TABLE OF CONTENTS

Chapter Title Page No.

2. REVIEW OF LITERATURE 45-101

2.1 Curcuma longa Linn. 45-49

2.1.1 Pharmacological review of C. longa 47
2.2 Glycyrrhiza glabra Linn. 49-63
2.2.1 Pharmacological review of G. glabra 51
2.3 Terminalia chebula 63-74
2.3.1 Pharmacological review 65
2.4 Anthracinum 30 73-74

2.5 Drugs Showing Wound Healing Activity 74-75

2.6 Phytochemicals for wound healing activity 75-83

2.6.1 Polyphenols 75
2.6.2 Flavonoids 76
2.6.3 Tannins 77
2.6.4 Phenolic acids 78
2.6.5 Phenyl propanoids 78
2.6.6 Terpenes and terpenoids 79
2.6.7 Alkaloids 79
2.6.8 Saponins 80
2.6.9 Plant vitamins 80
2.6.10 Miscellaneous compounds 81
2.6.11 Plants having wound healing activity 81
Reference 84
CHAPTER 2 REVIEW OF LITERATURE

2. REVIEW OF LITERATURE

2.1 Curcuma longa Linn.

Haridra in Sanskit means, an efficacious drug for jaundice. It is known to be

one of the oldest spices that have been used in Western and Southern parts of
India for thousands of years and is a major part of Ayurvedic medicine. That
is why it is also avowed that this spice belongs to India indigenously and also
referred to as ‘Indian saffron’.

Originating in India, Turmeric had reached China by 700 AD, East Africa by
800 AD and West Africa by 1200 AD, and also had begun to become popular
all through the world. It is also known that the Arab traders had carried with
them turmeric to Europe in the 13th century.

Marco Polo, while on his several legendary voyages to India via the Silk
Route, was so impressed by turmeric that he had mentioned it as a vegetable
possessing properties of saffron, but actually is not saffron.1

Biological Source: Drug consists of dried rhizomes of Curcuma longa Linn.

belonging to family Zingiberaceae2

Part used: Rhizomes and Tubers

Figure 2.1 : Photograph of Curcuma longa Linn.

Taxonomic Hierarchy3
Kingdom : Plantae
Subkingdom : Viridaeplantae
Infrakingdom: Streptophyta

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Division : Tracheophyta
Subdivision : Spermatophytina
Infradivision : Angiospermae
Class : Magnoliopsida
Superorder : Lilianae
Order : Zingiberales
Family : Zingiberaceae
Genus : Curcuma L.
Species : Curcuma longa L.

Vernacular names3
Sanskrit : Haridra, Nisa
Bengali : Haldi, Halud
English : Turmeric, Saffron
Gujrati : Halada, Halder
Hindi : Haldi
Malayalam : Munjal
Marathi : Haldi
Tamil : Munjal
Telugu : Pasupu
Distribution: Hotter provinces of India, Ceylon, Malay Peninsula – Malay
Islands

Chemical Constituents

Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates

(69.4%) and moisture (13.1%). The essential oil (5.8%) obtained by steam
distillation of rhizomes has a-phellandrene (1%), sabinene (0.6%), cineol
(1%), borneol (0.5%), zingiberene (25%) and Sesquiterpenes (53%). Curcumin
(diferuloylmethane) (3–4%) is responsible for the yellow colour, and
comprises curcumin I (94%), curcumin II (6%) and curcumin III (0.3%).
Demethoxy and bisdemethoxy derivatives of curcumin have also been
isolated. Curcumin was first isolated in 1815 and its chemical structure was

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determined by Roughley and Whiting in 1973. It has a melting point at 176–

177°C; forms a reddish- brown salt with alkali and is soluble in ethanol, alkali,
ketone, acetic acid and chloroform.

2.1.1 Pharmacological review

Hepatoprotactive activity: Turmeric has been found to have a

hepatoprotective characteristic similar to silymarin. Animal studies have
demonstrated hepatoprotective effects of turmeric with a variety of
hepatotoxic insults, including carbon tetrachloride (CCl4)4,5, galactosamine6,
acetaminophen (paracetamol)7 and Aspergillus aflatoxin.8 hepatoprotective
effect of Turmeric is a result of its antioxidant properties, as well as its ability
to decrease the formation of proinflammatory cytokines. In rats with CCl 4-
induced acute and sub-acute liver injury, curcumin administration
significantly decreased liver injury in test animals compared to controls.8
Turmeric extract inhibited fungal aflatoxin production by 90%, when given to
ducklings infected with Aspergillus parasiticus. Turmeric and curcumin also
reversed biliary hyperplasia, fatty changes, and necrosis induced by aflatoxin
production.11 Sodium curcuminate, a salt of curcumin, also exerts choleretic
effects by increasing biliary excretion of bile salts, cholesterol, and bilirubin,
as well as increasing bile solubility, therefore possibly preventing and treating
cholelithiasis.9

Antioxidant Effects: Water and fat soluble extracts of turmeric and its
curcumin component exhibit strong antioxidant activity, comparable to
vitamins C and E510. A study of ischemia in the feline heart demonstrated that
curcumin pretreatment decreased ischemia-induced changes in the heart.11
An in vitro study measuring the effect of curcumin on endothelial heme-
oxygenase-1, an inducible stress protein, was conducted utilizing bovine
aortic endothelial cells. Incubation (18hrs) with curcumin resulted in
enhanced cellular resistance to oxidative damage.12

Anti-inflammatory Effects: The volatile oils and curcumin of C. longa exhibit

potent anti-inflammatory effects.13,14,15 Oral administration of curcumin in

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instances of acute inflammation was found to be as effective as cortisone or

phenylbutazone, and one-half as effective in cases of chronic inflammation.16
In rats with Freund’s adjuvant-induced arthritis, oral administration of C.
longa significantly reduced inflammatory swelling compared to controls. 15 In
monkeys, curcumin inhibited neutrophil aggregation associated with
inflammation. C. longa’s anti-inflammatory properties may be attributed to its
ability to inhibit both biosynthesis of inflammatory prostaglandins from
arachidonic acid, and neutrophil function during inflammatory states.
Curcumin may also be applied topically to counteract inflammation and
irritation associated with inflammatory skin conditions and allergies,
although care must be used to prevent staining of clothing from the yellow
pigment.

Cardiovascular Effects: Turmeric’s protective effects on the cardiovascular

system include lowering cholesterol and triglyceride levels, decreasing
susceptibility of low density lipoprotein (LDL) to lipid peroxidation, and
inhibiting platelet aggregation. These effects have been noted even with low
doses of turmeric. In a study of 18 atherosclerotic rabbits, turmeric extract
demonstrated decreased susceptibility of LDL to lipid peroxidation, in
addition to lower plasma cholesterol and triglyceride levels. The higher dose
did not decrease lipid peroxidation of LDL, but cholesterol and triglyceride
level decreases were noted, although to a lesser degree than with the lower
dose. Turmeric extract’s effect on cholesterol levels may be due to decreased
cholesterol uptake in the intestines and increased conversion of cholesterol to
bile acids in the liver. Inhibition of platelet aggregation by C. longa
constituents is thought to be via potentiation of prostacyclin synthesis and
inhibition of thromboxane synthesis.16,17

Antimicrobial Effects: Turmeric extract and the essential oil of Curcuma

longa inhibit the growth of a variety of bacteria, parasites, and pathogenic
fungi. A study of chicks infected with the caecal parasite Eimera maxima
demonstrated that diets supplemented with 1-percent turmeric resulted in a

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reduction in small intestinal lesion scores and improved weight gain.

Another animal study,18 in which guinea pigs were infected with either
dermatophytes, pathogenic molds, or yeast, found that topically applied
turmeric oil inhibited dermatophytes and pathogenic fungi, but neither
curcumin nor turmeric oil affected the yeast isolates. Improvements in lesions
were observed in the dermatophytes and fungi-infected guinea pigs, and at
seven days post-turmeric application the lesions disappeared. Curcumin has
also been found to have moderate activity19 against Plasmodium falciparum
and Leishmania major organisms.20

2.2 Glycyrrhiza glabra Linn.

Glycyrrhiza glabra Linn is commonly known as Yashti madhuh. It is one of the

most widely used herbs from the ancient medical history of Ayurveda, both
as a medicine and also as a flavoring herb. It is a very sweet, moist, soothing
herb that detoxifies and protects the liver and is also a powerful anti-
inflammatory, being used in conditions as varied as arthritis and mouth
ulcers.

G. glabra, also known as licorice and sweet wood, 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.

Liquorice has been used in medicine for more than 4000 years. The earliest
record of its use in medicine is found in ‘code Humnubari’ (2100 BC). It was
also one of the important plants mentioned in Assyrian herbal (2000BC).
Hippocrates (400BC) mentioned its use as a remedy of ulcers and quenching
of thirds. The drug was also mentioned by Theophrastus and Dioscorides. In
traditional Siddha system of medicine, liquorice is used as a demulcent,
expectorant, anti-tussive, laxative and sweetener21. It is used with success for
acute respiratory problems, gastric ulcers, gastritis, inflammatory conditions
in general and adrenal exhaustion. Components of licorice root have both

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estrogenic and anti-estrogenic activity. It is thus an important herb for

treating hormone-related female problem.22

Biological Source: Drug consists of dried rhizomes or stolons of G. glabra

belonging to family Leguminoceae

Part used: Roots and Rhizome (powder, teas, tonic, extracts, tinctures,
decoction)

Figure 2.2 : Photograph of Glycyrrhiza glabra Linn.

Taxonomic Hierarchy23
Kingdom : Plantae
Subkingdom : Tracheobionta
Superdivision: Spermatophyta
Division : Magnoliophyta
Class : Magnoliopsida
Superorder : Rosidae
Order : Fabales
Family : Fabaceae
Genus : Glycyrrhiza L.
Species : Glycyrrhiza glabra L.
Vernacular Names
Sanskrit: Yashti‐madhuh. Madhuka
Kannada: Yastimadhuka, atimaddhura
Hindi: Jothi‐madh, Mulhatti

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Malayalam: Iratimadhuram
Tamil: Atimaduram
Telugu: Atimadhuranu, Yashtimadhukam
English: Licorice, Liquorice, Sweet wood
Distribution: It is locally found in Bahariyah and Siwa oases. It is native of
Mediterranean region and middle East countries. Globally it is found in parts
of Asia and cultivated worldwide.

Chemical Constituents: A number of components have been isolated from

the roots of G. glabra, including a water-soluble, biologically active complex
that accounts for 40-50% of total dry material weight. This complex is
composed of triterpene saponin, flavonoids, polysaccharides, pectins, simple
sugars, amino acids, mineral salts, asparagines, bitters, essential oil, fat,
female hormone estrogen, gums, mucilage (Rhizome), protein, resins,
starches(30%), sterols, volatile oils, tannins, glycosides, and various other
substances.24,25

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% range. Among the natural
saponin, 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.
2.2.1 Pharmacological review

Anti-bacterial Activity: Shirazi et al. had studied the in vitro inhibitory effects
of G. glabra aqueous extract against the growth of Salmonella typhi, S. paratyphi
B, Shigella sonnei, S. flexneri and enterotoxigenic E. coli was investigated using
well and disc diffusion method. S. paratyphi B showed no susceptibility to
liquorice with concentrations lower than 7.5%, however all tested bacterial
strains exhibited susceptibility to high concentration of liquorice.26

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The antibacterial activities of the alcohol, ethyl acetate, acetone and

chloroform extracts of 5 plant species were studied. The extracts of G. glabra
roots showed various antibacterial activities against 13 bacterial [Link]
alcohol extracts did not inhibit B. subtilis var. niger, B. brevis, E. faecalis, L.
monocytogenes, P. aeruginosaand Y. enterocolitica. The ethyl acetate extracts did
not inhibit B. subtilis or Y. enterocolitica, and the acetone extracts did not
inhibit E. faecalis, L. monocytogenes, P. aeruginosaor Y. enterocolitica. The
chloroform extracts showed no inhibition effect against P. aeruginosaor Y.
enterocolitica.27

Alonso had studies the glycyrrhizin, habitually used as a vehicle in orally

administered products, where it inhibits the growth of some bacteria, as well
as dental plaque formation. In regards to its antibacterial action, in vitro
studies have demonstrated inhibitory effects for licorice aqueous and
ethanolic extracts on S. aureus and S. pyogenes cultures.28 It exhibited
antimicrobial activity against both Gram-positive and Gram-negative bacteria
by Gupta et al.29

Antioxidant Activity: Ashawat et al. had studied antioxidant activity of

extracts by using individual extract as well as its combination with equal
amount of ascorbic acid,indicated increased antioxidant activity via reducing
power with reference to equal amount of standard ascorbic acid.30

Visavadiya et al. showed antioxidant property of G. glabra root extracts using

in vitro models. Aqueous and ethanolic extracts demonstrated dose
dependent the scavenging activity against nitric oxide radicals. Further, both
extracts showed strong reducing power and iron-chelating capacities. In the
Fe2+/ascorbate system, both extracts were found to inhibit mitochondrial
fraction lipid peroxidation. In copper-catalyzed human serum and low
density lipoprotein oxidation models, both extracts significantly (P<0.05)
lengthened the lag phase along with a decline in the oxidation rate,
conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive
substance formation. So, ethanolic extract of G. glabra possess considerable

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antioxidant activity and protective effect against the human lipoprotein

oxidative system.31 Glycyrrhetic acid is used in cosmetics as a wound healer,
anti-inflammatory and decongestant agent; it is applied as emulsion, talcum
powder or toothpaste. Its antioxidant properties have been evidenced through
its inhibition of lipid peroxidation in rat liver, and its protective action on
mitochondrial functions under oxidative stress. A marked decrease in the
catalase enzyme activity was detected in the blood of these animals. Thus,
licorice-eco extract is helpful to formulate cosmetic products for the protection
of skin and hair against oxidative processes.

The hydroalcoholic extracts of G. glabra exhibited anti-inflammatory activities

evaluated for the possible mode of action by studying their antioxidant
potential. They investigated if standardized hydroalcoholic extracts of plants
such as G. glabra produced by Hofigal Stock Company could modulate the
respiratory burst of human activated neutrophils, as a consequence of their
antioxidant capacity.

Enzyme Inhibitory Activity: Zuidhoff et al. had shown in vitro inhibition of

the tyrosinase enzyme by methanol extract of licorice. Active principles able
to inhibit tyrosinase act by modifying the action site of the enzyme, thus
reducing its activity. Most of tyrosinase inhibitors are reducing agents, which
produce their effects through their reducing capacity. Thus, licorice-eco
extract is of great use to formulate cosmetic products with depigmenting
activity.32 Isoliquiritigenin inhibited rat lens aldose-reductase using DL-
glyceraldehyde as substrate. Licochalcones A and B, licopyranocoumarin,
licoarylcoumarin, licocoumarone, glycyrrhisoflavone and glisoflavone
inhibited xanthine oxidase.33

Antifungal activity: Hojo and Sato were screening antifungal compounds

from various plant materials. Oil-based extract of licorice; OEL) was found to
have high fungicidal effect against Arthrinium sacchari M001 and Chaetomium
funicola M002, and its active compound was identified as glabridin (3-(2’,4’-
dihydroxyphenyl)-8-dimethylpyrano [8,7-e]chroman). OEL was effective

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against not only filamentous fungi but also some bacteria, especially thermo-
resistant bacilli such as genera of Bacillus and Alicyclobacillus.31 Glabridin to
be active against both yeast and filamentous fungi and also showed resistance
modifying activity against drug resistant mutants of Candida albicans at a MIC
of 31.25-250mg/ml by Fatima al.34 In regards to its antifungal action, in vivo
inhibition of Mycobacterium smegmatis and Candida albicans has been reported,
which was attributed to the action of isoflavonoids such as glabridin, glabrol
and derivatives of these. A recent study demonstrated the inhibitory effects of
a licorice root aqueous extract (MIC=1.56mg/ml) on cultures of Candida
albicans, which had been obtained from mouth lesions of 5-months old infants.
These results support the use of licorice based mouthwash to treat candida-
induced lesions in HIV patients. Therefore, licorice-eco extract is of great use
to formulate cosmetic products with purifying and antiseptic activities.

Antihyperglycemic Activity: Kalaiarasi et al. had studied antihyperglycemic

effect of 18β-glycyrrhetinic acid, aglycone of glycyrrhizin, on streptozotocin-
diabetic rats. Oral administration of 18β-glycyrrhetinic or glibenclamide, for
45 days, prevented the above changes and improved towards normalcy.35,36

Antimalarial Activity: The Chinese pharmacopoeia accepts G. glabra, G.

uralensis and G. inflata, as sources of Gan Cao. The chalcone licochalcone A
isolated from all Glycyrrhiza species in different amounts and had shown
good antimalarial activity. In in vivo tests against P. yoelii in mice resulted in
complete eradication of the malaria parasite without toxicity.37 The burden of
malaria is getting worse, mainly due to the increasing resistance of P.
falciparum against the widely available antimalarial drugs.

Licochalcone A inhibited in vitro growth of both chloroquine-susceptible

(3D7) and chloroquine-resistant (Ddz) strains of P. falciparum to same extent in
[3H] hypoxanthine uptake assay.

There is an urgent need for new, more affordable and accessible antimalarial
agents possessing original modes of action. Natural products have played a
dominant role in the discovery of leads for the development of drugs to treat

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human diseases. Batista had published review covering nonalkaloidal natural

compounds from plants with antiplasmodial and antimalarial properties,
belonging to the classes of terpenes, limonoids, flavonoids, chromones,
xanthones, anthraquinones, miscellaneous and related compounds.38

Anti-viral and Immunostimulatory effects Ammonium glycyrrhinate (amide

of the glycyrrhetinic acid) showed antiviral activity against vaccinia, herpes
simplex 1 and the vesicular stomatitis virus. In chicken embryos, licorice root
saponins inhibited the development of type A influenza virus, possibly due to
interferon production, as it was found in other studies about the saponin
glycyrrhizin. An in vitro study evidenced the inhibitory action of glycyrrhizin
on HIV cultures. An in vitro assay carried out in Germany, demonstrated that
glycyrrhizin inhibited the SARS virus (coronavirus, which causes atypical
pneumonia), more efficiently than synthetic drugs (ribavirin, 6-azauridine,
pyrazofurin, mycophenolic acid). Even when the action mechanism is still
unclear, evidences indicate that glycyrrhizin acts by stimulating nitric oxide
synthesis, via nitric oxide synthase. Most of the Glycyrrhiza phenols reduced
the viable cell number of mock-infected and HIV-infected MT-4 cells to
comparable extents.39 G. glabra showed immunostimulatory effects in by
increasing TCD69 lymphocytes production and macrophage production from
human granulocytes. Additionally, glycyrrhizin has been reported to be
involved in the decrease of IgG and IgA (P<0.01), which plays an essential
role in hypersensitivity mechanisms. Recent studies carried out with rats,
demonstrated that glycyrrhizin inhibited the Arthus phenomenon and the
Schwartzman reaction, and that the alcohol extract of licorice root inhibited
type I allergic reactions induced by injection of Ascaris lumbricoides IgE
containing serum. Furthermore, in vivo assays have shown that licorice root
extracts prevented the rise in the amount of immune-complexes associated to
some autoimmune conditions, such as systemic lupus erythematosus. It is
known that the activation of the immune system slows down with age, which
results in decreased cell regeneration. Therefore, licorice-eco extract is helpful
to treat aged skin. Utsunomiya et al studied immunostimulatory properties of

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glycyrrhizin by infecting BALB/c mice with influenza virus A2 (H2N2), were

unable to survive 10 times the mean lethal dose (LD50) of virus.40 Sekizawa et
al reported that the transplanting of splenic T-cells from glycyrrhizin-treated
mice conferred resistance to infected mice that had not been treated with
glycyrrhizin. The transplanting of other splenic cell subsets did not improve
the survival of infected mice, indicating that glycyrrhizin was a specific
inhibitor of the cell-mediated immunological response. The administration of
γ-interferon monoclonal antibody to infected mice blocked the anti-viral
activity of glycyrrhizin treatment. These results confirm that the anti-viral
activity of glycyrrhizin is due to its stimulating of γ-interferon production by
T-cells. Glycyrrhizin has also been demonstrated as effective in the treatment
of herpes simplex-induced encephalitis in mice.41 Licorice and glycyrrhizate
compounds have long been used in the treatment of chronic viral hepatitis in
China and Japan but the possible mechanism of anti-viral activity remains
unknown. In vitro studies have demonstrated that glycyrrhizin is effective at
inhibiting the growth of a host of viruses under culture conditions including
pathogenic flaviviruses,42 alphaviruses,43 and herpes simplexvirus.44 Studies
such as these suggest a direct effect of glycyrrhizin on viral growth, possibly
through an inhibition of viral particle to cell membrane binding, replication
mechanisms, or through cellular signal transduction mechanisms. In vivo and
human studies tend to agree with the anti-viral efficacy of glycyrrhizin, but
the mechanism of action may be more complex and promote an immune
response. Aqueous extract of the root is reported to inhibit the spinach mosaic
virus.

Memory Enhancing Activity: Dhingra et al. had studied to investigate the

effects of G glabra on learning and memory in mice by elevated plus-maze and
passive avoidance paradigm to test learning and memory. The aqueous
extract of liquorice significantly improved learning and memory of mice.
Furthermore, it significantly reversed the amnesia induced by diazepam.
Antiinflammatory and antioxidant properties of liquorice may be contributing
favorably to the memory enhancement effect. Since scopolamine-induced

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amnesia was reversed by liquorice, it is possible that the beneficial effect on

learning and memory was due to facilitation of cholinergic transmission in
mouse brain. However, further studies are necessitated to identify the exact
mechanism of action. In the present investigation, G. glabra has shown
promise as a memory enhancing agent in all the laboratory models
employed.45

Expectorant Activity: While the specific mechanism of action remains

unknown, Glycyrrhiza has been shown to work as effectively as codeine in the
throat, decreasing irritations and producing expectorant effects. One
proposed explanation is that in the same way that carbenoxolone, a
semisynthetic compound derived Murray from Glycyrrhiza, is able to
stimulate gastric mucus secretion, it is also able to stimulate tracheal mucus
secretions and hence produce demulcent and expectorant effects.46 Licorice is
a helpful remedy for coughs as it facilitates the movement of mucus from the
respiratory tract.47

Spasmolytic Activity: Mills et al. showed that liquiritin present in the roots of
Glycyrrhiza is inactive as an antispasmodic. However when hydrolysed by
heat and converted to isoliquiritigenin, it was shown to exhibit strong
spasmolytic activity.48

Antiallergic activity: Glycyrrhizin, 18β glycyrrhetinic acid and Liquiritigenin

have antiallergic activity, which can relive IgE – induced allergic diseases
such as dermatitis and asthma.49

Anti-Ulcer Activity: The effects of Pepticare (a herbomineral formulation of

the Ayurveda medicine consisting of the herbal drugs: G. glabra E. officinalis
and T. cordifolia) on gastric secretion and gastric ulcers in pylorus ligation and
on ethanol-induced gastric mucosal injury in rats. The reduction in ulcer
index in both the models along with the reduction in volume and total acidity,
and an increase in the pH of gastric fluid in pylorus-ligated rats proved the
anti-ulcer activity of Pepticare. It was also found that Pepticare was more
potent than G. glabra alone in protecting against pylorus-ligation and ethanol-

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induced ulcers. The increase in the levels of superoxide dismutase, catalase,

reduced glutathione and membrane bound enzymes like Ca2+ ATPase, Mg2+
ATPase and Na+ K+ ATPase and decrease in lipid peroxidation in both the
models proved the anti-oxidant activity of the formulation. Thus it can be
concluded that Pepticare possesses anti-ulcer activity, which can be attributed
to its anti-oxidant mechanism of action.50

Glycyrrhizic acid and its aglycon occurs in the form of the two stereoisomers,
18β (cis) and 18ά (trans). The 18β GA isomer extracted from the root of
licorice has anti viral, expectrorant, antitumor and antiulcer effects.48

Perhaps the most predominant and consistent medicinal use for licorice as a
demulcent for the digestive system, indeed, carbenoxolone, a widely used
pharmaceutical treatment for gastric ulcers, is a synthetic derivative of
glycyrrhetic acid.

Bennett et al.51 demonstrated using a rat model of aspirin-induced gastric

mucosal damage. The anti-ulcer effects of licorice extract may be due to
reduced gastric secretions caused by an inhibition of gastrin release. The
results from clinical studies evaluating the efficacy of deglycyrrhizinated
licorice suggest that several components exist in the extract, which promote
gastric healing, although inconsistencies are apparent between these studies.

Botanical compounds with anti-ulcer activity include flavonoids (i.e.

quercetin, naringin, silymarin, anthocyanosides, sophoradin derivatives)
saponins (i.e. from Panax japonicus and Kochia scoparia), tannins (i.e. from
Linderae umbellatae), gums and mucilages (i.e. gum guar and myrrh). Among
herbal drugs, liquorice, aloe gel and capsicum (chilli) have been used
extensively and their clinical efficacy documented.52,53

Hepatoprotective effeces: Watari studied the protective role of glycyrrhetic

acid in animal and human models when liver cells are challenged. It decreases
inflammatory states by reducing cytokines like tumor necrosis factor-alpha
and increasing protective antioxidants like heme oxygenase-1. These shielded
tissues release fewer markers of liver damage, repairing and regenerating

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them more rapidly. The hepatoprotective properties of glycyrrhizin in

hepatotoxin (3’- methyl-4-dimethylaminoazobenzene) treated mice. Animals
treated with glycyrrhizin had a reduced incidence of hepatic cells showing
morphological evidence of injury, including degenerated mitochondria,
increased number660 of lysosomes, atrophied Golgi apparatus,
pseudonuclear inclusions and increased mitotic cells.54 Glycyrrhizin was
found to significantly inhibit the CCl4-induced release of AST and LDH due
to an alteration of membrane fluidity by the glycyrrhizin, or perhaps an
inhibition of CCl4-induced membrane lipid peroxidation. Glycyrrhizin
exhibited no significant suppressive activity of free radical generation,
whereas 18β-glycyrrhetic acid inhibited this activity. Hepatoprotective
mechanism of glycyrrhizic acid is due to its aglycone, 18β glycyrrhetic acid,
which inhibits both free radical generation as well as lipid peroxidation. The
in vivo protection of glycyrrhizin against CCl4- induced hepatotoxicity was
more recently illustrated by Jeong.55 Extracts of herbal plants G. glabra showed
a novel hepatoprotective effects against diclofenac –induced hepatotoxicity in
rats.56 Glycyrrhizin reduced the mortality of acetaminophen overdosed mice
more effectively, attenuate acetaminophen-induced hepatotoxicity, and
reduced the number and area of γ-GT positive foci, thus protecting liver
function was illustrated by Xu-ying.57

Anticonvulsant: Shirish et al. used lithium-pilocarpine model of status

epileptics to assess the anticonvulsant activity using maximum electroshock
seizure (MES) test and pentylenetetrazol (PTZ) using albino mice and rats.
The ethanol extract of G. glabra did not reduce the duration of tonic hind leg
extension in the MES test. However, the extract significantly and dose
dependently delayed the onset of clonic convulsions induced by
pentylenetetrazol. The extract also protected rats against seizures induced by
lithium-pilocarpine.58

Antiinflammatory: Alonso showed anti-inflammatory activity of glycyrrhetic

acid with 1/8 potency as compared to cortisol; this activity reaches 1/5

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potency, if glycyrrhetic acid is administered as sodium hemisuccinate

(identical to carbenoxolone). Other flavonoid components of licorice root,
such as liquiritoside, have also shown in vitro inflammatory activity. The
activity of 18-α-glycyrrhetic acid was found to be stronger than that of its β
isomer, and similar to that of glucocorticoids. Both glycyrrhizin and its
aglycone have mineralocorticoid effects due to the inhibition of hepatic D’-5-
β-reductase. The modifications that glycyrrhetic acid and hydrocortisone
produce on the activity of certain enzymes have been correlated with their
anti-arthritis effects, due to the structural similarity of both compounds and
their activity at the suprarenal level. Both glycyrrhizic acid and glycyrrhetic
acid inhibited leukocyte migration towards swollen areas in animal models.
Glycyrrhizin inhibited activated peritoneal macrophages, phospholipase A
activity and prostaglandin E2 synthesis. Liquiritoside demonstrated
experimental inhibition of ciclooxygenase, lipooxygenase and platelet
peroxidase. In animal assays, glyderinine (a glycyrrhizic acid derivative)
showed stronger antipyretic, analgesic and anti-inflammatory activities than
hydrocortisone and amidopyrine; unlike other anti-inflammatory drugs, it
did not damage the gastroduodenal mucosa. Applied as an ointment, it
showed very good penetration in the skin and tolerability. In this regard, a
0.1% glycyrrhizin concentration in a gel or an emulsion, increased penetration
of externally applied Diclofenac sodium. [14] Glycyrrhetinic acid inhibits the
enzyme 11-betahydroxy steroid dehydrogenase, which is responsible for
converting cortisol, the active form into its inactive metabolites. Thus
inhibition of the enzyme by glycyrrhetinic acid significantly increases the
levels of cortisol and also stimulation of the glucocorticoid receptors. This in
turn potentiates the action of hydrocortisone, the main glucocorticoid secreted
by the adrenal cortex.59

Anti-carcinogenic Effects: Wang evaluated anti-carcinogenic effects of

licorice extract and glycyrrhizate compounds.60 The in vitro anti-mutagenic
properties of triterpene compounds, such as glycyrrhizin, have been well
documented, although the mechanism of this action is still poorly understood.

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An early report on the anti-mutagenic effects of glycyrrhizin and glycyrrhetic

acid demonstrated, using a modified Ames test, that both of these compounds
inhibited the mutagenicities of 3-amino-1-methyl-5H-pyrido[ 2,3-b]indol (Trp-
p-2), 2-acetyl aminofluorene, and benzo(α)pyrene, in the presence S9 fraction
hepatic enzymes.61 When the assay was repeated using mutagens not
requiring metabolic activation, such as methyl glyoxal, glyceraldehyde and
glucose pyrolysate, glycyrrhizin inhibited the number of induced S.
typhimurium TA98 revertants, whereas glycyrrhetic acid promoted the
number of revertants per plate. Ikken et al. speculated glycyrrhetic acid may
act by inhibiting the metabolic activation of some mutagens. Both licorice
extract and glycyrrhizin inhibited the mutagenic effects of Trp-p-1 and Trp-p-
2 in S. typhimurium TA98 whereas licorice extract exerted a moderate to strong
antimutagenic effect against several N-nitrosamine mutagens.62 Licorice
extract and glycyrrhizin were also effective at inhibiting the mutagenic effects
of metabolically pre-activated Trp-p-1, suggesting that the antimutagenic
effects are not due solely to the inhibition of the activating enzymes in order
to elucidate the inhibition mechanism of chemically induced mutagenicity by
licorice extract, glycyrrhizin, 18β and 18α glycyrrhetic acid. Only the licorice
extract was antimutagenic towards ribose–lysine, suggesting that a
nonglycyrrhizin compound is the active antimutagenic component of this
extract. However, licorice extract was not antimutagenic to the activities of the
frameshift mutagens 9-aminoacridine or acriflavine, suggesting a specificity
in its mechanism of action. These results led to the possibility that the root
extract might be acting as an antimutagen either by enhancing a DNA repair
response or by directly interfering with the mutagen. Glycyrrhetic acid
inhibited the growth of B16 cells in a concentration-dependent manner.

Several studies have been conducted on the effects of licorice and glycyrrhizin
on the growth and acid production of oral bacteria associated with the
development of dental caries. Glycyrrhizin could significantly reduce the
growth and acid production of Streptococcus, Actinomyces, and Bacterionema
species. Licorice powder, ammoniated glycyrrhizin, and monoammonium

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glycyrrhetic acid competitively reduced the metabolism of sucrose, glucose,

and fructose, but were themselves minimally fermentable. In contrast to these
results, Segel R et al. reported that neither licorice “juice,” nor glycyrrhizin
inhibited the growth of seven Streptococcus mutans strains. In the presence of
sucrose, 0.5–1% glycyrrhizin had no effect on growth, but significantly
inhibited bacterial adherence to glass by nearly 100% at the highest
concentration tested.63 Licorice juice had similar anti-adherent properties with
concentrations of 5 and 10% providing almost 100% activity. The buffering
capacity of glycyrrhizin was not sufficient to affect the fall in pH caused by
bacterial sucrose degradation. In an additional study evaluating the
mechanism of the anti-adherent property of glycyrrhizin,64 examined by Sela
MN et al its effect on bacterial glucosyltransferase activity —an enzyme
required in the formation of insoluble glucans required in plaque
development. A crude preparation of S. mutans glucosyltransferase was
significantly inhibited by glycyrrhizin in a concentration-dependent manner.
At 12mM glycyrrhizin there was a 50% inhibition of total glucan formation
and a 90% inhibition of adhered glucans formation. Although glycyrrhizin
was able to inhibit the activity of the soluble glucan-forming
glucosyltransferase, the IC50 was 36mM. The authors concluded that
inhibition of bacterial glucosyltransferase activity may be a mechanism by
which glycyrrhizin inhibits oral bacterial adherence, but that additional
enzyme systems may also be affected.

Miscellaneous Studies: Glycyrrhizin has been tested to determine its

interaction with cellular membranes of erythrocytes and hepatic lysosomal
preparations. Glycyrrhizin was found to protect erythrocytes against the
hemolysis induced by other saponin compounds including digitonin, excin,
tomatin, and saponin A.65 The effect of glycyrrhizin was concentration-
dependent but it was only effective at preventing hemolysis at concentrations
approximately 400 times greater than the hemolysin. Glycyrrhizin was found
to be as efficacious against the sapogenins digitogenin, tomatidine, and
sapogenin A, indicating that its mechanism of action is not the result of the

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inhibition of membrane glycosidases of erythrocytes. The possibility remains

that glycyrrhizin prevents access of hemolysin to its receptor, or alters
membrane fluidic dynamics at these high concentrations. To test this
possibility, Nakagawa K investigated the effects of glycyrrhizin on the release
and activity of acid phosphatases from hepatic lysosomal preparations. Both
glycyrrhizin and 18β glycyrrhetic acid attenuated acid phosphatase activity,
but did not affect β-N-acetylglucosaminidase activity. The reduction of
lysosomal acid phosphatase activity was due to its release from the lysosomes
rather than a direct inhibition of the enzyme suggesting an alteration in
membrane fluidity.66

2.3 Terminalia chebula

Terminalia chebula is a popular traditional medicine not only used in India but
also in other countries of Asia and Africa. This is used in traditional medicine
due to the wide spectrum of pharmacological activities associated with the
biologically active chemicals present in this plant. It is used for the treatment
of number of diseases like cancer, paralysis, cardio vascular diseases, ulcers,
leprosy, arthritis, gout, epilepsy etc. It has been reported as antioxidant67,
antidiabetic68, antibacterial69, antiviral70, antifungal, antiulcer, antimutagenic,
wound healing activities etc.

T. chebula is routinely used as traditional medicine in the name of ‘Kadukkaai’

by tribal of Tamil Nadu in India to cure several ailments such as fever, cough,
diarrhea, gastroenteritis, skin diseases, candidiasis, urinary tract infection and
wound infections.71 Antibacterial activity of T. chebula extracts against several
bacterial strains has been reported.72 Extracts from different parts of diverse
species of plants like root, flower, leaves, seeds, etc. exhibit antibacterial
properties were applied on cotton material for wound, healthcare care
application.73

It is used extensively in the preparation of many Ayurvedic formulations for

infectious diseases such as chronic ulcers, leucorrhoea, pyorrhoea and fungal
infections of the skin.

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Biological Source: Drug consists of dried fruits of Terminalia Chebula Retz.

belonging to family combretaceae

Part used: Fruits

Figure 2.3 : Photograph of Terminalia Chebula Retz.

Taxonomic Hierarchy74
Kingdom : Plantae
Subkingdom : Tracheobionta
Superdivision: Spermatophyta
Division : Magnoliophyta
Class : Magnoliopsida
Superorder : Rosidae
Order : Myrtales
Family : Combretaceae
Genus : Terminalia L.
Species : Terminalia chebula (Gaertn.) Retz.
Vernacular Names
Filipino : Chebulic myrabolan
French : Myrobolan noir
Tibetan : Somz moox kh'ook
Malay : Manja puteri (unripe fruits)
Thai : Samo thai (central)
Vietnamese : Chieu lieu xanh
Sanskrit and Bengali: Haritaki

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Hindi : Harad
Marathi and Gujrati : Harada
Telugu : Karkchettu
Tamil : Kadukkaya
Distribution: T. chebula occurs naturally from the sub-Himalayan region of
Nepal and northern India, through India to Sri Lanka, Burma, Thailand, Indo-
China and southern China. It has been introduced to Singapore, where it
failed, but it was planted successfully in the botanical garden in Bogor, Java. It
was also introduced to Peninsular Malaysia.75

Chemical Constituents: In T. chebula, 33% of the total phytoconstituents are

hydrolysable tannins (which may vary from 20-50%) and are responsible for
pharmacological activity. These tannins contain phenolic carboxylic acid like gallic
acid, ellagic acid, chebulic acid and gallotannins such as 1,6 di-O galloyl-β-D-glucose,
3,4,6 tri-O-galloyl-β- D-glucose, 2,3,4,6 tetra-O-galloyl-β-D-glucose, 1,2,3,4,6 penta-
Ogalloyl-β-D-glucose. Ellagitannin such as punacalagin, casurarinin, corilagin and
terchebulin and others such as chebulanin, neochebulinic acid, chebulagic acid and
chebulinic acid reported in literature. The tannin content varies with the geological
variation. Flavonol glycosides, triterpenoids, coumarin conjugated with gallic acid
called chebulin, as well as phenolic compounds were also isolated.76 Various
methods have been reported for extraction of phytoconstituents from T. chebula for
studying their pharmacological activities. total eight compounds viz. gallic acid,
methyl gallate, ethyl gallate, chebulagic acid, tetra-O-galloyl-β-D-glucose, ellagic
acid, chebulinic acid and penta-O galloyl-β-D-glucose from T. chebula were isolated
on reverse phase chromatography.77 There are seven varieties of T. chebula all of
which are more or less used in similar fashion but vary in specific usages and
quality.78

2.3.1 Pharmacological review

Antibacterial activity: Two antibacterial compounds, gallic acid and ethyl

ester against methicillin-resistant Staphylococcus, have been isolated from ethyl
alcohol extract of fruits of T. chebula.79 Various extracts of T. chebula exhibit
antibacterial activity against a number of bacterial species.80 T. chebula is well
effective against Helicobacter pyroli, a bacterium responsible for gastritis, ulcer

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and stomach cancers. The ether, alcoholic and aqueous extracts of T. chebula
were tested against Helicobactor pylori, but aqueous extract of the plant, at a
concentration of 1-2.5 mg/ml, inhibited urease activity of H. pylori.81 Several
biologically active components were isolated from butanol fraction of fruit
extract of T. chebula and tested against six intestinal bacteria. Ethanedioic acid
showed strong and moderate inhibitory activity against Clostridium perfringens
and Escherichia coli, respectively, with no adverse effects on the growth of the
four tested lactic acid-producing bacteria. Ellagic acid exerted a potent
inhibitory effect against C. perfringens and E. coli, but little or no inhibition
was observed for behenic acid, β-caryophyllene, eugenol, isoquercitrin, oleic
acid, α-phellandrene, β-sitosterol, stearic acid, α-terpinene, terpinen-4-ol,
terpinolene, or triacontanoic acid.82 The ethanolic extract of T. chebula fruit
was found effective against both gram-positive and gram-negative bacteria
such as Salmonella typhi SSFP 4S, Staphylococcus epidermidis MTCC 3615,
Staphylococcus aureus ATCC 25923, Bacillus subtilis MTCC 441 and Pseudomonas
aeruginosa ATCC 27853 suggesting its broad spectrum antimicrobial activity.83

Antifungal activity: Aqueous extract of T. chebula reported to show antifungal

activity against a number of dermatophytes (e.g. Epidermophyton, Floccosum,
Microsporum gypseum and Tricophyton rubrum) and yeasts (e.g. Candida
albicans).84,85,86 Aqueous, alcoholic and ethyl acetate extracts of leaves of T.
chebula were found effective compared to that of the reference standard
Carbendazim.87

Antiamoebic and immunomodulatory activities: The antiamoebic effect of a

crude drug formulation of T. chebula was investigated in experimental caecal
amoebiasis in rats with a curative rate due varying degrees of inhibition of
enzyme activities such as DNase, RNase, aldolase, alkaline phosphatase, acid
phosphatase, α-amylase and protease in axenically cultured amoebae.88 It was
evaluated in experimental amoebic liver abscess in golden hamsters and in
immunomodulation studies. The formulation had a maximum cure in hepatic
amoebiasis. In immunomodulation studies, humoral immunity was enhanced

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where T-cell counts remained unaffected in the animals, but cell-mediated

immune response was stimulated.89

Antiplasmodial activity: The water extract of T. chebula showed

antiplasmodial activity in vitro by its ability to inhibit the uptake of [3H]
hypoxanthine into the P. falciparum K1 multidrug-resistant strain and in vivo.90
Acetone seed extract of T. chebula was also found to have good antiplasmodial
activity in a study.91

Molluscicidal activity: The molluscicidal activity of ethanolic extract of T.

chebula fruit powder was studied against the vector snail Lymnaea acuminata
and was found time and concentration dependent. Column, thin layer and
high performance liquid chromatography analyses demonstrated that the
active molluscicidal component in T. chebula was tannic acid. Hence, T. chebula
could be a potent source of molluscicides against the snail L. acuminate.92

Anthemintic activity: The ovicidal and larvicidal activities of ethyl acetate,

acetone, and methanol extracts of dried leaves and seeds of T. chebula were
tested in vitro on Haemonchus contortus based on egg hatch and larval
development assays and showed inhibition.93

Antiviral activity: The extract of fruits of T. chebula showed inhibitory effects

on human immunodeficiency virus-1 reverse transcriptase.94 Hot water
extract of T. chebula showed anti-herpes simplex virus (HSV) activity in vivo
and anti-cytomegalovirus (CMV) activity both in vitro and in vivo in a study.95
A study proved that T. chebula fruits contain four human HIV-type 1 integrase
inhibitors such as gallic acid and three galloyl glucoses, and suggested that
galloyl moiety had a major role for inhibition of the 3′-processing of HIV-1
integrase by these compounds.96 T. chebula can also be used in sexually
transmitted diseases and AIDS.97 Acetone extract of T. chebula has emerged as
a new alternative to treat pandemic swine influenza A infection due to its low
cost, easy preparation and potential effect.98 Herpes simplex virus 1 (HSV-1)
is the cause of lifelong latent infection of sensory neurons. Two hydrolyzable
tannins, chebulagic acid and punicalagin, isolated from the dried fruits of T.

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chebula inhibited HSV-1 entry at non-cytotoxic doses in A549 human lung

cells by preventing binding, penetration, and cell-to-cell spread, as well as
secondary infection.99

Antimutagenic and anticarcinogenic activities: The effect of 70% methanol

fruit extract of T. chebula was studied on growth of several malignant cell lines
including a human (MCF-7) and mouse (S115) breast cancer cell line, a human
osteosarcoma cell line (HOS-1), a human prostate cancer cell line (PC-3) and a
non-tumorigenic, immortalized human prostate cell line (PNT1A) using
assays for proliferation (3H-thymidine incorporation and coulter counting),
cell viability (ATP determination) and cell death (flow cytometry and Hoechst
DNA staining). ). In all cell lines studied, the extract decreased cell viability,
inhibited cell proliferation, and induced cell death in a dose dependent
manner. Acetone extract of T. chebula contain phytochemicals with promising
antimutagenic and anticarcinogenic properties.100 One of the fractionated
compounds from ethanol fruit extract of T. chebula, chebulagic acid, showed
potent dual inhibition against COX and 5-LOX. It also showed anti-
proliferative activity against HCT-15, COLO-205, MDA-MB-231, DU-145 and
K562 cell lines.101
Antioxidant activity: In a study, 6 extracts and 4 pure compounds of T.
chebula exhibited anti-lipid peroxidation, anti-superoxide radical formation
and free radical scavenging activities at different magnitudes of potency.102
The aqueous extract of T. chebula protected the antioxidant enzymes from
reactive oxygen species (ROS) produced by gamma radiation in the rat liver
microsomes and mitochondria. The ethanol extract of the fruits of T. chebula
decreased the level of lipid peroxidase in albino rats.103 Both treatment and
pretreatment of the cultured rat primary hepatocytes with T. chebula aqueous
fruit extract significantly reversed the t-BHP-induced cell cytotoxicity and
lactate dehydrogenase leakage. In addition, T. chebula extract exhibited in vitro
ferric-reducing antioxidant activity and 2,2-diphenyl-1-picryhydrazyl free
radical-scavenging activities. Histopathologic examination of the rat livers
showed that T. chebula extract reduced the incidence of liver lesions including

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hepatocyte swelling and neutrophilic infiltration, and repaired necrosis

induced by t-BHP.104 Further, a hepatoprotective compound, isolated from the
ethanol extract of the fruits of T. chebula, was identified as a mixture of
chebulic acid and its minor isomer, neochebulic acid that also reduced the
tert-butyl hydroperoxide (t-BHP)-induced cell cytotoxicity in isolated rat
hepatocyte experiment.105 An aglycone isolated from the fruits of T. chebula,
triethylchebulate, significantly inhibited FeSO4 /Cys-induced microsomes
lipid peroxidation and protected both H2O2- -induced RBCs hemolysis and
RBCs auto-hemolysis in a dose-dependent manner. Furthermore,
triethylchebulate demonstrated potent DPPH free-radical scavenging ability
and moderately suppressed azide-induced mitochondria ROS formation. The
results demonstrated that triethylchebulate was a strong antioxidant and free-
radical scavenger, which might contribute to the anti-oxidative ability of T.
chebula.106

Antidiabetic and retinoprotective activities: Oral administration of methanol

extract of T. chebula reduced the blood sugar level in normal and alloxan
diabetic rats significantly within 4h. Continued daily administration of the
drug produced a sustained effect.107 The chloroform extract of T. chebula seeds
produced dose-dependent reduction in blood glucose of diabetic rats in both
short term and long term study. Renoprotective activity was also observed in
T. chebula treated rats.108 Oral administration of ethanol extract of fruits of T.
chebula reduced the levels of blood glucose and glycosylated hemoglobin in
streptozotocin (STZ)-induced experimental diabetic rats.109 Aqueous extract of
T. chebula reduced the elevated blood glucose and increase in glycosylated
hemoglobin. It also showed a marked improvement in controlling the
elevated blood lipids as well as decreased serum insulin levels. The in vitro
studies with pancreatic islets showed that the insulin release was nearly two
times more than that in untreated diabetic animals without producing toxicity
on liver and kidney function tests.110

Antianaphylactic and adaptogenic activities: T. chebula along with several

other medicinal plants helps to resist against a number of stressors in different

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ways.111 T. chebula, when given following anaphylactic shock, reduces the

serum histamine level showing a strong antianaphylactic activity.112

Antinociceptive activity: The petroleum ether, chloroform, ethanol and water

extracts of T. chebula fruits were evaluated for their analgesic activity using
the tail immersion model in mice. The ethanolic extract of the plant exhibited
analgesic response in acute and chronic pain studied with maximum
analgesic response on 14th day. The results suggested that T. chebula could be
a potential candidate for bioactivity-guided isolation of natural analgesic
agents in the management of chronic pain.113

Antiulcerogenic activity: Animals pretreated with hydroalcoholic extract of

T. chebula showed reduction in lesion index, total affected area and percentage
of lesion in comparison with control groups in the aspirin, ethanol and cold
restraint stress-induced ulcer models. The T. chebula extract increased mucus
production in aspirin and ethanol-induced ulcer models and showed
antisecretory activity in pylorus ligated model leading to a reduction in the
gastric juice volume, free acidity, total acidity, and significantly increased
gastric pH.114

Anti-arthritic activity: The hydroalcoholic extract of T. chebula produced a

significant inhibition of joint swelling as compared to control in both
formaldehyde-induced and CFA-induced arthritis. T. chebula treatment also
reduced serum TNF-α level and synovial expression of TNF-R1, IL-6 and IL-
1β. The authors believed that T. chebula could be used as a disease-modifying
agent in treatment of rheumatoid arthritis.115

Wound healing activity: Topical administration of alcoholic extract of the

leaves of T. chebula caused much faster healing of rat dermal wounds in vivo
due to improved rates of contraction and a decreased period of
epithelialization. Biochemical studies revealed increase in total protein, DNA
and collagen contents in the granulation tissues of treated wounds. The levels
of hexosamine and uronic acid also increased up to day 8 post-wounding. The
tensile strength of tissues in extract-treated incision wounds increased. These

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results strongly documented the beneficial effects of T. chebula in the

acceleration of the healing process.116 Healing activity of ethanol extract of T.
chebula against the indomethacin-induced stomach ulceration was reported.117
In alloxan induced diabetic rats, the hydroalcoholic extract of T. chebula fruit
exhibited reduction in the wound area due to faster epithelialization
compared to controls.118 Tannins extracted from immature fruits of T. chebula
inhibited Staphylococcus aureus and Klebsiella Pneumonia in vitro and promoted
cutaneous wound healing in rats due to a powerful anti-bacterial and
angiogenic activity of the extract.119 The wound healing activity of ethanol
extract of fruits of T. chebula in the form of an ointment showed significant
response in excision and incision models in albino rats.120

Cytoprotective and antiaging : Gallic acid and chebulagic acid, isolated from
fruit extract of T. chebula, blocked cytotoxic T lymphocyte (CTL)-mediated
cytotoxicity. Granule exocytosis in response to anti-CD3 stimulation was also
blocked by the above phytochemicals at the equivalent concentrations.121 The
ethanol extract of the fruits of T. chebula inhibited oxidative stress and the age-
dependent shortening of the telomeric DNA length. In the peroxidation
model using t-butanol, T. chebula extract showed a notable cytoprotective
effect on HEK-N/F cells. In addition, the T. chebula extract exhibited
cytoprotective effect against UVB-induced oxidative damage. The life-span of
the HEK-N/F cells was elongated by 40% as a result of the continuous
administration of T. chebula extract compared to controls.122 The extracts of T.
chebula gall were tested for antioxidative and tyrosinase inhibition activities as
well as for proliferative and MMP-2 inhibition activities on early aging
human skin fibroblasts to evaluate in vitro anti-aging activity. The cold water
extract of T. chebula gall indicated the highest stimulation index (SI) on normal
human fibroblast proliferation. The extract also demonstrated MMP-2
inhibition on fibroblasts 1.37 times more potent than ascorbic acid. The study
confirmed the traditional use of T. chebula gall in many Thai medicinal plant
recipes for longevity.123

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Radioprotective activity : Treatment of mice with aqueous extract of Triphala

in different doses consecutively for five days before irradiation delayed the
onset of mortality and reduced the symptoms of radiation sickness compared
to controls.124 In an experiment, aqueous extract of the fruit of T. chebula was
able to neutralize DPPH, a stable free radical and protected the plasmid DNA
pBR322 from undergoing the radiation-induced strand breaks. The
administration of T. chebula prior to whole body irradiation of mice resulted in
reduction of peroxidation of membrane lipids in the liver and decrease in
radiation-induced damage to DNA. T. chebula extract also protected the
human lymphocytes from undergoing the gamma radiation-induced damage
to DNA exposed in vitro to gamma-radiation.125

Cardioprotective activity: Cardioprotective effect of ethanol extract of T.

chebula fruits was investigated in isoproterenol induced myocardial damage
in rats. It was reported that the pretreatment with T chebula extract had
cardioprotective effect due to the lysosomal membrane stabilization
preventing myocardial necrosis and inhibition of alterations in the heart
mitochondrial ultrastructure and function in the experimental rats.126,127,128

Hepatoprotective activity: The 95% ethanol extract of T. chebula fruit showed

hepatoprotective activity against anti-tuberculosis (anti-TB) drug-induced
toxicity which could be attributed to its prominent anti-oxidative and
membrane stabilizing activities.129

Chemomopreventive activity: In an investigation, T. chebula extract treatment

prevented nickel chloride induced renal oxidative stress, toxicity and cell
proliferation response in male Wistar rats. It was suggested that T. chebula
extract could be used as therapeutic agent for cancer prevention as it blocked
or suppressed the events associated with chemical carcinogenesis.130

Hypolipidemic and hypocholesterolemic activities: T. chebula extract

administration showed hypolipidaemic activity against experimentally
induced atherosclerosis131 and hypocholesterolemic activity against
cholesterol-induced hypercholesterolemia and atherosclerosis.132 Triphala

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formulation was found to have hypolipidaemic effects on the experimentally

induced hypercholesteremic rats.

Antispermatogenic activity: The oral administration of T. chebula extracted in

acetone, methanol, 50% ethanol, and in aqueous solvents caused histological
alterations in seminiferous tubules in testes of treated mice. However,
aqueous bark extract of the plant showed more testicular alterations than
those treated with other extracts. The level of sialic acid in the epididymis and
that of fructose in the seminal vesicle were significantly reduced in aqueous
extract-treated mice compared to controls. Sperm parameters, however, were
adversely affected in mice in all extracts-treated groups compared to controls.
The results of the study in mice suggested that the aqueous bark extract of T.
chebula is more effective in its suppressive effect on the male reproductive end
points than the other extracts.133
2.4 Anthracinum 30134,135

Anthracinum is a nosode has proven a great remedy in epidemic spleen

diseases of domestic animals, and in septic inflammation, carbuncles, and
malignant ulcers but a lethal dose of anthrax is very small. Anthracinum is
prepared by triturating (grinding) the puss from anthrax. It is a very effective
prophylactic against anthrax, according to homeopaths. This nosode has a
long history. It was made & used during the days of Hahnemann, father of
modern homeopathy, by a vet surgeon called Lux. Homeopaths claim that
"Anthracinum works like magic”.

Figure 2.4 : Photograph of Anthacinum 30

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Anthracinum is indicated when:

 Black/blue blisters.
 Septic fever with chills, and painful, hard swelling of lymph glands.
 Intolerable burning with offensive pus.
 Black blood oozes from all orifices.
 Restlessness.
 Exhaustion.
 Excessive thirst but can hardly swallow.
 Succession of boils.
 Sloughing ulcers and gangrene.
2.5 Drugs Showing Wound Healing Activity

Pentoxifylline used to improve healing by changing the flow characteristics of

blood by reducing platelet aggregation, leukocyte adhesion and increasing
red blood cell membrane flexibility. It has been used to treat PVD –
intermittent claudication.

Hormones like Oestrogen plays a role in wound healing, particularly in

postmenopausal women who are known to have reduced dermal collagen
and dermal thickness. There are some case studies of the application of topical
oestrogen to non-healing leg ulcers in postmenopausal women that have
improved wound healing.

Phenytoin, a drug used to treat seizures, when given orally is known to cause
gingival hyperplasia. Some studies have been published on the topical
application resulting in a decrease in inflammatory response, an increase in
collagen synthesis and an increase in new blood vessel formation.

Prostacyclin analogues are used in the treatment of intermittent claudication;

severe limb ischaemia; prevention of imminent gangrene and to reduce pain.
They can be used to promote healing in arterial and vasculitic ulcers.

Drugs such as diltiazem and nifedipine are useful in treating vasculitic ulcers.
They help improve blood flow to the digits and are helpful in preventing
necrosis in the extremities.

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Vitamin A has been known to stimulate both humeral and cell mediated
immune mechanisms. There have been some studies to show that it can
reverse the effects of oral corticosteroids in the way they delay wound
healing.

Vitamin C is one of the most important agents in wound healing. It is

involved in the stimulation of fibroplasia. It is required for the hydroxylation
of lysine and proline during the pathway in the synthesis of collagen, most
critically important for tensile strength of a wound. Vitamin C influences
resistance to infection, it is essential for both neutrophil and fibroblast
function and it strengthens and promotes new blood vessel formation.

Zinc is important to wound healing because of its part in the structural

integrity of protein. It is essential for the functioning of at least 200 enzymes
in the body and plays a vital role in vitamin A metabolism. It is involved in
the cross-bonding of collagen and is known to promote re-epithelialisation.
Thus the management of wound healing is a complicated and expensive
program.

2.6 Phytochemicals for wound healing activity

Medicinal plants that possess wound healing activity perform their action
through their phytochemicals they have in them. Not all phytochemicals have
wound healing activity, rather the following are the most responsible group
of compound that assist wound healing process in many ways.

2.6.1 Polyphenols: These diverse groups of compounds have received much

attention as potential natural antioxidant in terms of their ability to act as both
efficient radical scavengers and metal chelators.136 High correlation
coefficients between the phenolic content and antioxidant activities have been
reported for various food commodities.137 The antioxidant property of honey
is well known, because it contains a number of compounds with antioxidant
properties such as, flavonoids, phenolic acids, proteins, amino acids, ascorbic
acid, HMF, and some enzymes. Polyphenolscan increase the activity of
catalase and glutathione peroxidase, which detoxify H2O2 by converting it to

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O2 and H2O. They are also known to stimulate wound healing. As an example
polyphenols of areca have been stated to promote wound healing of incision
and dead space wounds and the period of epithelialization in the excision
wounds.138

2.6.2 Flavonoids: Flavonoids are a large group of natural products widely

distributed in nature. They are present in fruits, vegetables, chocolates, herbs
and beverages, such as wine, tea or beer. The chemical diversity, size, three-
dimensional shape, and physical and biochemical properties of flavonoids
allow them to interact with targets in different subcellular locations to
influence biological activity in plants, animals, and microbes. They have a
C6-C3-C6 backbone, and apart from modifications to this backbone, the
marked structural variety of flavonoids is due to their conjugation to sugars at
different sites of the molecule.139

Any drug that inhibits lipid peroxidation is believed to increase the viability
of collagenfibrils by increasing the strength of collagen fibers, preventing the
cell damage and by promoting the DNA synthesis.140 Flavonoids have been
documented to possess potent antioxidant and free radical scavenging effect,
which is believed to be one of the most important components of wound
healing. Bioflavonoids are thought to benefit connective tissue by binding to
elastin, preventing its degradation by elastases. They reduce lipid
peroxidation not only by preventing or slowing the onset of cell necrosis but
also by improving vascularity. The high mobility of the electrons in the
benzenoid nucleus of flavonoids accounts for both their antioxidant and free-
radical scavenging properties, whereas the structural resemblance between
the flavonoid aglycone and many substances inherent to the biochemistry of
normal biological cells, e.g., nucleic acid bases, coenzymes, steroid hormones,
and neurotransmitters, explains their inhibition of enzymes,
cytoplasmic/nuclear hormone receptors, and neurotransmitters, as well as
gene induction. Many studies have shown that antimicrobial activities of

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plants can also be attributed to their flavonoid content;hence, they are helpful
in prevention of wound infection.

Most of the delay in wound healing is due to insufficient or excessive

fibroblast activity. Thus, inhibition of fibroblast growth by flavonoids such as
apigenin could be beneficial for the treatment of any skin injury. Quercetin,
may be useful in healing after renal transplantation. Rutin, naringin and
quercetin protect DNA damage induced by ultra violet. Strong antihistamine
activity has been shown by thymonin from Mentha spicata var. (Labiatae)
Santin may contribute to the well known anti-inflammatory activity of the
plant Tanacetum parthenium by inhibiting thecyclo-oxygenase and the 5-
lipoxygenase pathways.

2.6.3 Tannins: Tannins are phenolic compounds that typically act as

astringents and are found in a variety of herbal products used for wound
healing. Their astringent and antimicrobial property responsible for wound
contraction and increased rate of epithelialization. Research results indicated
that using the oxidation of linoleic acid as a model system, 3, 4, 5tri-O-
galloylquinic acid displays significantly greater antioxidant properties when
compared with ascorbic acid and the commercially used n-propyl gallate as
well as gallic acid itself. Resveratrol, found in red wine have been suggested
to be responsible for health benefits of wine grape through antioxidant

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CHAPTER 2 REVIEW OF LITERATURE

mechanism. Triphenolic stilbene like epigallocatechin gallate, inhibited cell

death induced byter - butyl hydroperoxide in the presence of ferric ion.141

2.6.4 Phenolic acids: Phenolics play a beneficial role in protecting tissue

from the harmful effects of reactive oxygen species (ROS) through regulation
of antioxidant enzyme response through the phenolic-dependent peroxidases
with dependency on pentose phosphate pathway but with reduced
dependency on SOD and CAT. Oregano being rich in phenolics, as an exam
plerosmarinic acid, is an effective direct quencher of free radicals.142

2.6.5 Phenyl propanoids: The phenyl propanoid curcumin and its

demethoxy and bisdemethoxy derivatives are known to possess anti-
inflammatory and antioxidant activity. Together with quercetin, curcumin
(diferuloylmethane), may be useful in healing after renal According to the
study made in Turkey, a phenyl ethanoid glycoside verbascoside was found
to show significant inhibitory effect on carrageenan-induced hind paw edema
in mice was shown to possess a significant wound healing activity in these
models.

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CHAPTER 2 REVIEW OF LITERATURE

2.6.6 Terpenes and terpenoids: Terpenoids are known to promote the

wound healing process, mainly due to their astringent and antimicrobial
properties, which seem to be responsible for wound contraction and increased
rate of epithelialization. Triterpenes are also responsible for promotion of
rapid wound healing.143 Sesquiterpene lactones areknown to possess
antioxidant activity property, which may contribute to the wound healing
process Four related terpenoidal compounds from Centella asiatica; asiatic
acid, madecassic acid, asiaticoside and madecassoside known to increase
collagen synthesis in dose dependent fashion through modulation of gene
expression.144

2.6.7 Alkaloids: Alkaloids are known to promote wound healing process

due to their antioxidant and antimicrobial activities. Extracts from Symphytum
asperum and Symphytum caucasicum contain allantoin, claimed to be a cell
proliferation stimulating agent responsible for their wound-healing
propertiy.145 Reportedly the alkaloid fraction of areca enhances the collagen
production and hence wound healing. But contrary to the above study, there

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CHAPTER 2 REVIEW OF LITERATURE

was no increase in the hydroxyproline content of granulation tissue in

arecoline and polyphenol treatments and insignificant change in wound
breaking strength of the granulation tissue with polyphenol treatment of the
dead space wound model.146

2.6.8 Saponins: Saponins are known to promote wound healing process due
to their antioxidant and antimicrobial activities. For example, asiaticoside, a
saponin is thought to be one of its active constituents Centella asiatica.
Asiaticoside solution applied topically twice daily for seven days to punch
wounds in guinea pigs resulted in increase in hydroxyproline, increase in
tensile strength, increased collagen content, and better epithelialization
Triterpene saponins are also reported to possess immunomodulatory
properties.147

2.6.9 Plant vitamins

Vitamin A, C, and E are important in the wound healing process. Vitamin A is

required for epithelial and bone tissue development, cellular differentiation,
and immune system function. Substantial evidence supports the use of
vitamin A as a preoperative nutritional supplement.148 Ascorbic acid acts as a
cofactor for the synthesis of collagen as well as elastin fibers.149

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2.6.10 Miscellaneous compounds: Polyunsaturated fatty acids due to their

unsaturation possess anti-oxidative effect, which is related to reacting with
reactive oxygen species (ROS). Plant proteins as papain and chymopapain
found in the epicarp of papaya are helpful in wound healing due to their
antimicrobial and antioxidant activity.150

Research results showed that emodin, an anthraquinone glycoside, promoted

repair of rats' excisional wounds via a complex mechanism involving
stimulation of tissue regeneration and regulating signaling pathway.151
Capsaicin (trans-8-ethyl- N-vanillyl-6-nonen- amide); is a principal pungent
ingredient present in hot red and chili pepers that belong to the plant genus
Capsicum (Solanaceae). Pungent vanilloids in ginger, like gingerol and
paradol are alsoknown to possess antioxidant activity. A polyphenolic
compound lawsone from Lawsonia inermis were studied for its wound healing
activity and gave a significant wound healing.152

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 CHAPTER 2 REVIEW OF LITERATURE

2.6.11 Plants with potential wound healing activity153,154,155,156,157

Some medicinal plants have been employed in folk medicine for wound care
that either promote direct wound repair or exhibit antimicrobial and other
related properties which are beneficial in overall wound care. Some of the
plants used in wound care have also been shown to possess a combination of
these properties. The list of potential wound healing property contain plant is
given in Table 2.1.

Table 2.1: Plants having wound healing property

Sr. No. Plants Pant part Model applied

1. Ageratum conyzoides Root, alcohol Excision wound model
2. Acalypha langiana Leaf ,Aqueous Excision
Andrographis Leaf, alcohol, pet ether& Excision, incision, dead
3.
paniculata aqueous space
4. Butea monosperma Bark,alcohol Excision
5. Bryophyllum pinnatum Leaf, alcohol Excision
6. Calotropis gigantea Latex Excision and incision
7. Centella asiatica Plant Excision
8. Colutea cilicia Fruit &leaf, aqueous Excision and incision
Excision, incision, dead
9. Crotalaria verrucosain Aqueous
space
10. Colebrookea oppositifola Leaf, alcohol Excision and incision
Excision, incision ,dead
11. Cordia dichotoma Fruit, alcohol
space
12. Datura alba Leaf, alcohol Burn wound
13. Dissotis theifolia Stem, methanol Excision model
14. Elaeis guineensis Leaf, methanol Excision model
15. Euphorbia heterophylla Leaf ,ethanol Excision wound model
Excision , incision ,dead
16. Eucalyptus globulus Leaf, ethanol
space
17. Euphorbia neriifolia Latex, aqueous Excision
Root, petroleum ether,
Excision, incision, dead
18. Echinops echinatus ethanol chloroform, and
space
distilled water
Whole plant, ethanol and Excision, incision, dead
19. Elephantopus scaber
aqueous space
20. Ficus religiosa Leaf, hydro alcohol Excision and incision
21. Flaveria trinerva Methanol Excision and incision
22. Ficus deltoidea Whole plant, aqueous Excision model
23. Glycyrrhiza glabra Root, ethanol Excision
Rhizomes, alcohol and Excision, incision, dead
24. Gentiana lutea
petroleum ether space

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 CHAPTER 2 REVIEW OF LITERATURE

25. Glycosmis pentaphylla Leaf, methanol Excision

26. Hemigraphis colorata Leaf paste Excision,
27. Hippophae rhamnoides Leaf, aqueous Excision
28. Heliotropium indicum Whole plant , ethanol Excision and incision
29. Indigofera enneaphylla Aerial parts, alcoholic Excision and incision
30. Ixora coccinea Flower, alcohol Dead space
Excision, incision, dead
31. Jatropha curcas Bark, methanol
space
32. Kalanchoe pinnata Leaf, ethanol Excision wound model
33. Lantana camara Leaf, ethanolic extract Burn wound
Excision, incision, dead
34. Limonia acidissima Fruit pulp, hexane
space
Excision and incision
35. Laura nobilis Aqueous
model
36. Lawsonia alba Leaf Excision and incision
37. Leucas lavandulaefolia Maethanol Excision and incision
Fruit pulp, hexane and
38. Momardica balsamina Excision
methanol
Excision, incision, dead
39. Moringa olifera Leaf, aqueous
space
Excision, dead space
40. Morinda citrifolia Leaf, ethanol
wound
Leaf, chloroform and Excision and incision
41. Madhuca longifera
ether wound model
42. Napoleona imperialis Leaf, methanol Excision model
Excision, incision, dead
43. Nelumbo nucifera Rhizomes, methanol
space
Leaves, alcoholic and Excision, incision, dead
44. Ocimum sanctum
aqueous space
Fruit, aqueous & Excision, incision, dead
45. Plantain banana
methanol space
Excision, incision, dead
46. Quercus infectoria Leaf,ethanol
space
47. Rubia cardifolia Roots, alcoholic extract Excision wound model
n-hexane, chloroform,
48. Rubus sanctus ethyl acetate and Excision and incision
Methanol
49. Solanu xanthocarpum Fruit, methanol Excision and incision
50. Sambucus ebulus Leaf, methanol Excision and incision
51. Thespesia populnea Fruit, aqueous Excision and incision
52. Vinca rosea Leaf,ethanol Excision model
53. Wedelia calendulaceae Aqueous extract Incision and excision

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