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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
Review
Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar 470003, M.P., India
Shri Ramnath Singh Mahavidyalaya (Pharmacy), Gormi, Bhind 477660, M.P., India
a r t i c l e
i n f o
Article history:
Received 3 March 2011
Received in revised form
20 September 2011
Accepted 23 September 2011
Available online 29 September 2011
Keywords:
Phyllanthus amarus
Hepatoprotective
Anti-inammatory
Anticancer
Diuretics
Nephroprotective
Antioxidant
Antiviral
Antibacterial
Antihyperglycemic
Antihypercholesterolemic
a b s t r a c t
Ethnopharmacological relevance: Phyllanthus amarus Schum. & Thonn. belongs to the family Euphorbiaceae
is a small herb well known for its medicinal properties and widely used worldwide. P. amarus is an
important plant of Indian Ayurvedic system of medicine which is used in the problems of stomach,
genitourinary system, liver, kidney and spleen. It is bitter, astringent, stomachic, diuretic, febrifuge and
antiseptic. The whole plant is used in gonorrhea, menorrhagia and other genital affections. It is useful in
gastropathy, diarrhoea, dysentery, intermittent fevers, ophthalmopathy, scabies, ulcers and wounds.
Materials and methods: The present review covers a literature across from 1980 to 2011. Some information collected from traditional Ayurvedic texts and published literature on ethanomedicinal uses of
Phyllanthus amarus in different countries worldwide.
Results: Phytochemical studies have shown the presence of many valuable compounds such as lignans,
avonoids, hydrolysable tannins (ellagitannins), polyphenols, triterpenes, sterols and alkaloids. The
extracts and the compounds isolated from P. amarus show a wide spectrum of pharmacological activities including antiviral, antibacterial, antiplasmodial, anti-inammatory, antimalarial, antimicrobial,
anticancer, antidiabetic, hypolipidemic, antioxidant, hepatoprotective nephroprotective and diurectic
properties.
Conclusion: The present review summarizes information concerning the morphology, ecology, ethnopharmacology, phytochemistry, biological activities, clinical applications and toxicological reports of P.
amarus. This review aims at gathering the research work undertaken till date on this plant in order
to provide sufcient baseline information for future works and commercial exploitation.
2011 Elsevier Ireland Ltd. All rights reserved.
Abbreviations: 2AA, 2-aminoanthracene; 2NF, 2-nitrouorene; 3D7, chloroquine-sensitive strain of Plasmodium falciparum; 4-NQO, 4-nitroquinolone-1-oxide; ABTS, 2,2 azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid); AF2, 2-aminouorene; AH, aniline hydroxylase; ALP, alkaline phosphatase; ALT, alanine transaminase; AP-1, transcription
factors; AST, aspartate transaminase; CAT, catalase; CD4, T-helper cell; CFA, complete freunds adjuvant; COX-2, cyclooxygenase; CTX, cyclophosphamide; DHBV, duck
hepatitis B virus; DHHDP, 1-galloyl-2,3-dehydrohexahydroxydiphenyl; DLA, Daltons lymphoma ascites tumor; DMN, dimethylnitrosamine; DMSO, dimethyl sulphoxide;
DNA, deoxy ribonucleic acid; DPPH, 2-diphenyl-1-picrylhydrazyl; EAC, Ehrlich ascites carcinoma; EC50 , effective concentration 50%; ENNG, N-ethyl-N-nitrosoguanidine; FRAP,
ferric reducing antioxidant power; FT-IR, Fourier transform infrared spectroscopy; GGT, -glutamyl transpeptidase; GPX, glutathione peroxidase; GSH, cellular glutathione;
GST, glutathione-S-transferase; HBeAg, hepatitis B effective antigen; HBsAg, hepatitis B suppresive antigen; HBV DNA, hepatitis B viral DNA; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HE, hexane extract; HepA, Hepatitis A; HepA2 , Hepatitis A2 ; HIV, human immunodeciency virus; HPLC, high-performance liquid chromatography;
HPTLC, high-performance thin layer chromatography; HTG, hepatic triglyceride; i.p., intraperitoneal injection; IC50 , inhibitory concentration 50%; ID50 , inhibitory dose 50%;
IFN-a/c, interferon; IL-1, interleukin-1; IL-10, interleukin-10; IL-12, interleukin-12; IL-18, interleukin-18; iNOS, endotoxin-induced nitric oxide; IR, infra red; KC, Kupffer
cells; LPO, lipid peroxidation; LPS, lipopolysaccharides; MDA, malondialdehyde; MDR, multi-drug resistance; MICs, minimum inhibitory concentrations; mRNA, messenger
ribo nucleic acid; NDEA, N-nitrosodiethylamine; NF-kB, NF-kappa ; NMR, nuclear magnetic rasonance; 4-NQO, 4-nitroquinolone-1-oxide; P. amarus, Phyllanthus amarus; P.
debilis, Phyllanthus debilis; P. fraternus, Phyllanthus fraternus; P. kozhikodianus, Phyllanthus kozhikodianus; P. maderaspatensis, Phyllanthus maderaspatensis; P. niruri, Phyllanthus
niruri; P. urinaria, Phyllanthus urinaria; PAF, platelet activating factor; PCV, packed cell volume; PGE2 , prostaglandin E2 ; P.O., per oral; ROS, reactive oxygen species; SCGE, single
cell gel electrophoresis; SEF, supercritical-uid extraction; SL, silymarin; SOD, superoxide dismutase; STG, serum triglyceride; STZ, streptozotocin; TBARS, thiobarbituric acid
reactive substances synthase; TLC, thin layer chromatography; TNF-, tumor necrosis factor ; UV, ultra violet; WBC, white blood carpuscles; WHV, Woodchuck hepatitis virus.
Corresponding author. Tel.: +91 9425647546.
E-mail address: vkdixit2011@rediffmail.com (V.K. Dixit).
1
Present address: Division of Pharmaceutics, Central Drug Research Institute, Lucknow (U.P.) 226001, India.
0378-8741/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2011.09.040
287
Contents
1.
2.
3.
4.
5.
6.
7.
8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Historical perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Botanical description and vernacular names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biogeography and ecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacognostic characters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Phytochemical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analytical techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.
Antiamnesic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.
Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.
Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4.
Anti-diarrhoeal, gastroprotective and antiulcer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5.
Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.
Analgesic, anti-inammatory, anti-allodynic and anti-oedematogenic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.
Antinociceptic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.8.
Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.9.
Antiplasmodial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.10.
Antiviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.11.
Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.12.
Aphrodisiac activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.13.
Contraceptive effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.14.
Diuretic and antihypertentive activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.14.1.
Clinical study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.15.
Hepatoprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.16.
Hypoglycemic and hypocholesterolemic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.16.1.
Clinical study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.17.
Immunomodulatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.18.
Nephroprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.19.
Radioprotective effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.20.
Spasmolytic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.21.
Effect on reproductive organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
Toxicological assessment and contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Bhumyaamalaki (Phyllanthus amarus Schum. & Thonn., Euphorbiaceae), which is widely spread throughout the tropical and
subtropical countries of the world including India is most commonly used in the Indian Ayurvedic system of medicine in
problems of stomach, genitourinary system, liver, kidney and
spleen. P. amarus has been described in Ayurveda by the Sanskrit
name Bhoomyaamalakee, Taamalakee and Bhoodhatree. It was
described to have the properties of Rasa, Guna, Veerya and Vipaaka.
The Ayurvedic literature has shown its uses as Kaasahara (antitussive), Shwaasahara (antispasmodic, antidyspnoic), Kaphapittahara
(which relieves the Kapha Pitta Dosha), Pipaasaaghna (which
relieves Polydipsia), Raktapittahara (hemorrhage disease), Paanduhara (antianemic), Kaamalaahara (which cures jaundice),
Kushthaghna (indicated in leprosy), Daahaghna (refrigerant,
relieves burning sensation), Kshatakshayaghna (indicated in
Trauma) and Mootrarogahara (which cures urinary disorders). The
use of P. amarus is gaining momentum because of its novel antiviral
activity against hepatitis B virus and for several other biological
activities such as kidney and gallbladder stones, for cold, u, tuberculosis, and other viral infections; liver diseases and disorders
including hepatitis, jaundice and liver cancer (Unander et al., 1993).
It also acts against liver cell toxicity and improves the immune
system of patients and has been found effective against hepatitis
A (Jayaram et al., 1997). P. amarus is often used in the traditional
system of medicine for a variety of ailments including dropsy, diabetes, jaundice, asthma and bronchial infections (Foo and Wong,
1992). In the Ayurvedic system of medicine it is used in problems
of stomach, genitourinary system, liver, kidney and spleen. It is
bitter, astringent, stomachic, diuretic, febrifuge and antiseptic. The
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are in minor quantities present (Sharma et al., 1993). Lignans isolated from P. amarus are phyllanthin, hypophyllanthin,
niranthin, phyltetralin, nirtetralin, isonirtetralin, hinokinin, lintetralin, isolintetralin, demethylenedioxy-niranthin, 5-demethoxyniranthin etc., avonods such as gallocatechin, rutin, quercetin3-O-glucopyranoside, phyllanthusiin, quercetin, kaempferol
3--d-glucopyranoside, kaempferol etc., ellagitannins include
geraniin, amariin, furosin, geraniinic acid B, amariinic acid, amarulone, repandusinic acid A, corilagin, isocorilagin, elaeocarpusin,
phyllanthusiin A, B, C, D and melatonin; securinega-type alkaloids such as isobubbialine and epibubbialine and sterol such as
amarosterol A, amarosterol B.
P. amarus had been reported to have pharmacological
effects such as antimicrobial, antiviral activities against hepatitis B, chemoprotective, antimutagenic and hypoglycaemic agent.
Methanolic extract of P. amarus exhibited immunomodulatory
activity. Ellagitannins (geraniin and corilagin) were shown to be
the most potent mediators of the antiviral HIV activity. Phyllanthin and hypophyllanthin present in P. amarus exhibited antitumor
activities against EAC in Swiss albino mice, cytotoxic effects on
K-562 cells, and hepatoprotective and antioxidant effects. The
present review assesses the potential of P. amarus in relation to its
traditional uses and in terms of ndings based on modern bioscientic research. The link between conventional remedies and recent
research in various areas has been well established in other plants
which facilitate to determine effective mode of action of plant
derived products. The plant is known to contain several pharmacological important biomolecules whose efcacy is well established
by several biochemical and pharmacological studies. This review
intent to compile various studies on this plant and critically evaluates the issues related to ethnopharmacology, phytochemistry,
pharmacology, clinical studies and toxicology of P. amarus.
Table 1 represents ethnomedicinal uses of P. amarus in different countries and Table 2 represents the ethnomedicinal uses of P.
amarus used by different tribes of countries worldwide.
Table 1
Ethnomedicinal uses of P. amarus in different countries worldwide.
Region
Ethnomedicinal uses
Amazonia
Aruba
Bahamas/Caribbean
Barbados
Brazil
Cuba
Haiti
India
2. Historical perspectives
Indonesia
P. amarus has been indexed in majority of published phytochemical, pharmacological and ethno-botanical reviews and research
articles till date with different named. This species, P. amarus has
been confused with Phyllanthus niruri Linn. In the past, Linnaeuss
P. niruri, though well dened in the Hortus Cliffortianus, became
confused owing to his erroneous reduction of other species to the
synonyms of the former and subsequent misidentication by other
authors. The commonest weedy species so mistaken for P. niruri by
Muller and others was dened as Phyllanthus swartzii Kosteletzsky
in 1836, based on P. niruri of Swartz; but the earliest name of this
species appears to be P. amarus Schum. & Thonn. For a full discussion on the botanical description and nomenclature of this species
reference has been made to the excellent discussion by Webster
(1957). The earliest botanical descriptions could be observed from
South India, Sri Lanka and Indonesia which have cited Phyllanthus
urinaria and P. niruri respectively (Van Rhede, 1690; Rumphius,
1750). In the Ayurvedic system in India, no denitive botanical
description exists in the original literature and the plants indicated
by many of the old Sanskrit words have been lost in course of history (Handa et al., 1951; Chopra et al., 1958). It was the opinion
of Dymock (1886) and Dymock et al. (1893) that the same common names in a number of Indian languages apply for both P. niruri
and P. urinaria. Similar reports have stated that even the rather
visually different P. urinaria was often used interchangeably with
those species earlier known as P. niruri in the traditional system
of India (Van Rhede, 1690; Dymock, 1886; Kirtikar and Basu, 1975)
and suggested that the practioners did not differentiate it according
Nigeria
Peru
Trinidad
United States
Elsewhere
289
Table 2
Ethnomedicinal uses of Phyllanthus amarus Schum. & Thonn.
S.N.
Place
Local name
Plant part
used
Disease
Method of use
Reference
Dharapuram Taluk,
Tamil Nadu, India
Keelanelli
Whole plant
1. Migraine
2. Jaundice
Paliyar tribals in
Theni district of
Tamil Nadu, India
Eastern part of
Rajasthan, India
Keelanelli
Leaves
Jaundice
Bhumiamla
Whole plant,
leaves
Gonorrhea and
syphilis
Skin diseases,
malaria
Uttara kannada,
Western Ghats,
India
Eastern region of
Shimoga district,
Karnataka, India
Dindigul District,
Tamil Nadu, Indian
Nelli
Whole plant
Malaria
Nelanelli
Root juice
Jaundice
Kizhnelli
Leaves
Menstrual problem
Buldhana district;
Maharashtra,
Indian
North Andaman
Island, India
Bhui-awala
Whole plant
Jaundice
Nallesari
Whole plant
Jaundice
Sivagangai district,
Tamil Nadu, India
Keelaanelli
Leaves
1. Diabetes
2. Jaundice
10
Shimoga district of
Karnataka, India
Nela nelli
(Bhumyamalaki)
Leaves
1. Jaundice
2. Chronic
dysentery
11
Kattunaykas tribes
of Mudumalai
Wildlife Sanctuary,
Nilgiris district
Tamil Nadu, India
Kila nelli
Whole plant
Jaundice
Table 2 (Continued)
S.N.
Place
Local name
Plant part
used
Disease
Method of use
Reference
12
Kancheepuram
district Tamil
Nadu, India
Keezhanelli
Leaves
Jaundice
13
India
Bhumi amalaki
Whole plant
14
Northern India
Bhui amla
Whole
Not stated
15
Sitamata Wildlife
Sanctuary of
Chittorgarh and
Udaipur district
Rajasthan, India
Esan North East
local govt. area of
Edo State, Nigeria
Delta State Nigeria
Not stated
Leaves
Liver disease,
dyspepsia,
anorexia, moderate
constipation,
chronic colitis,
irritable bowel
syndrome, urinary
tract infection
Jaundice,
aphrodisiac,
dysentery
Syphilis,
gonorrhea,
jaundice
Abenaghe
Leaves
Stomachache
Ibuko-oyeke
Leaves
Stomachache
18
Oyomokiso,
aman keeden
Leaves
Malaria
19
20
Eyin olobe
Hlinvi
Whole plant
Arial
21
Semi-arid
Northeasten Brazil
Dangme West
district of Ghana
Quebra-pedra
Leaves
Diabetes
Diabetes, fever,
malaria
Kidney problems
Ofobi okpabi
Whole plant
Malaria
16
17
22
23
Surinamese
migrants in
Netherland
Fini bita
Whole plant
Stomach-ache,
cleaning uterus,
laxative, health
promotion, disease
prevention
24
Akha people in
Thailand and China
Yu Jae
Leaves
Rashes, itches
291
Table 3
Vernacular name of P. amarus worldwide (Medicinal Plants of India, 1987,
http://knol.google.com/k/pankaj-oudhia/phyllanthus-amarus-l/3nerdtj3s9l79/20).
S.No.
Language
Vernacular names
1
2
3
4
5
6
7
8
9
10
11
12
13
Tamil
Hindi
Bengali
Gujarathi
Marathi
Oriya
Bihari
Telugu
Kanada
Malayalam
Rajasthani
Sanskrit
English
14
15
16
17
French
German
Spanish
African names
18
Keelanelli (Keezhanelli)
Bhuyiavla, Jangli amla
Bhuiamala, Sadahazurmani
Bhonya anmali
Bhuivali
Bhuiaola, badianala
Muikoa, Kantara, Pirikantaru
Nela uirika, Nelavusari
Nela nelli, Kirunelli
Kizhkkayinelli, Kilanelli
Gugario
Bhumyaamlaki, Bhoodhatree, Thamalaki
Black catnip, Carry me seed, Child
pick-a-back, Gale of wind, Gulf leaf ower,
Hurricane weed, Shatterstone, Stone breaker
Poudre de plomb (Ivory coast)
Weisse Blattblume
Yerba magica (Cuba)
Ahlivi (Mina-Togo), Bomagua kene (Ivory
coast), Bounou (Ivory coast), Bounou honlin
(Ivory coast), Hinlinew (West Africa),
Mokichinento (KorokoroEast Africa),
Tsekulemegbe (Ouatchi-Togo)
Black catnip, carry-meseed, chanca piedra,
djari-bita, egg woman, ni-bita, or
escondida, gale-of-(the)-wind, hurricane
weed, quebra-pedra, quinine creole, quinine
weed, seed-under-leaf, stone breaker and
yerba de la nina (Morton, 1981)
5. Pharmacognostic characters
6. Phytochemical studies
The secondary metabolites present in P. amarus are alkaloids,
avonoids, hydrolysable tannins (Ellagitannins), major lignans,
polyphenols, triterpenes, sterols and volatile oil. The main active
constituents of P. amarus are lignans (phyllanthin, hypophyllanthin, nirurin niranthin, phyltetralin, niranthine, nirtetralin etc.
(Morton, 1981; Chevallier, 2000; Srivastava et al., 2008; Kassuya
et al., 2006; Huang et al., 2003; Maciel et al., 2007; Singh
et al., 2009), avonoids (quercetin, quercetrin, rutin, gallocatechin, phyllanthusiin, kaempferol etc.), (Foo and Wong, 1992;
Foo, 1993a; Londhe et al., 2008; Morton, 1981), Ellagitannins viz.
geraniin, amariin, furosin, geraniinic acid, amariinic acid, amarulone, repandusinic acid, corilagin, isocorilagin, elaeocarpusin,
phyllanthin D gallic acid, repandusinic acid A etc. (Foo and Wong,
1992; Foo, 1993a; Foo, 1995), triterpenes (phyllanthenol, phyllanthenone, phytllantheol etc.) (Maciel et al., 2007; Foo and Wong,
1992), alkaloids (securinine, dihydrosecurinine, tetrahydrosecurinine, securinol, phyllanthine, allosecurine, nor-securinine,
epibubbialine, isobubbialine, 4-methoxy dihydrosecurinine, 4methoxytetrahydrosecurinine, 4-hydrosecurinine etc.) (Houghton
et al., 1996; Kassuya et al., 2006; Foo and Wong, 1992), sterol
(amarosterol-A, amarosterol-B etc.) (Ahmad and Alam, 2003) and
volatile oil (linalool, phytol etc.) (Moronkola et al., 2009). A detailed
extraction, isolation and characterization method was optimized
for phyllanthin (Hamrapurkar et al., 2009).
The oils obtained from P. amarus were analyzed for its
constituents by means of gas chromatography (GC) and gas chromatography coupled with mass spectrometry (GC/MS). The GC
293
Table 4
Phytoconstituents reported in P. amarus.
S. No.
Secondary metabolites
Phyto-constituents
References
Lignans
Flavonoids
Hydrolysable tannin
(Ellagitannins)
Tannin precursors
Simple tannins
Complex tannins
Alkaloids
Triterpenes
6
7
Sterols
Volatile oil
Lintetralin, isolintetralin,
demethylenedioxy-niranthin,
5-demethoxy-niranthin
(3-(3,4-dimethoxy-benzyl)-4-(7-methoxybenzo[1,3]dioxol-5-yl-methyl)-dihydrofuran2-one,
4-(3,4-dimethoxy-phenyl)-1-(7-methoxybenzo[1,3]dioxol-5-yl)-2,3-bismethoxymethyl-butan-1-ol
Rutin, astragalin, kaempferol,
quercetin-3-O-glucoside, quercetin, quercitrin
Gallic acid, ellagic acid, gallocatechin
1,6-digalloylglucopyranose, 4-O-galloylquinic
acid
Geraniin, amariin, furosin, geraniinic acid B,
amariinic acid, amarulone, repandusinic acid A,
corilagin, isocorilagin, elaeocarpusin,
phyllanthusiin A, B, C and D, melatonin
Securinine, dihydrosecurinine,
tetrahydrosecurinine, securinol, phyllanthine,
allo-securine, nor-securinine, epibubbialine,
isobubbialine
4-methoxy-nor-securinine, 4-methoxy
dihydrosecurinine,
4-methoxytetrahydrosecurinine, 4
hydrosecurinine
Phenazine and phenazine derivatives
2Z, 6Z, 10Z, 14E, 18E, 22E-farnesylfarnesol
Lupeol, phyllanthenol, phyllanthenone,
phyllantheol, Oleanolic acid, ursolic acid
Amarosterol A, amarosterol B
Linalool, phytol
1-galloyl-2,4:
3,6-bis-dehydrohexahydroxydiphenoylglucopyranoside in which the cyclohexenetrione portion of
the dehydrohexahydroxydiphenoyl moieties were linked to the
O-3 and O-4 of the glucose moiety (Foo, 1993b). An unusual
ellagitannin, phyllanthusiin D was isolated from the biologically
active polar fraction of P. amarus. Its structure was established
as 1-galloyl-2, 4-(acetonyl-dehydrohexahydroxydiphenoyl)-3,
6-hexahydroxydiphenoyl-glucopyranoside (Foo and Wong, 1992).
Table 4 represents the secondary metabolites with their respective
phytochemicals present in P. amarus.
7. Analytical techniques
A HPLC analysis method was developed and validated to obtain
an easily performable and inexpensive method for the standardization of crude extract of P. amarus and ellagic acid. Ethanolic
extract of whole plant of P. amarus was dissolved in DMSO, ultrasonicated for 15 min, and diluted with 50% methanol. Analysis was
performed using water and methanol containing 0.06% TFA and
the peaks were detected at 254 nm. Ellagic acid showed a linear
relationship in the range of 1.7420.91 g/mL and a single-point
calibration was allowed. The method was shown to be precise with
respect to time (RSD of 1.84%, 3 days, n = 6) and concentration (RSD
of 2.54%, three levels, n = 6). The overall mean content of ellagic acid
was 2.06%. A recovery experiment was performed and it showed
an accuracy of 100.4% (Dhooghe et al., 2011). A simple, specic and
precise RP-HPLC method has been developed and validated for the
estimation of phyllanthin, present in P. amarus. Furthermore, the
developed method was also used to successfully quantify the phyllanthin in plant extract. The mobile phase optimized for RP-HPLC
Foo (1993a)
Maciel et al. (2007)
Foo and Wong (1992)
Ahmad and Alam (2003)
Moronkola et al. (2009)
was methanolwater 66:34 (% v/v) which was very simple and cost
effective. The detection was carried out using variable wavelength
UVvis detector set at 229 nm. Linearity for the developed method
was found over the concentration range 150 g/mL with a correlation coefcient of 0.999 (Alvari et al., 2011). An online-hyphenated
high-performance liquid chromatography-photodiode array-mass
spectrometry (HPLC-PDA-MS) analytical method was developed
for the simultaneous determination of six lignans of therapeutic
importance in four Phyllanthus spp. (P. amarus, P. maderaspatensis,
P. urinaria, and Phyllanthus virgatus). HPLC with monolithic reverse
phase silica column (4.6 100 mm) and simple isocratic elution of
methanolwater mixed with dioxane facilitated the separation of
lignans of diverse nature such as diarylbutyrolactone, tetrahydrofuran, isomeric aryltetralin, and diarylbutane type for quantitative
analysis. Targeted lignans viz. heliobuphthalmin lactone, virgatusin, hypophyllanthin, phyllanthin, nirtetralin, and niranthin were
conrmed unambiguously in four Phyllanthus species by their
abundant molecular adduct ions, retention time, UV, and mass
spectra as compared with those of reference compounds. Advantages and limitations of both detection techniques for qualitative
(ngerprinting) and quantitative analysis of the above mentioned
lignans in four Phyllanthus spp. are discussed. The method was validated following international guidelines. The described method can
be utilized for assays and stability tests of P. amarus extracts as well
as traditional Indian medicine based on Phyllanthus herb (Shanker
et al., 2011). Phyllanthin was extracted from the plant P. amarus
by Soxhlet and supercritical-uid extraction (SFE) and isolated by
column chromatography. A HPTLC method was established and
validated for analysis. The method was used for quantitative analysis and macro and micro ngerprinting analysis of phyllanthin.
This study also revealed that SFE enabled more efcient isolation of phyllanthin than Soxhlet extraction (Hamrapurkar et al.,
2010; Annamalai and Laxmi, 2009). Phyllanthin was isolated from
the aerial parts of P. amarus by silica gel column chromatography
employing gradient elution with hexaneethyl acetate solvent mixture. It was obtained in high yields (1.23%), compared to reported
procedures and the purity was ascertained by HPTLC and reversed
phase HPLC analysis (Krithika et al., 2009). A sensitive, selective,
and robust HPTLC method using chiral TLC plates for qualitative
and quantitative analysis of phyllanthin, hypophyllanthin, niranthin, and nirtetralin, the active lignans of Phyllanthus species, was
developed and validated. The effectiveness and role of various stationary phases viz TLC silica gel 60F254 , HPTLC silica gel 60F254 , and
chiral TLC plates in the quantitation were evaluated. A precoated
chiral TLC plate was found suitable for the simultaneous analysis of
four pharmacologically active lignans. For achieving good separation, the optimized mobile phase of n-hexane-acetone-1, 4-dioxane
(9:1:0.5 by volume) was used. A densitometric determination of the
above compounds was carried out in reection absorption mode at
620 nm. Optimized chromatographic conditions provided well separated compact bands for the tested lignans. The calibration curves
were found linear in the concentration range of 100500 ng/band
(Srivastava et al., 2008). Sharma et al. (1993) have developed a
reversed phase HPLC procedure for standardizing P. amarus on the
basis of its two bioactive lignans, phyllanthin and hypophyllanthin.
The method has been found to be sensitive, precise and efcient to
record more than 98% recovery of these two lignans. The leaves
of P. amarus were found to contain the highest amount of phyllanthin (0.7% w/w) and hypophyllanthin (0.3% w/w) as compared
to other parts of the plant. A method for amount determination
of gallic acid in P. amarus capsules was established by HPLC (Guo
et al., 2007). Methanolic extract of P. amarus and standard phyllanthin and hypophyllanthin were developed in the chromatographic
conditions. They showed the presence of standard phyllanthin and
295
and extracted with CHCl3 to yield an oily residue (165 mg). Examination by TLC showed the presence of ve Dragendorff-positive
zones. The residue was then subjected to preparative TLC on silica gel to yield ve compounds (PA1PA5). PAl (0.026% yield),
PA2 (0.021% yield) and PA3 (0.018% yield w/w) were characterized as phyllanthine, securinine and nor-securinine, respectively
by comparison of their spectral data with standard values. Two
new securinega-type alkaloids, isobubbialine and epibubbialine
were isolated from the leaves of P. amarus, as well as the three
known alkaloids, phyllanthine, securinine and nor-securinine. The
structures of the unknown compounds were determined by means
of UV, IR, mass and NMR spectroscopy (Houghton et al., 1996).
The 70% aqueous acetone extract of the aerial part of P. amarus
was fractionated over a column of Sephadex LH20 using aqueous
methanol to yield various fractions subjected to repeate chromatographic treatment alternating between MCI-gel CHP-20 using
aqueous methanol and Sephadex LH20 with aqueous ethanol led
to the isolation of amariinic acid, a novel ellagitannin, together
with 4-O-galloylquinic acid, elaeocarpusin, furosin, geraniinic acid
B, amariinic acid and potassium salt of repandusinic acid B and their
structures were established on the basis of chemical and 13 C NMR
spectrum (Foo, 1995). An unusual ellagitannin was isolated from
the biologically active polar fraction of aerial part of P. amarus. The
hydrolysable tannin fraction was obtained by column chromatography of the water soluble portion of the 70% aqueous acetone
extract of the aerial parts of the plant on Sephadex LH20 using aqueous methanol. Further chromatography of the fraction on MCI-gel
CHP-20 yielded phyllanthusiin D as an amorphous powder which
gave a [M-H] ion peak at m/z 991 with fast atom bombardment
(FAB) mass spectrometry (Foo and Wong, 1992).
Chemical constituents isolated and characterized so far from P.
amarus and their structures are given in Figs. 28.
8. Pharmacological activity
8.1. Antiamnesic activity
The effect of aqueous extract of leaves and stems of P. amarus
was evaluated on cognitive functions and brain cholinesterase
activity in male Swiss albino mice. P. amarus (50, 100 and
200 mg/kg) produced a dose-dependent improvement in memory
scores of young and older mice. P. amarus also reversed successfully
the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam
(1 mg/kg, i.p.). Interestingly, brain cholinesterase activity was also
reduced. Piracetam 400 mg/kg, i.p. was used as positive control
(Joshi and Parle, 2007). Nootropic activity of [6]-gingerol and phyllanthin was studied in mice using elevated plus maze and passive
avoidance paradigm. [6]-gingerol (25 and 50 mg/kg, p.o.) and phyllanthin (7.5 and 15 mg/kg, p.o.) signicantly attenuated amnestic
decits induced by diazepam, scopolamine (0.4 mg/kg, i.p.) and
natural aging. [6]-gingerol and phyllanthin increased step down
latencies signicantly in the aged mice, diazepam and scopolamine
induced amnesic mice as compared with piracetam (200 mg/kg,
i.p.). [6]-gingerol and phyllanthin signicantly decreased whole
brain acetyl cholinesterase activity (Joshi and Parle, 2006).
Fig. 4. Continued.
297
cold water) and ethanolic extracts of leaves of P. amarus was investigated for antimicrobial activity against S. typhi. Ethanolic extracts
of P. amarus revealed the strongest activity against S. typhi with
8.0 mm zone of growth inbibition followed by hot water (4.7 mm)
and cold water (3.8 mm). Ciprooxacin had the highest zone of inhibition (9.0 mm) against S. typhi followed by ooxacin (6.0 mm) and
amoxicillin (4.0 mm) (Oluwafemi and Debiri, 2008). Antimicrobial
effect of the plant extracts of P. amarus showed that the organic
and aqueous extracts of P. amarus were inhibitory to Streptococcus faecalis, while the extracts were not inhibitory to C. albicans.
Agar-well determined minimum inhibitory concentration (MIC)
values ranged between 3.125 and 6.25 mg/mL while the disc diffusion determined MIC values ranged between 6.25 and 25.0 mg/mL.
The agar-well determined MIC values for the ethanolic P. amarus
extracts (3.12 mg/mL) were lower than the corresponding disc diffusion MIC determined values (6.2525.00 mg/mL). Bacteriocidal
and bacteriostatic effect varied with, solvent type of extract, concentration and method of the test adopted. The active components
of the plant have no antifungal effect on the tested yeast, C. albicans (Okigbo and Igwe, 2007). The antimicrobial potential of the
299
compounds isolated from P. amarus. It was reported that Lucena1 was signicantly more resistant to the cytotoxicity of P. amarus
derivatives: the hexane extract (100 g/mL), the lignans-rich fraction (LRF, 100 g/mL) and the lignans nirtetralin (43.2 g/mL),
niranthin (43 g/mL) or phyllanthin (43 g/mL) exerted cytotoxic
effects on K-562 cells with 40.3, 66.0, 62.0, 61.0 or 24.1% of cell
death, respectively. The cellular toxicity observed on Lucena-1 was
16.3, 40.4, 29.4, 30.2, or 24.8%, respectively. These results suggested
a potential action of P. amarus derivatives as MDR reversing agents,
mainly due to their ability to synergize with the action of conventional chemotherapeutics (Leite et al., 2006). Administration of 75%
ethanolic extract of P. amarus at doses 250 and 750 mg/kg body
weight i.p. in mice for 14 days signicantly reduced the myelosuppression and improved the WBC count, bone marrow cellularity
as well as the number of maturing monocytes. P. amarus administration was found to decrease the activity of phase I enzyme.
Administration of P. amarus also increased the cellular glutathione
(GSH) and glutathione-S-transferase (GST), thereby decreasing the
effect of toxic metabolites of cyclophosphamide (CTX) on the cells.
Administration of P. amarus did not reduce the tumor reducing
activity of CTX. In fact, there was a synergistic action of CTX and P.
amarus in reducing the solid tumors in mice. It was indicated that
administration of P. amarus can signicantly reduce the toxic side
effects of CTX and is not interfering with the antitumor efciency
of CTX. When the aqueous extract of P. amarus was administered
to cancer bearing mice, it lowered the tumor incidents, level of
carcinogen-metabolizing enzymes levels of liver cancer markers
dose dependently (Kumar and Kuttan, 2005). The 75% methanolic
extract of aerial parts of P. amarus has been administered orally (750
and 250 mg/kg body weight) in the radiation (6 Gy) induced balb/c
mice for its protective activity against carcinogenesis. The WBC
count, bone marrow cellularity and -esterase activity increased
signicantly as compared to only radiation exposed mice. The
antioxidant enzymes such as superoxided dismutase (SOD), catalase (CAT), (glutathione-S-transferase) GST, glutathione peroxidase
(GPX), and glutathione reductase, both in blood and tissue, which
was reduced by radiation induced. P. amarus possesses the ability
to inhibit the unusual enzymatic pathways peculiar to cancer cells
proliferation and growth rather than a direct toxic effect of killing
the different types of cancer cells (Kumar and Kuttan, 2004). The
aqueous extract of P. amarus 150 and 750 mg/kg body weight thrice
weekly for 8 weeks treatment exhibited potent anticarcinogenic
activity against 20-methylcholanthrene (20-MC) induced sarcoma
development and increased the survival of tumor harboring balb/c
mice. The extract administration (p.o.) was also found to prolong
the life span of DLA and EAC bearing mice and reduced the volume of transplanted solid tumors (Rajeshkumar et al., 2002). The
aqueous extract of the entire plant of P. amarus, at the concentration of 10, 25, 50 and 100 g/plate showed an antimutagenic effect
against induction by 2-aminouorene (AF2), 2-aminoanthracene
(2AA) and 4-nitroquinolone-1-oxide (4-NQO) in S. typhimurium
strains TA98 and TA100, and in E. coli WP2 uvrA/pKM101. The
inhibition of N-ethyl-N-nitrosoguanidine (ENNG)-induced mutagenesis was observed only with S. typhimurium TA100. The extract
also exhibited activity against 2-nitrouorene (2NF) and sodium
azide-induced mutagenesis with S. typhimurium TA98 and TA100,
respectively. Based on the alkaline elution method, the plant extract
prevented in vivo DNA single-strand breaks caused by dimethylnitrosamine (DMN) in hamster liver cells. When the extract was
administered 30 min prior to the administration of DMN, the elution rate constant decreased more than 2.5 times, compared to the
control (Sripanidkulchai et al., 2002). Methanolic extract of stems
and leaves of P. amarus was tested for its antimutagenic activity
in S. typhimurium strains TA1535, TA100, and TA102 (Ames test).
P. amarus extract 500 mg/kg body weight for 12 days was able
to inhibit the activation and mutagenicity of 2-acetaminouorene
301
capsaicin-induced neurogenic pain. The extract of these Phyllanthus species when given intraperitoneally, produced dose related
and pronounced antinociception when assessed against chemical models of nociception, including acetic acid, formalin and
capsaicin-induced pain. Orally, these species were less potent and
efcacious than given by intraperitoneally (Santos et al., 2000).
8.8. Antioxidant activity
Antioxidant activity of aqueous extract of whole plant of P.
amarus at the dose of 200 mg/kg body weight/day was evaluated in streptozotocin (STZ)-induced diabetic male Wistar albino
rats. Antioxidant enzymes; GR, GPX and GST, CAT and SOD were
also assayed. Diabetic treated animal group showed a signicant decrease in renal LPO, protein oxidation and a signicant
increase in GSH content and GR, GPX and GST activities when compared with STZ-induced diabetic rats. The activities of SOD and
CAT decreased signicantly in STZ-induced diabetic rats, but were
normalized in diabetic treated group (Karuna et al., 2011). The
aqueous extract of whole plant of P. amarus showed signicant
(p < 0.05) potential in scavenging free radicals, and in inhibiting
lipid peroxidation. Furthermore, the extract proved to contain a
high content of phenolic compounds which were found to have
strong and signicant (p < 0.05) positive correlations to free-radical
scavenging potential, lipid peroxidation inhibition capacity and
cyto-protective efciency against Cr(VI)-induced oxidative cellular damage (Guha et al., 2010). Aqueous extract of P. amarus at
a dose of 200 mg/kg body weight/day for 8 weeks treated male
albino Wistar rats showed a signicant decrease in plasma LPO
and a signicant increase in plasma vitamin C, uric acid, GSH
level, GPX, CAT and SOD activities. Single cell gel electrophoresis (SCGE) experiment revealed that aqueous extract of P. amarus
was devoid of genotoxicity and had a signicant protective effect
against H2 O2 , STZ and nitric oxide (NO) induced lymphocyte DNA
damage (Karuna et al., 2009). Free-radical scavenging activity of
50% ethanolic extract of aerial parts of P. amarus extract and
phyllanthin was examined using 2,2-diphenyl-2-picrylhydrazyl
(DPPH) assay. The DPPH free-radical scavenging activity was
concentration-dependent in both cases and reaches a maximum at
a concentration of 300 g/mL for P. amarus extract and 20 mol/mL
for phyllanthin. No difference in inhibition was noted with further increase in concentration of either of the compounds. Results
indicated that phyllanthin exhibited very high antioxidative property as compared to P. amarus extract which is clearly evident
by its low IC50 value of 7.4 mol/mL (Krithika et al., 2009). The
antioxidant activity of some of its principal constituents, namely
amariin, 1-galloyl-2,3-dehydrohexahydroxydiphenyl (DHHDP)glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin
D, rutin and quercetin 3-O-glucoside were examined for
their ability to scavenge free radicals in a range of systems
including DPPH, 2,2-azobis-3-ethylbenzthiazoline-6-sulfonic acid
(ABTS)/ferrylmyoglobin, ferric reducing antioxidant power (FRAP)
and pulse radiolysis. The compounds showed signicant antioxidant activities with differing efcacy depending on the assays
employed. Amariin, repandusinic acid and phyllanthusiin D
showed higher antioxidant activity among the ellagitannins and
were comparable to the avonoids, rutin and quercetin 3-Oglucoside (Londhe et al., 2008). Pretreatment with P. amarus leaves
extracts on antioxidant enzymes in gastric mucosa homogenate
was studied. Signicant reductions (p < 0.05) in the gastric mucosa
catalase (CAT), super oxide dismutase (SOD) and glutathione-stransferase (GST) activities were observed in the ethanol group
compared with the normal control group. P. amarus acetone
extracts (1000 mg/kg) and cimetidine (100 mg/kg) caused an elevation by 53 and 52% for CAT, 8 and 14% for SOD and 33 and
38% for GST respectively when compared with the ethanol group.
303
were most active (0.24 g/mL). HIV-1 replication was also blocked
in CD4+ lymphoid cells with comparable EC50 values. Applying
a cell-based internalization assay, it was demonstrated 7075%
inhibition of virus uptake at concentrations of 2.5 g/mL for the
wateralcohol extract and geraniin. In addition, a concentrationdependent inhibition of HIV-1 reverse transcriptase (RT) was
demonstrated in vitro. The 50% inhibitory concentration (IC50 ) values varied from 1.8 to 14.6 g/mL (Notka et al., 2003). Study on
25 compounds isolated from P. amarus, P. multiorus, P. tenellus and P. virgatus found that niranthin, nirtetralin, hinokinin and
geraniin at the non-cytotoxic concentration of 50 m, suppressed
effectively both HBsAg and hepatitis B effective antigen (HbeAg)
expression, of these, niranthin showed the best anti-HBsAg activity, while the most potent anti-HBeAg activity was observed with
hinokinin (Huang et al., 2003). Analysis in HuH-7 cells (human hepato cellular carcinoma cell line) with transfected plasmids using a
luciferase reporter showed that DMSO solution of whole plant of
P. amarus at the concentration of 50, 100 or 200 g/mL specically
inhibited HBV enhancer I activity. To identify the mechanism of
this HBV enhancer I inhibition, liver-enriched cellular transcription factors were co-expressed in HuH-7 cells. The C/EBP and
as well as HNF-3 and (hepatocyte nuclear factor), transcription factor signicantly upregulated the HBV enhancer I activity.
In contrast, co-transfection of HNF-I or had no effect upon
the HBV enhancer I activity. Exposure to P. amarus inhibited C/EBP
and -mediated up-regulation of HBV enhancer I activity in a
dose-dependent manner, whereas HNF-3- and -mediated upregulation of HBV enhancer I was unaffected. In vitro gel shifts
showed that P. amarus inhibited complexing of C/EBP transcription factors to a consensus oligonucleotide sequence, whereas DNA
binding of AP-1 and SP-1 transcription factors was unaffected
(Ott et al., 1997). P. amarus inhibited hepatitis B virus polymerase
activity, decreased episomal hepatitis B virus DNA content and suppressed virus release into culture medium. When DSMO solution of
whole plant of P. amarus 80 mg/kg body weight i.p. daily for 7 days
was administered to transgenic mice, hepatic HBsAg mRNA level
was decreased, indicating transcriptional or post-transcriptional
down-regulation of the transgene. Increase in hepatitis B virus
mRNA expression after stimulation of the glucocorticoid responsive
element was also suppressed by P. amarus, suggesting involvement
of the hepatitis B virus enhancer in this response. Disruption by P.
amarus of hepatitis B virus polymerase activity, mRNA transcription and replication supports its role as an antiviral agent (Lee et al.,
1996). The effect of an aqueous extract of whole plant of P. amarus
at the concentration of 1 mg/mL on the cultured hepatoma cell
line HepA2 has been reported. The cell line had been transfected
with tandemly arranged HBV DNA and continued to synthesize
and secrete both HBsAg and HBeAg. Extract of P. amarus reversibly
inhibited cellular proliferation and suppressed HBsAg production
but not HBeAg production in HepA2 cells. P. amarus also suppressed
HBsAg gene expression at mRNA level in a time-dependent manner,
and selectively abolished the HBsAg gene promoter driven chloramphenicol acetyltransferase activity (Yeh et al., 1993). Ethanolic
extract and subsequent fractions (hexane, chloroform, butanol and
water) were tested for in vitro effects on HBsAg, HBeAg and HBV
DNA in serum samples positive for HBV antigens followed by the
screening of respective antigens by ELISA. HBV DNA was determined by molecular hybridization. The extracts were effective
against HBV antigens, the butanol extract being the most potent.
The chromatographic fractions showed an enhanced activity. The
active fractions inhibited the interaction between HBsAg/HBeAg
and their corresponding antibodies suggesting anti-HBs, anti-Hbe
like activity and also an effect on HBV DNA (Mehrotra et al., 1991).
Extracts of P. amarus have been shown to inhibit the DNA polymerase of HBV and Woodchuck hepatitis virus (WHV) in vitro.
Woodchuck carriers of WHV were treated intraperitoneally with
by Coxs proportional hazards analysis after adjusting for the variables that inuence the duration of jaundice. Only initial serum
bilirubin was an independent predictor of duration of jaundice.
The analysis showed that P. amarus powder did not signicantly
reduce the duration of jaundice in persons with virus B hepatitis (Narendranathan et al., 1999). The efcacy of P. amarus to treat
acute viral hepatitis (AVH) was evaluated in parallel to another drug
Essentiale (an essential phospholipid extracted from soybean oil)
and compared with a group of patients who were treated symptomatically with vitamins as the controls. Serological prole of 93
sporadic AVH cases of the study showed that 25.8% had an acute
infection due to hepatitis A virus (HAV), 52.6% suffered due to hepatitis B viral (HBV) infection, while 19.3% of cases were classied
as non-A non-B hepatitis (NANB) by exclusion. On follow up of the
patients at the end of treatment period of 4 weeks with respective drug regimen, it was seen that both P. amarus and Essentiale
brought about signicant biochemical and clinical normalcy among
the HAV infected patients compared to control group (p < 0.001). In
acute HBV group, P. amarus treated patients recovered faster than
the essentiale treated group and the controls (p < 0.001). Essentiale
was found to help the non-A non-B hepatitis patients to resume
earlier biochemical normalcy than by P. amarus and control treatments. P. amarus seemed to accelerate the clearance of HBsAg in
86.9% of convalescing AVH-B cases in 3 months time as against
48.0% in the Essentiale treated group and 50.0% in the controls
(Jayaram et al., 1997). The role of P. amarus in eradication of the
virus in hepatitis B carriers was evaluated by administering it to
30 asymptomatic carriers of HBsAg in a dosage of 250500 mg
thrice daily for 48 weeks. It was found that none of the 30 subjects cleared HBsAg. P. amarus was well tolerated, with no clinical
side effects or changes in the organ proles for safety evaluation.
It was found that P. amarus was not effective in clearing HBsAg
in asymptomatic carriers of the antigen (Doshi et al., 1994). Sixtyve adult asymptomatic chronic carriers of hepatitis B virus were
enrolled to the randomized controlled efcacy study of P. amarus.
Thirty-four received P. amarus 600 mg per day for 30 days and
31 received placebo in identical capsules. The conversion rate of
HBsAg was 6% in the study group at day 30. When 20 subjects in
the P. amarus group were given a further 30-day treatment and 22
placebo recipients given P. amarus 1200 mg per day for 30 days,
the conversion was observed in 1 (5%) in the higher dose group.
The results indicated that P. amarus, whole plant except root, given
at the studied dosage and duration, had a very minimal effect on
eradication of HBsAg asymptomatic chronic carriers (Thamlikitkul
et al., 1991). A total of 79 human carriers of HBV, out of these, 40
were given 200 mg of dried, powdered whole plant of P. amarus,
three times daily. The remaining 39 carriers were given lactose
placebo at the same dosage and frequency. Carriers were assigned
randomly to the treatment or control groups and neither the carriers nor their physicians were told of the assignment. The drug
or placebo was administered for 30 days then stopped; the carriers were then tested monthly for up to 9 months after cessation of
treatment or placebo. Thirty-seven of the treated carriers and 23
of the controls returned for follow-up. Of the treated subjects 59%,
but only 4% of 23 control subjects, became HBsAg-negative after
30 days and remained so until the end of the follow-up period.
Thirteen out of 14 carriers with HBsAg but without HBeAg became
negative, while only ve out of 17 HBsAg positive, HBeAg-positive
subjects lost the surface antigen. HBsAg did not reappear in any
of these subjects. The individuals who remained HBsAg-positive
are now being treated for longer periods to determine whether
active replication of virus requires longer duration of therapy. There
was no evidence of toxicity in the treated individuals, but these
observations were based primarily on clinical examination
(Blumberg et al., 1990). In a preliminary study, carriers of hepatitis B virus were treated with a preparation of the plant
305
P. amarus (200 mg doses in gelatin capsule presterilized with ethylene oxide, three times daily) for 30 days. 22 of 37 (59%) treated
patients had lost hepatitis B surface antigen when tested 1520
days after the end of the treatment compared with only 1 of 23
(4%) placebo-treated controls. Some subjects have been followed
for up to 9 months. In no case has the surface antigen returned.
Clinical observation revealed few side effects which include fatigue,
malaise, fever, chills, urticaria, anorexia, nausea, abdominal pain,
diarrhoea, headache, dizziness, disturbance of sleep and skin rash
(Thyagarajan et al., 1988).
8.12. Aphrodisiac activity
The effect of methanolic extract of the leaves of P. amarus on the
hormonal parameters of male guinea pigs was investigated. The
hormonal parameters investigated were testosterone, leutinizing
and follicle stimulating hormone. Methanolic extract of P. amarus
leaves (50800 mg/kg) caused a statistically signicant increase in
the level of testosterone of the male guinea pigs, from 2.3 0.06 to
3.9 0.05, 4.3 0.6 and 2.8 0.6 after the 7th, 14th and 21st day of
the administration of the extracts, respectively. Furthermore, the
methanolic extract of P. amarus (800 mg/kg) caused an insignicant change in the level of leutenizing (LH) and follicle stimulating
(FSH) hormones from 3.1 0.22 and 1.6 0.50 to 3.0 0.08 and
1.5 0.13, respectively (Obianime and Uche, 2009).
8.13. Contraceptive effect
Antifertility effect of an alcoholic extract of the whole plant of P.
amarus at a dose of 100 mg/kg body weight for 30 days orally was
investigated in cyclic adult female mice. The results revealed no
signicant change in absolute body and organ weights in extract
fed animals indicated no alteration in general metabolic status.
Cohabited females with normal male mice were unable to become
pregnant as their cyclicity was affected. These factors are related
to a change in the hormonal milieu that governs female reproductive function. Upon withdrawal of feeding for 45 days, these effects
were reversible. Thus, this extract manifests a denite contraceptive effect in female mice (Rao and Alice, 2001).
8.14. Diuretic and antihypertentive activity
8.14.1. Clinical study
Diuretic, hypotensive and hypoglycaemic effects of P. amarus
on human subjects were assessed. Nine mild hypertensives (four
of them also suffering from diabetes mellitus) were treated with
a preparation of the whole plant of P. amarus for 10 days. Suitable parameters were studied in the blood and urine samples of
the subjects along with physiological prole and dietary pattern
before and after the treatment period. Signicant increase in 24 h
urine volume, urine and serum Na levels was observed. A signicant
reduction in systolic blood pressure in non-diabetic hypertensives
and female subjects was noted. Blood glucose level was also significantly reduced in the treated group. Clinical observations revealed
no harmful side effects (Srividya and Periwal, 1995).
8.15. Hepatoprotective activity
The effect of aqueous leaves extract of P. amarus on matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases
was evaluated in alcohol and thermally oxidized polyunsaturated
fatty acid-induced hepatic brosis. The matrix metalloproteinase
expression was found to be signicantly decreased and the levels
of tissue inhibitors of matrix metalloproteinases and the collagen were signicantly increased in alcohol and thermally oxidized
polyunsaturated fatty acid treated male Wistar albino rats. Administration of P. amarus extract 3 mL/day for 45 days signicantly
decreased the levels of collagen and tissue inhibitors of matrix metalloproteinases; and positively modulated the expression of matrix
metalloproteinases. It revealed that P. amarus effectively modied
alcohol and thermally oxidized polyunsaturated fatty acid-induced
brosis (Surya Narayanan et al., 2011). The protective effect of
phyllanthin, a known principal constituent of P. amarus on ethanolinduced rat liver cell injury was evaluated. Primary cultures of
rat hepatocytes (24 h culturing) were pretreated with phyllanthin (1, 2, 3 and 4 g/mL) for 24 h. After 24 h pretreatment, cells
were treated with ethanol (80 L/mL) for 2 h. Ethanol decreased
%MTT, increased the release of ALT and AST with increase in the
production of intracellular ROS and lipid peroxidation. Phyllanthin demonstrated its role in protection by antagonizing the above
effect induced by ethanol. Phyllanthin also restored the antioxidant
capability of rat hepatocytes including level of total glutathione,
and activities of SOD and glutathione reductase (GR) which were
reduced by ethanol (Chirdchupunseree and Pramyothin, 2010). The
hepatoprotective activity of 50% ethanolic extract of aerial parts
of P. amarus plant (100, 200, and 300 mg/kg body weight daily
for 30 days) against CCl4 -induced liver damage in Swiss strain
female albino mice was determined. Carbon tetrachloride administration caused a signicant increase in liver and ALT, AST, ALP and
acid phosphatase (ACP), while total protein content signicantly
decreased as compared to vehicle control. The effect was dosedependent. Oral administration of aqueous extract of P. amarus
caused signicant mitigation of CCl4 induced changes. P. amarus
attenuated the toxic effects of carbon tetrachloride (CCl4 ) and
caused a subsequent recovery towards normalization. Administration of P. amarus at 300 mg/kg body weight offered maximum
recovery (98100%) against CCl4 (Krithika and Verma, 2009a,b).
The protective effect of P. amarus extract and phyllanthin was
studied on CCl4 -induced toxicity in human hepatoma HepG2 cell
line. The results indicated that CCl4 treatment caused a signicant
decrease in cell viability. It was observed that phyllanthin (4.18,
8.36 and 12.54 g/mL for 24 h) effectively alleviated the changes
induced by CCl4 in a concentration-dependent manner with much
smaller strengths as compared to (200, 400 and 600 g/mL) P.
amarus water ethanol extract (Krithika et al., 2009). Silymarin and
standardized extract obtained from the whole plant of P. amarus
100 mg/kg body weight against CCl4 -induced hepatotoxicity in rats
were found effective as hepatoprotective as evidenced by plasma
and liver biochemical parameters. The combination of silymarin
and P. amarus (50 mg + 50 mg/kg body weight for 6 days orally on
male Rattus norvegicus strain showed synergistic effect for hepatoprotection and silymarin with ethanolic extract of P. amarus
showed better activity due to the higher concentration of phyllanthin in ethanolic extract in comparison to aqueous extract
of the plant (Yadav et al., 2008). The hepatoprotective effect of
methanolic extract of the leaves of P. amarus was evaluated against
ethanol-induced oxidative damage in adult male Wistar albino
rats. Methanolic extract of P. amarus (250 and 500 mg/kg body
weight/day and ethanol 5 g/kg body weight/day 20% w/v) were
administered orally to animals for 4 and 3 weeks respectively.
It was reported that the ethanol treatment markedly decreased
the level of reduced GSH, SOD, and CAT in the liver, which were
signicantly enhanced by P. amarus treatment. GST, which was
increased after chronic ethanol administration, was signicantly
reduced by P. amarus treatment in the liver (Faremi et al., 2008).
In vitro study, P. amarus aqueous extract (14 mg/mL) increased
%MTT reduction assay and decreased the release of AST and ALT in
rat primary cultured hepatocytes being treated with ethanol. Hepatotoxic parameters studied in vivo included serum AST and ALT,
serum triglyceride (STG), hepatic triglyceride (HTG), TNF-, interleukin 1 (IL-1), together with histopathological examination. In
307
and avonoids (rutin, and quercetin 3-O-glucoside) at the concentration of 0.1, 0.2, 0.3 and 0.4 nM effectively prevented lipid
peroxidation and protein oxidation in mitochondria. The compounds also prevented radiation induced single-strand breaks in
pBR322 plasmid DNA (Londhe et al., 2009). 75% methanolic extract
of aerial parts of P. amarus at concentrations of 250 and 750 mg/kg
body weight on balb/c mice were found to elevate the antioxidant
enzymes in the intestine and decrease the lipid peroxidation levels.
Histopathological evaluations of the intestine revealed decreased
damage to intestinal cells. P. amarus was found to protect the
clastogenic effects of radiation as seen from decreased number
of micronuclei. The administration of P. amarus was also found to
decrease the percentage of chromosomal aberrations (Harikumar
and Kuttan, 2007). The radioprotective effect of 75% methanolic
extract of aerial parts of P. amarus was investigated in adult balb/c
mice. P. amarus extract (750 and 250 mg/kg body weight) significantly increased the total WBC count, bone marrow cellularity,
and -esterase activity as compared to untreated radiation exposed
animals. P. amarus treatment also increased the activity of various
antioxidant enzymes, such as SOD, CAT, GST, GPX, and GR, both
in blood and tissue, which were reduced by radiation treatment.
There was also a signicant increase in GSH levels of blood and tissue. Lipid peroxidation levels, which were increased after radiation,
were signicantly reduced by P. amarus treatment, both in serum
and liver (Kumar and Kuttan, 2004).
8.20. Spasmolytic activity
Potential spasmolytic activity of the extracts of P. amarus was
judged by their ability to reduce forces of smooth muscle contraction of a 2 cm long piece of guinea pig ileum induced by
EC50 acetylcholine (27 5 g/L) or EC50 histamine (102 13 g/L)
(Mans et al., 2004).
8.21. Effect on reproductive organs
The effect of a carbamate insecticide, carbofuran was studied
on estrous cycle and follicular growth in virgin female Wistar rats
as well as recovering from the damaged estrous cycle with treatment of P. amarus lignans viz. phyllanthin and hypophyllanthin.
Since, phyllanthin and hypophyllanthin at the dose of 100 mg/kg
body weight have been found to be systemically transformed into
enterolignan(s), which is known to be responsible for augmenting
estrous cycle in rats (Islam et al., 2008b). The aqueous crude extracts
of P. amarus were administered to 38-week old sexually mature
male albino to determine the effect of extract on the male reproductive organs of these animals. The results from the study revealed
that the aqueous crude extracts of P. amarus caused varying degrees
of testicular degeneration as well as reduction in the mean seminiferous tubular diameter (STD) in the treated rats (Adedapo et al.,
2003).
9. Toxicological assessment and contraindications
Histological studies to know the effects of oral administration of
aqueous extract of P. amarus on the kidney of adult Wistar albino
rats were carried out at the doses of 500 and 1000 mg/kg body
weight respectively for 28 days, while the control rats received
equal volume of distilled water. The rats were sacriced on day
29 of the experiment and kidneys were dissected and quickly xed
in 10% formal saline for routine histological study. The histological ndings indicated that the treated sections of the kidneys
showed hypertrophy of blood vessels, mild-severe inltrate of
chronic inammatory cells and varying degrees of tubular necrosis
when compared to the control sections. The ndings indicated that
the administration of P. amarus extract has some adverse effects
10. Conclusion
The scientic research on P. amarus suggests a huge biological potential of this plant. It is strongly believed that detailed
information as presented in this review on the phytochemical and
various biological properties of the plant might provide detailed
evidence for the use of this plant in different diseases. It has
various traditional uses that differ from one country to another
whereas some important uses for the treatment of jaundice, diabetes, dysentery, fever, gonorrhea, syphilis and stomachache and
skin diseases are almost common. P. amarus, a potent herbal
medicine is attracting researchers since many decades due to its
high therapeutic value. There is a demand to standardize the properties of P. amarus and their detailed clinical trials. Pharmacological
and chemical studies have demonstrated that the extracts of the
plant possess various pharmacological actions viz. antiviral, antiinammatory antimalarial, antimicrobial, anticancer, antidiabetic,
hypolipidemic, hepatoprotective and nephroprotective. Owing to
the impressive preclinical therapeutic potential, the plant extracts
have been evaluated in human trials for the treatment of HIV, jaundice, hypertension and diabetes.
P. amarus is reported to contain lignans, avonoids, hydrolysable
tannins (ellagitannins), polyphenols, triterpenes, sterols and
alkaloids. The phytochemicals exhibited different structural characteristics with various pharmacological actions. The lignans
nirtetralin, phyltetralin or niranthin isolated from P. amarus signicantly inhibited PAF-induced paw oedema formation in mice.
Niranthin decreased the specic binding of 3[H]-PAF in mouse
cerebral cortex membranes. Phyltetralin, nirtetralin and niranthin
also inhibited carrageenan-induced paw oedema and neutrophil
inux. Niranthin also showed the best anti-HBsAg activity while
the most potent anti-HBeAg activity was observed with henokinin.
The presence of high contents of phenolic compounds in the aqueous extract of P. amarus was found to have strong and signicant
antioxidant activity. Phyllanthin isolated from aqueous extract
of leaves of P. amarus exhibited very high antioxidant activity.
Amariin, repandusinic acid and phyllanthusiin D showed higher
antioxidant activity. A gallotanin containing fraction and the isolated elllagitanins geraniin and corilagin were shown to be most
potent mediators of antiviral activities. The puried gallatanins
geraniin and corilagin were most active to inhibit HIV-1 replication in Hela CD4+ cells. Mixture of phyllanthin and hypophyllanthin
309
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