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ATHIMATHURAM-CLINICAL EVIADNCE


Glycyrrhiza glabra Monograph
Page 230 Alternative Medicine Review Volume 10, Number 3 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.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.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,and both glabridin and glabrene possess estrogen-like
activity.5
O
O
H
H
H
COOH
O
HO O
HO
HO
HO
HO COOH
COOH
O
Glycyrrhizin
Copyright© 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 3 September 2005
Monograph Glycyrrhiza glabra
Alternative Medicine Review Volume 10, Number 3 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.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 Aand 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
Copyright© 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 3 September 2005
Glycyrrhiza glabra Monograph
Page 232 Alternative Medicine Review Volume 10, Number 3 2005
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.
34
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.
9
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.
13
Copyright© 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 3 September 2005
Monograph Glycyrrhiza glabra
Alternative Medicine Review Volume 10, Number 3 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
© 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 3 September 2005
Glycyrrhiza glabra Monograph
Page 234 Alternative Medicine Review Volume 10, Number 3 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
Copyright© 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 3 September 2005
Monograph Glycyrrhiza glabra
Alternative Medicine Review Volume 10, Number 3 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.

1 comment:

  1. Happy to be a part in vizhudhugal.

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    C.S.Rakhavi,

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