Saturday, January 21, 2012

Saya chooranam -Immuno modulator

Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
8
Content list available at: www.iaphp.in
Journal of Advances in Pharmacy and Healthcare Research
Journal home page: http://www.japhr.iaphp.in
ISSN 2231-6817
Evaluation of Immunomodulatory Activity of Saya Churnam (A Poly Herbal Formulation) on Albino rats.
Y. Santhammal1, S. Arthika1, N. Sharly Elgal1, R. Ganesan2, P. Satyarajeswaran2, S.N. Gaidhani2, G.Pramod Reddy2* and T. Anadan2
1Department of Bio-technology, Bishop Heber College, Tirucharappalli, T.N. India.
2Department of Pharmacology, Siddha Central Research Institute, Chennai, T.N., India.
Key words:
Saya churnam, Immunomodulation, Antibody titer,
Delayed type hyper sensitivity, Ig E.
Corresponding Author:
Dr. G. Pramod Reddy, Department of Pharmacology, Siddha Central Research Institute, Anna hospital Campus, Arumbakkam, Chennai, T.N., India.
gpramod01@gmail.com
Abstract:
The immunomodulatory activity of Saya churnam (a poly herbal formulation) on Albino rats was evaluated by using Cyclophosphamide as an immunosuppressant. The Poly herbal formulation was administered orally at the dosage levels of 200mg/kg/day and 400mg/kg/day body weight of rat. The assessment of immunomodulatory activity on specific and non- specific immunity were studied by Hemagglutination antibody (HA) titer, delayed type hypersensitivity (DTH), Identification of Ig E, hematological , biochemical analysis. Induction of immune suppression in rats was achieved by using Cyclophosphamide (CP) (100mg/kg/day, p.o). Oral administration of Saya Churnam (SC) showed a significant increase in the production of circulating antibody titer in response to sheep red blood cells (SRBCs). A significant (p< 0.001) increase in the both primary and secondary HA titer was observed when compared to control group, where as in Cyclophosphamide treated group Saya Churnam showed significant (p<0.01) increase in HA titer. Saya churnam showed significant (p<0.01) Delayed type hypersensitivity (DTH) reaction by facilitating the foot pad thickness response to SRBCs in sensitized rats. Also biochemical and hematological analysis showed a significant (p<0.001) increase in Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), Alkaline Phosphatase (ALP) and WBCs. The study demonstrates that Saya churnam triggers both specific and non-specific responses to a greater extent. The study showed significantly increased results in Heme agglutination (HA) titer, DTH response, Ig E test, biochemical, hematological analysis.
INTRODUCTION
Indian traditional systems of medicines like Siddha and Ayurveda which generally involve herbal formulations have suggested the body’s natural resistance to disease (Sagrawat and Khan, 2007). Recent studies with plants have revealed many compounds with potent antioxidant, antineoplastic, antiulcer, anti-inflammatory and immunostimulating potential (Wanger, 1990). Immune activation is an
effective as well as protective approach against emerging infectious diseases, and this immune system known to be involved in etiology and pathophysiological mechanisms of several diseases. It is believed that the immunomodulatory drugs promote positive health and maintain organic resistance against infections by establishing body’s equilibrium and conditioning the body tissues (Dasgupta et
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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al., 1998). The restorative and rejuvenating power of these herbal remedies might be due to their action on the immune system and thereby responsible for the protection of the organism from extraneous substance and maintaining homeostasis.
Plant and plant products are being used as a source of medicine since long. Non – toxic herbal preparations are used to improve the general health by stimulating body’s immunity. In this poly herbal formulation (Terminalia chebula, Piper longum, Piper cubeb, Alpinia galangal, and Myristica officinalis) each herb have a capacity to induce immune response and each herb have anti-inflammatory, anti-ulcer, and other activities.
The Siddha system of medicines not only provides hat alternative, but also scores over the side effects and cost factors of allopathic medicine. Herbal preparation can be more effective and safer (Vinothapooshan et al., 2011) than conventional medicines. Non-toxic herbal drug preparations that are used to improve general health by stimulating body’s immunity (Kumar et al., 1999).
Herbal medicine has become an integral part of standard health care (Agarwal et al., 2010). This formulation of Saya churnam was obtained from the ancient Siddha text (Agasthiar, 1995). In Siddha normally this Saya churnam is prescribed for Tuberculosis, Jaundice, Anemia, Diabetes mellitus, Arthritis. On the basis of literature there are no reports on Saya Churnam for immunomodulatory system.
The present study was undertaken to investigate and to validate the Immunomodulatory activity of Saya churnam.
MATERIALS AND METHODS
Site of the experiment: The experiment was conducted at the Department of Pharmacology, Siddha Central Research Institute, Chennai, in February, 2011.
Plant material: Fruits and rhizome of the plants were procured from local market and it was authentified by Sasikala Ethirajulu, Assistant Director, Department of Pharmacognosy, Siddha Central Research Institute, Chennai.
Preparation of poly herbal formulation: Fruits of Terminalia chebula, Piper longum, Piper cubeb, Myristica officinalis and Rhizome of Alpinia galangal was collected. It was cleaned without any dust particles or other unwanted materials. Each herb is finely powdered and it was mixed in different ratio. The collected fruits and rhizome are fried little and powdered as mentioned in the ancient text. Then the poly herbal powder was used for the further studies. Now this formulation is used for the evaluation study.
Drug and chemicals: All the drugs and chemicals are analytical grade while the other drugs procured were Cyclophosphamide (Biochem pharmaceutical, Mumbai), ELISA commercial kit from Biotran Diagnostics, U.S.A.
Animals: Healthy Wistar albino rats both male and female (180-230 gm) were used for the study. All the animals were housed which were under standard conditions of temperature (25 ± 2? C), 12h light/ dark cycles and fed with standard pellet food and water. The animals were divided into four groups consisting of six animals each. A group of
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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six un- treated rats were taken as control (group I). Group II animals received standard drug Cyclophosphamide on day 9th and 16th orally in a dosage range of 100mg/kg/day. The Saya churnam was fed orally for 21 days at a dosage of 200 mg/kg/day (group III), 400) mg/kg/day, (group IV) mg/kg/day for assessment of immunomodulatory activity.
Test compound formulations: The different ratio of all the fruit and rhizome powder was measured and prepared in honey with water in the ratio of 7:3 prior to oral administration of animals. Freshly prepared drug solution was used. The vehicle alone served as control.
EXPERIMENTAL PROCEDURE
Antigenic material: Preparation of sheep RBCs (SRBCs): Sheep blood was collected in sterile Alsever’s solution in 2:1 proportion of Alsever’s solution (Freshly prepared). Blood was kept in the refrigerator and processed, for the preparation of SRBCs batch, by centrifugating at 2000rpm for ten minutes and washing with physiological saline 4-5 times and then suspending into buffered saline for further use (Kirtikar et al., 1961).
Heamagglutinating Antibody (HA) Titer: The rats of all groups are pre-treated with drug for 21 days. And each rat immunized with 0.1X109 SRBC/rat by i.p. route, including control rats. The immunization (Agarwal et al., 1999) was given on day 7th and 14th. The animals were treated with Saya churnam for 21 days. The titer was determined by titrating serum dilutions with SRBCs. The micro titer plates were incubated at room temperature for one hour and examined visually for agglutination has been expressed as HA titer.
Delayed Type Hypersensitivity (DTH) Response: Each group of animals (group I-IV) was immunized with SRBCs on day 7th and 14th. On day 21st Rats are administered 0.1ml of 1% SRBCs in the left hind foot pad by subcutaneous (Fulzele et al., 2003) injection, in the right hind foot pad administered 0.1 ml of 0.9% of normal saline was injected and the increased level of paw volume was measured by plethysmometer (Gayathri et al., 2005) in three different time (0 hour, 1 hour, 3 hour) intervals. The thickness between left and right hind paw volume was measured.
Identification of Ig E: On 21st day serum was obtained from all the group of animals. 25µl of serum was added to all the wells, add 100µl of Ig E biotin reagent then allowed to incubation of an hour. Discard the contents and add 300 µl of wash buffer and discarded that it was carried out four times. Then added 100 µl of Ig E enzyme reagent allowed it for incubation of half an hour. Discard the contents and added 300 µl of wash buffer and discarded it was carried out 4 times after that.1 ml of working substrate solution was added allowed for 15 minutes incubation then added 0.05ml of stop solution read the absorbance at 450 nm.
Liver function and blood parameters test: Activities of Serum Glutamate Oxalate Transaminase (Sharififa et al., 2009) (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), Alkaline Phosphatase (ALP) and Hematological parameters (RBC, WBC, Hb, PLT) were estimated by using kits (Span Diagnostics, India). For this purpose four groups of animals (one control+three
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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Table 1: Effect of Saya Churnam on primary and secondary antibody titer.
Treatment
Primary antibody titer
Secondary antibody titer
Control
6.88±0.83
7.66 ± 0.98
CP 100mg/kg
5.23±0.63**
4.86 ± 1.04**
SCLD 200mg/kg
5.72 ± 1.04***
6.12 ± 0.89***
SCHD 400mg/kg
7.76 ± 1.32***
8.56 ± 0.98***
The values are expressed as (Mean ± S.D), n=6,**p<0.01 and *** p<0.001
Treatments) as described above were used and treated with drug for 21 days.
Statistical analysis: The statistical analysis was performed by using student t Test followed by one way analysis (ANOVA).
RESULTS
Heamagglutination antibody (HA) Titer: Effect of Saya churnam low dose (SCLD) and Saya churnam high dose (SCHD) on primary and secondary antibody response on HA titer is shown in (Table 1). Primary antibody response on day 14th in saya churnam (200mg, 400mg/kg/p.o) treated group with normal immune status showed significant increase (p<0.01) in HA titer when compared with the control group. A significant decrease in the antibody titer was observed in the Cyclophosphamide–treated group when compared with the control group. In immunosuppressed groups, where the immunity was suppressed by administration of Cyclophosphamide on day nine, Saya churnam (400mg/kg/p.o) administration produced a significant (p<0.01) rise in the antibody titer when compared with the Cyclophosphamide – treated group. Secondary antibody titer on twenty first day in Saya churnam both low dose and high dose treated groups with normal immune status group showed a significant rise (p<0.01) in the antibody titer when compared with the control group. In the immunosuppressed groups where the immunity was suppressed by administration of Cyclophosphamide on day sixteenth Saya churnam both low dose and high dose showed a significant rise (p<0.01) in HA titer when compared with the Cyclophosphamide group.
Delayed type hypersensitivity: Effect of Saya churnam on cell mediated immune response by DTH induced foot pad oedema is shown in (Table 2). In the all groups of rats with normal immune status, of Saya churnam low dose (200mg/kg/p.o) and Saya churnam high dose(400mg/kg/p.o) showed significant (**p<0.01,*P<0.05) potentiated DTH response in terms of increase in the mean difference of paw thickness when compared with control group. The drug treated group of rats showed significant (p<0.01) potentiated DTH response in terms of increase in the mean difference of paw thickness. Heightened delayed type hypersensitivity reaction suggests activation of cellular immune system.
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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Table 2: Effect of Saya churnam treatment on cell mediated immune response by delayed type hypersensitivity induced footpad oedema.
Treatment
SRBC’s (in left hind paw)
Saline (in right hind paw)
0 hrs
1 hrs
3 hrs
0 hrs
1 hrs
3 hrs
Control
0.81±0.14
1.14±0.32
2.04±0.33
0.81± 0.15
0.91±0.19
0.96±0.36
SCLD200mg/kg
0.78±0.20**
1.30±0.42**
2.35±0.45**
0.88±0.16*
0.87±0.15*
0.86±0.23**
SCHD400mg/kg
0.98±0.12**
1.36±0.32**
3.64±0.36**
1.00±0.21*
0.65±0.15*
1.05±0.40**
The values are expressed as (Mean ± S.D), n=6.*P<0.05 and **p<0.01.
Identification of Ig E: The administration of Saya churnam both low dose and high dose (200mg/kg/day and 400mg/kg/day) showed significantly increased (*p<0.05) levels of immunoglobulin level when compared to control in the animal serum sample
Table 3: Effect of Saya churnam on Ig E
Treatment
Ig E
Control
16±4.5
SCLD 200 mg/kg
13.6±2.8*
SCHD 400mg/kg
14.3±4.9*
The values are expressed as (Mean ± S.D), n=6.*p < 0.05.
Liver function and test: There was a significant elevation in SGOT, SGPT, ALP as a result of treatment with Saya churnam on both low dose and high dose in this study (***p<0.001,*p<0.01) (Table 4). The drug treated group compared with control group which showed significantly increased values.
Hematological parameter test: In hematological analysis observed significant differences in hematological parameters and drug treated groups are compared with control and Cyclophosphamide treated group. Result shows increased level of WBC, RBC, HGB, PLT on low dose and high dose treated group when compared with control group.
DISCUSSION
Immunostimulatory agents of plant and animal origin enhance the (Fulzele et al., 2003) immune responsiveness of an organism against a pathogen by activating the immune system. However these
poly herbal formulations should be subjected to systematic studies to substantiate the therapeutic
claims made with regard to their clinical utility (Joshi et al., 2003). Immunomodulation is a procedure which can alter the immune system of an organism by interfering with its functions; if it results in an enhancement of immune reaction it is named as immunostimulative drug which primarily implies stimulation of specific and non- specific system. Immunomodulation through natural substances may be considered an alternative for the prevention (Zhang et al., 2011) and cure of disease. Immuno-suppression implies mainly reduce resistance against infections, stress and may occur on account of environmental or chemotherapeutic factor (Makare et al., 2001). The results obtained in the present study indicate that Saya churnam is a potent immunostimulant, stimulating specific and non-specific immune mechanisms.To evaluate the effect of Saya churnam on humoral response, its influence was tested on sheep erythrocyte specific
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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HA titer in rats (Benaceraf et al., 1978). Cyclophosphamide showed significant inhibition in
Table 4: Effect of Saya churnam on liver enzymes.
Treatment
SGOT U/L
SGPT U/L
ALP U/L
Control
56.42 ± 11.9
19.18 ± 3.72
88.8 ± 16.1
CP 100mg/kg
111.3 ± 18.42***
31.58 ± 9.11**
120.02 ±14.1***
SCLD 200mg/kg
59.73 ± 11.12***
36.68 ± 10.7 **
150.55 ± 16.88 ***
SCHD 400mg/kg
62.85 ± 10.98 ***
47.58 ± 7.06**
270.9 ± 73.65 ***
The values are expressed as (Mean ± S.D), n=6.**p<0.01 and ***p<0.001.
antibody titer response, while saya churnam counteract the suppression of both primary and secondary humoral (Kulkarni et al., 2007)
responses induced by Cyclophosphamide. It indicates that the Saya churnam has the significant effect on humoral antibody response. In DTH test, the DTH response, which directly correlates with cell mediated immunity (CMI), was found to be the highest at maximum dose of 400mg/kg/day tested in this study. Increase in the DTH response indicates that Saya churnam has stimulatory effect on lymphocytes and accessory cell types (Mitra et al., 1999) required for the expression of the reaction Cell mediated immunity the mechanism behind this elevated DTH during the CMI responses could be due to sensitized T- lymphocytes. When challenged by antigen they are converted to lymphoblast and secrete variety of molecules including pro-inflammatory lymphokines, attracting more scavenger cells to the site of reaction (Fulzele et al., 2003).
Increase in the DTH response indicates that the drug has a stimulatory effect on lymphocytes and accessory cell types required for the expression of the reaction (Mitra et al., 1999). Foot volume was enhanced after Saya churnam treatment suggesting cell (Sen et al., 1992) mediated immune enhancement. Immunoglobulin level is a direct measure to detect the humoral immunity. Serum immunoglobulin refers to a group of serum molecules produced by B- lymphocytes, they are soluble and secreted from of B-cell receptors and are produced to a maximum level to counter the invasion by an antigen, and hence they are also called as (Ismail and Asad, 2009) antibodies.
Identification of Ig E also showed the presence Ig E in the tested animals. The results shown significantly increased level of immunoglobulin in Saya churnam treated group when compared with control and Cyclophosphamide treated group. Estimation of LFT enzymes did not show any toxicity effect which was concomitant with any
Table 5: Effect of Saya churnam on Hematological parameters
Groups
WBC
RBC
HGB
PLT
Control
6.7± 3.5
5.32±1.11
9.0 1 ±1.93
406.9±108.3
CP 100mg/kg
3.81± 4.01*
6.96±2.81*
12.42±5.4 *
169.5±200.1**
SCLD 200mg/kg
5.52±2.34 ***
6.61±2.52***
11.32±4.46***
267.2±105.4***
SCHD 400mg/kg
7.63±2.07 ***
6.69±2.33***
11.56±4.43***
342.1±155.7***
The values are expressed as (Mean ± S.D),n=6.*P<0.05, **p<0.01and ***p<0.001.
Santhammal et al, JAPHR 2011, Vol 1 Issue 3 Research Article
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significant increase in relative weight of liver. High dosage 400mg/kg/day showed increased level of SGPT, SGOT, and ALP. And the results of the presence study revealed that significant difference in the blood parameters. Findings of the present study showed an overall stimulatory effect of Saya churnam on humoral as well as cell-mediated immunity in rats.
CONCLUSION
On the basis of the results obtained in the current study, it can be concluded that the saya churnam has the potential to stimulate cell-mediated and humoral immunity and it may be a potential therapeutic candidate in several immunosuppressed clinical conditions. However, more exhaustive work needs to be performed to substantiate the claim.
REFERENCES
Agarwal, R., S. Diwanay, P. Pakti and B. Patwardhan, 1999. Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J. Ethnopharmacol., 67: 27-35. 10616957
Agasthiar, G.N., 1995. Agasthiar Gowmathi Nool 400. Thamarai Pathippagam., 94.
Benacerraf, B., 1978. A hypothesis to relate the specificity of T lymphocytes and the activity of I region specific Ir genes in macrophages and B lymphocytes. J of Immunology. 120:1809-1812.
Dasgupta, P.S.C. and A. Gomes, 1998. Immunopotentiating activity of immune-21: A poly herbal product. Indian J. Pharmacol., 30:163-168.
Fulzele, S.V., P.M. Satturwar, S.B. Joshi and A.K. Dorle, 2003. Study of the immunomodulatory activity of Haridradi ghrita in rats. Indian J Pharmacology., 35:51-54.
Sharififar, F., S. Pournourmohammadi and M. Arabnejad, 2009. Immunomodulatory activity of aqueous extract of Achillea wilhelmsii C. Koch in mice. Indian J. Exp. Biol., 47: 668-671.
Fulzele, S.V, P.M. Satturwar, S.B. Joshi and A.K. Dorle, 2003. Study of the immunomodulatory activity of Haridradi ghrita in rats. Indian J Pharmacology., 35:51-54.
Gayathri, V., V.V. Asha and A. Subramoniam, 2005. Preliminary studies on the immuno-modulatory and antioxidant properties of selaginella species. Indian J. Pharmacol., 37:381-385.
Joshi, S.B., P.M. Satturwar, S.V.Fulzele and A.K. Dorle, 2003. Study of the immunomodulatory activity of Haridradi ghrita in rats. Indian J Pharmacology., 35:51-54.
Kirtikar, K.R. and B.D. Basu, 1961. Indian Medicinal Plants. Lalit Mohan Basu Publications, Allahabad.
Kulkarni, A.V, B.D. Siraskar, S.S. Jadhav, S.M. Dhonde, A.S. Kulkarni and S.S. Bingi, 2007. Study of hydroalcoholic extract of <I>Portulaca oleracea</I> L. for immunomodulatory activity in mice. Indian J. Green pharmacy., 1,pp:45-49.
Kumar, P.V. R. Kuttan and G. Kuttan, 1999. Effect of “ Rasayanas” a herbal drug preparation on cell-mediated immune responses in tumor bearing mice. Indian J. Exp. Biol., 37:23-26.
Makare, N., S. Bodhankar and V. Rangari, 2001. Immunomodulatory activity of alcoholic extract of Mangifera indica L. in mice. J thnopharmacology., 78:133-137.
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Mitra, S.K, M. Gupta and D.N.K Sharma, 1999. Immunomodulatory effect of IM-133 Phytother Res., 13:341-343.
Sagrawat, H. and Y. Khan, 2007. Immunomodulatory plants: A phytopharmacological. pharmacognosy Rev., 1,pp: 248-260.
Fulzele, S.V., P.M. Satturwar, S.B. Joshi and A.K. Dorle, 2003. Study of the immunomodulatory activity of Haridradi ghrita in rats. Indian J Pharmacology., 35:51-54.
Sen, P., P.K. Mendiratta and A. Ray, 1992. Effects of Azadirachta indica on some biochemical, immunological and visceral parameters in normal and tressed rats. Indian J Exp Biol., 30: 1170-1175
Agarwal, S.S., S.C. Khadase and G.S. Talele, 2010. Studies on immunomodulatory activity of Capparis zeylanica leaf extracts. Int. J. Pharmaceutical sci. Nanotechnol., 3(1): 887-892
Ismail, S. and M. Asad, 2009.Immunomodulatory activity of Acacia catechu. Indian J Physiol Pharmacol., 53(1):25-33.
Vinothapooshan, G. and K. Kumar, 2011. Immunomodulatory activity of various extracts of Adhatoda vasica Linn. in experimental rats. African j. Pharmacy Pharmacl., 5(3):306-310
Wanger, H., 1990. Search for plant derived natural products with Immunostimulatory activity (recent advances). Pure Appl. Chemistry.,62:7:1217-1222.
Zhang, Z., Y. Yang and G. Xing, 2011. Immunomodulatory activity of polysaccharides from roots of actinidia kolomicta on macrophages. Int. j. biol., 3(2):

Tuesday, January 3, 2012

Monograph on Athimathuram


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 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 the Mediterranean 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.3 The isoflavones glabridin and
hispaglabridins A and B have significant antioxidant activity,4 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 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
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 u Volume 10, Number 3 u 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 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
© 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 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
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 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.
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