of benefit in treating women

with hirsutism and polycystic ovary syndrome.56

Several animal and in vitro studies indicate

glycyrrhizin and its constituents possess anticarcinogenic

activity against a variety of cancers, warranting

further investigation in clinical trials.26-29

Studies also show licorice constituents to be

effective in the treatment of eczema,57 melasma,58 eosinophilic

peritonitis,59 postural hypotension,60 erosive

gastritis,61 and as anti-malarial62 and anti-Leishmanial

agents.63 More recently, animal studies indicate aqueous

extracts of G. glabra may have memory-enhancing

activity via reversal of chemically-induced amnesia,

as measured by maze and passive avoidance

testing in mice.64

Drug-Botanical Interactions

There is an increased likelihood of cardiac

arrhythmias, particularly in individuals with ischemic

heart disease, when licorice is used in conjunction

with digoxin.65

Estrogen-based oral contraceptives may enhance

the mineralocorticoid side effects of licorice in

susceptible individuals. This may be due in part to estrogens

reacting with mineralocorticoid receptors or

inhibition of 11â-hydroxysteroid dehydrogenase.66

Hypokalemia, commonly associated with

metabolic acidosis, may co-present with essential

benign hypertension in patients using diuretics and

licorice simultaneously.67

Side Effects and Toxicity

One of the most commonly reported side effects

with licorice supplementation is elevated blood

pressure. This is thought to be due to the effect of

licorice on the renin-angiotensin-aldosterone system.

It is suggested licorice saponins are capable of potentiating

aldosterone action while binding to mineralocorticoid

receptors in the kidneys. The phenomenon

Monograph Glycyrrhiza glabra

Alternative Medicine Review u Volume 10, Number 3 u 2005 Page 235

is known as “pseudoaldosteronism.” In addition to

hypertension, patients may experience hypokalemia

(potassium loss) and sodium retention, resulting

in edema. All symptoms usually disappear with

discontinuation of therapy.25 Many studies report no

side effects during the course of treatment.32,33 Generally,

the onset and severity of symptoms depend on

the dose and duration of licorice intake, as well as

individual susceptibility. Patients with delayed gastrointestinal

transit time may be more susceptible to

these side effects, due to enterohepatic cycling and

reabsorption of licorice metabolites. The amount of

licorice ingested daily by patients with mineralocorticoid

excess syndromes appears to vary over a wide

range, from as little as 1.5 g daily to as much as 250

g daily.68

Dosage

Because individual susceptibility to various

licorice preparations is vast, it is difficult to predict

a dose appropriate for all individuals. Nevertheless,

a daily oral intake of 1-10 mg of glycyrrhizin, which

corresponds to 1-5 g licorice (2% glycyrrhizin), has

been estimated to be a safe dose for most healthy

adults.69 Studies of DGL for peptic ulcers employed

dosages ranging from 760-2,280 mg DGL daily.

SRI NAL AGATHIYAR SIDDHA HOSPITAL

Sunday, 2 September 2012

ATHIMATHURAM-CLINICAL EVIADNCE

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