Bhumyamalaki (Phyllanthus amarus, Phyllanthus niruri)


Bhumyamalaki (Phyllanthus amarus, Phyllanthus niruri)



Introduction          
Bhumyamalaki (Phyllanthus niruri- Phyllanthus amarus) is principally a kharif crop (growing in rainy season) growing as a contaminant weed in cultivated fields and in wasteland. Traditionally though a trusted medicine it is not cultivated as “medicinal plant” but is gleaned from fields or is gathered directly from forests or wastelands. Since the weed reduces the crop yield by 10 to 15% it is considered a ‘nuisance’ by farmers. However it obliges the medical fraternity and mankind by its pleiotropic actions. The herb is extolled in Ayurveda and by herbalists. The herbalists used to sell it in fairs and marketplaces. It is their wont even today. It has a long history in herbal systems of medicine in every tropical country where it grows. The way indigenous peoples employ it (standard infusion or weak decoction of the whole plant) is also very similar worldwide. [1], [2]                                                                                                   
As the shrub grows close to the ground and its leaves resemble those of Aamalakee (Amalaki) its Sanskrit epithet is    Bhoomyaamalakee (Bhumyamalaki). Another Sanskrit epithet is Bhoodhaatree (Bhoodhatri). Bhoo stands for earth and Dhaatree means a foster mother. Indigenous to India, for eons, this was a valuable drug in the medicinal chest of the proverbial grandmothers and the laity. In India, even today, it is a common household remedy for asthma, bronchitis, extreme thirst, jaundice and tuberculosis.  
Also indigenous to the Bahamas it is called hurricane weed or gale-wind grass. It is used there for poor appetite, constipation, fever, cough and cold. [3] 
The Spanish name for Phyllanthus niruri is Chanca Piedra. Translated in English it means “Shatter stone” or “Stone breaker” because the indigenous peoples of the Amazon have been using it to eliminate kidney stones and gallstones and is still in vogue there. “Stone breaker”! Quite an epithet to live up to!   [4], [5] 
In South America even in modern times Phyllanthus niruri is the most popular remedy for the treatment of gallstones and kidney stones. 
It is very popular in Peruvian herbal medicine for the treatment of hepatitis, UTI and as diuretic. 
In Brazilian herbal medicine it is considered an excellent remedy to remove urinary stones especially uric acid stones. [6] 
The flowers that seem to be borne on the leaves are called foliage flowers. Hence the epithet of the genus of this herb isPhyllanthus. [7] 
‘Phyllanthus’ means ‘leaf and flower’. The genus is named so because of its appearance where flower, fruit, and leaf appear ‘fused’[8] 
Charles von Linne was a Swedish physician, botanist and zoologist. Better known as Carl Linnaeus, he was the father of modern taxonomy and ecology. The epithet of this species niruri (“Shatter stone” or “break stone”) was assigned to this plant by Carl Linnaeus, and comes from its Indian vernacular name. [9] 
Though the plant has been used to treat/cure afflictions of various systems, for want of scientific documentations and clinical research, the skeptics considered the claims of cure more as a bluff than as a plant wonder. However phytochemical research since 1960 and clinical research thereafter established its pleiotropic actions. These actions were attributed to its remarkably complex chemical composition. [10], [11]
Other Names
Latin /Botanical/ Taxonomic: Phyllanthus niruri L. Phyllanthus fraternus Webster
          Phyllanthus amarus, Phyllanthus urinaria
Sanskrit: Bhumyamalaki (Bhoomyaamalakee), Bhoodhaatree
English:  Stone breaker, Seed under leaf
Aassamese: Bhui Aamala,
Bengalee: Bhumamala, Bhumi-Aamalakee 
Gujarati: Bhoy aawalee, Bhoy aamalee, Kanocha, Ranavli
Hindi: Bhueeaaolaa, Kanocha, Kanochha, Ranavli, Jar-Aamalaa
Kannada: Madarasa nelli, Nelanelli
Malayalam: Keezharnelli
Marathi: Bhueeaawalaa, Bhueeaawalee.
Tamil: Mela nelli, Keezharnelli
Telugu: Nullausereki, Nallausirike
AKA Spanish: Chanca Piedra, Portuguese: Quebra Pedra.  [12], [13]
Taxonomic classification
Kingdom:  Plantae
(Unranked): Angiosperms
(Unranked): Eudicots
(Unranked): Rosids
Phyllum:       Magnoliphyta
Division:     Magnoliophyta – Flowering plants
Class:         Magnoliopsida – Dicotyledons
Order:        Malpighiales, Euphorbiales, Tubiflorae
Family:      Phyllanthaceae, Euphorbiaceae – Spurge family [14], [15] 
Phyllanthus is the largest genus in the family Phyllanthaceae. It includes 500 to 1200 species growing in temperate and tropical zones. Many of them are of medicinal value. The genus has a remarkable diversity of growth forms but the species express more or less similar pattern. In recent times the family Phyllanthaceae is divided into four genera.  
Phyllanthus urinaria, Phyllanthus amarus and Phyllanthus niruri are similar species. The difference is thatPhyllanthus niruri has larger leaves than the other two and its fruit is wart-like. 
Geographical distribution 
This annual plant is widespread is tropical and subtropical regions of Asia, America and China. It is commonly found as a weed in coastal areas and sandy regions of both hemispheres. Although its botanical center of origin is unknown; it is regarded as indigenous to central and southern India, China, tropical areas of the Bahamas and other tropical areas throughout the world and the rain-forests of Amazon. It usually grows in the wild after first showers of monsoon in Jharkhand, Bihar, Chhattisgarh and and many other states of India. In Indian states it usually grows during second week of June and starts bearing fruits up to mid July to August. However under favorable conditions it can grow and survive up to mid winter. 
It may be found along with crops of gram, wheat, pea etc. It is found growing along the road sides, in the street corners and dumps of building materials. [16], [17], [18]
Plant Morphology
Macroscopic Characteristics
                                     
The Plant 
This is a small, branching, glabrous and erect annual herb. It has been seen growing in coastal areas. It looks like Aamala plant that grows near earth. It is a small erect annual plant. It grows 30 to 70 cm tall in height. In appearance it resembles weed and in rain forests spreads freely like a weed.

                                                      
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Root: is small, 2.5-11 cm long, nearly straight, gradually tapering with a number of fibrous secondary and tertiary roots; external surface light brown in color; fracture is short. 

  
Stem is slender, glabrous, yellowish or light brown, woody, terete (cylindrical), 20-75 cm long; branching is profuse, bearing 5-10 pairs of leaves; with internode 1-3.5 cm long; odor indistinct, taste slightly bitter 
Bark is smooth and light green. Younger parts are rough.


      
                                                                 

Leaf Leaves are numerous, on slender branches. The leaf is compound, leaflets are arranged in two rows with a rachis; alternate, opposite, elliptic-oblong or obtuse, distichous (arranged alternately in two vertical rows on opposite sides of the axis),  sessile, stipulate, entire, 1.5 cm long and 0.5 cm wide; rounded at base; greenish brown in color; odor indistinct, taste bitter.


  

Flowers numerous, yellowish, whitish or pale green which are often flushed with red. They are axillary, monoecious (having the male and the female reproductive organs on different parts); male flowers are one to three in number, female flowers are solitary. In the South Hemisphere, they bloom from July to April and in the North Hemisphere, from January to October.

                                       

Fruits are tiny, 1.8 to 2.5 mm in diameter, depressed globose smooth scarcely lobed capsules present underneath the branches.
                                                             



Seeds about 0.9 mm long, triangular, pale brown with 6-7 longitudinal ribs and many transverse striations on the back. [19], [20], [21], [22], [23], [24], [25], [26]

Microscopic Characteristics
Root: The transverse section shows 4-6 layers of cork consisting of thin-walled, rectangular, tangentially elongated and radially arranged cells filled with reddish-brown contents; the secondary cortex consists of 8-10 layers of thin-walled, elongated, parenchymatous cells; the secondary phloem narrow, consists of sieve elements, phloem parenchyma is traversed by narrow phloem rays; secondary xylem is represented by a broad zone of tissue composed of vessels, tracheids, fibers and parenchyma, all elements being thick-walled and lignified with simple pits; xylem rays are uniseriate.

Stem: The transverse section shows a single layer of epidermis, composed of thick-walled, flattened tangentially elongated cells; an older stem shows 4-5 layers of cork composed of thin-walled, tabular, tangentially elongated and radially arranged cells filled with reddish brown contents; the cortex is composed of 4-6 layers of oval, tangentially elongated thin-walled, parenchymatous cells and some cortical cells filled with yellowish brown content; the endodermis is quite distinct; the pericycle represented by a discontinuous ring composed of several tangentially elongated strands of lignified fibers with thick walls and narrow lumen; secondary phloem is narrow, composed of sieve elements, dispersed in a mass of phloem parenchyma; secondary xylem is composed of vessels, fibers and parenchyma and is traversed by numerous uniseriate rays; vessels are mostly simple pitted with a few show spiral thickenings; fibers are narrow, elongated, with narrow or sometimes blunt ends with simple pits; the centre is occupied by a pith composed of thin-walled, circular to oval parenchymatous cells and occasionally clustered crystals of calcium oxalate are present in parenchymatous cells of brown tissue.

Leaf: The transverse section of leaf shows a biconvex outline; epidermis on either side is a single layer covered externally by a thick cuticle; a palisade layer is present beneath the upper epidermis, intercepted by a few parenchymatous cells in the middle; meristele is composed of small strands of xylem towards the upper surface and phloem towards the lower surface; the rest of the leaf tissue is composed of thin-walled parenchymatous cells, some having clusters of calcium oxalate crystals; lamina shows a dorsi-ventral structure, with mesophyll differentiated into palisade and spongy parenchyma; epidermis on either side is composed of thin-walled tangentially elongated cells covered externally by a thick cuticle; anisocytic-type stomata are present on both epidermises; single layer palisade; mesophyll is composed of 3-5 layers of loosely arranged cells with a number of veins traversing this region; a few clusters of calcium oxalate crystals are present in spongy parenchyma.

Powder: The drug powder is brown in color; under the microscope it shows fragment of cork cells, vessels and fibers.  [27], [28], [29], [30] 

Parts Used
Root, leaves, fruits, milky juice, and whole plant

Phytochemistry

                               Phytochemicals of Phyllanthus amarus / Phyllanthus  niruri are as follows: 
           
Flavonoids
Rutinquercetinquercitrinastragalin, catechin, prenylated flavone glycoside, nirurin, niruriflavone

Terpenes and Triterpenes
Linonene, p-chymene, lupeol, lupeol acetate
2Z, 6Z, 10Z, 14E 18E, 22E-farnesil farnesol

Coumarins
Ellagic acid, methylbrevifolincarboxylate
Majolignans
Phyllanthin and hypophyllanthin, phylltetralin,niranthinhdroxyniranthin,dimethylenedioxyniranthinnirtetralin, isolintetralinlintetralin
Minolignans
Phyllanthusiin D, amariin, amarulone, amarinic acid
Tannins and Elagitannins
Repandusinic acid, geranin, corilagin,
 1,6-digalloylglucopyranoside, rutin , quercetin- 3-O-glucopyranoside , Amarulone, Phyllanthusiin D & Amariin, 1-Ogalloyl-2,4-dehydrohexahydroxydiphenoyl-glucopyranose elaeocarpusin, repandusinic acid A and geraniinic acid

Saponins
Diosgenin
Alkaloids
Norsecurinines, nirurine, phyllanthine,phyllochrysine, isobubbialine, epibubbialine,diarylbutane, nyrphyllin and alkaloids of thequinazolidine type
Othercompounds
Beta-glucogallin, linear and complex hetero xylans, niruriside
Hydrocarbons
Triacontanal, triacontanol
Common lipids
 Exact information not available
Phyosterols
 Exact information not available
Volatile oil 
Linalool and Phytol
Lignans

Polyphenols


                                                                                                           [31], [32], [33]

Recently, from the leaves of Phyllanthus  amarus S. P. Thyagarajan et al isolated two new securinega-type alkaloids, isobubbialine and epibubbialine, in addition to these known alkaloids, phyllanthine, securinine and norsecurinine are isolated [34]

Of recently a molecule wonder ‘arabinogalactan’ (AG) has been isolated from Phyllanthus niruri.
Some scientists isolated geraniin and 1346TOGDG from Phyllanthus niruri. [35] 

Phytochemicals iVarious Parts oPhyllanthus amarus / P. niruri
 
The whole plant
Rutin, quercetinquercitrin, prenylated flavonglycoside,nirurinellagic acid,hypophyllanthin, repandusinic acid,geranin, corilagindiosgenin,norsecurinines, β-glucogallin, linearand complex hetero xylans,niruriside
Leaf
Quercitrin, astragalinp-chymene,phyllanthin, niranthin,hydroxyniranthin, dimethylene-dioxyniranthinnirtetralin,isolintetralinlintetralin,phyllanthine
Root
Catechin, lupeol, phyllanthine
Stem
Phyllanthine
Aerial parts
Nirurine, triacontanal, triacontanol

                                                                                                                   [36], [37]

Identity, Purity and strength Tests
(1)
Foreign matter: Not more than 2 %
Total ash: Not more than 16 %
Acid-insoluble ash: Not more than 7 %
Alcohol-soluble extractive: Not less than 3 %
Water-soluble extractive: Not less than 13 % [38]

(2) Standards accepted by I.P. in 2010

Foreign organic matter:  Not more than 2.0 %
Ethanol-soluble extractive:  Not less than 6.0 %
Water-soluble extractive: Not less than 15.0 %
Total Ash: Not more than 8.0 %
Acid-insoluble ash: Not more than 5.0 %
Heavy metals 1.0 g complies with the limit test for heavy metals
Loss on drying Not more than 12.0 per cent, determined on 5 g by drying in an oven at 105°C
Microbial contamination Complies with the microbial contamination tests. [39]

Color Tests for identification
Observed colors after treating the solution of Phyllanthus niruri (Phyllanthus amarus) are:
1. Conc. HCl                   Green
2. NaOH (5%)               Brown
3. KOH (5%)                  Brown
4. FeCl3                                 Green to dark green

TLC Patterns 

Recently TLC, HPLC patterns are also used for the identification of Phyllanthus niruri. [40]

Various assays are also available to establish the identity of Phyllanthus amarus [41]

Cytological Identification
7 Chromosome counts in Phyllanthus amarus Schumach. & Thonn [42]

Genetic Identification
Although above-mentioned tests are useful to identify Phyllanthus niruri, genetiidentification method is goldstandard.
Recently SCAR markers are developed for the correct identification of Phyllanthus species. [43]

Purity Tests (Accepted Internationally)
Foreign Matter: Not more than 2%
Ash content:
  (A) Total Ash: Not more than 9%
  (B) Acid-soluble Ash: Not more than 2%
Loss on drying: Not more than 10%
Extractive Values:
  (A) Water-soluble Extract
       Hot Method:   Not less than 21%
       Cold Method: Not less than 14%

(B) Ethanol-soluble Extract
        Hot Method:    Not less than 13%
        Cold Method:  Not less than 7% 

Safety Tests
Heavy Metals:
Arsenic:             Not more than 5.0 mg/kg
Mercury:           Not more than 0. 5 mg/kg
Lead:                  Not more than 10.0 mg/kg
Chromium:      Not more than 0.3 mg/kg
Microbial Limits:
Total bacterial count:                                                Not more than 10cfu/g
Total yeast and mould count:                                 Not more than 10cfu /g 
Bile tolerant gram negative bacteria:                   Not more than 10cfu/g 

Specific Pathogens:
Salmonella spp:                        Absent in 25 g
Escherichia coli:                       Absent in 1g   
Staphylococcus aureus:           Absent in 1g          
Pseudomonas aeruginosa:         Absent in 1g  [44] 

Properties and Pharmacology

Ayurvedic Properties
Ganas (Classical Catagories)
        Charaka Ganas:  None
        Sushruta+Ganas: None

Energetics 

Rasa (Taste): Tikta (Bitter), Kashaaya (Astringent), Madhura (Sweet)
Weerya/Virya (Energy State): Sheeta (Cooling)
Wipaaka/ Vipak (End result, Post digestive effect): Madhura (sweet)
Prabhaawa/ Prabhav (Special Effect, Prominent Effect): None 

Note: Here I wish to clarify the meaning of these technical words: 
Virya (Weerya): Potency, power, vigor
Vipak (Wipaak): After digestion change of taste. The food we take is acted upon by jatharagni (digestive activity) and the taste of the food changes. The original rasa (taste) changes to vipak (new or same taste.)
Prabhav (Prabhaawa): Effect, prominent, peculiar or special action of an herb. Innate and specific property [45]
Gunas (Qualities): Laghu (Light), Rooksha (Dry)
Effects on Doshas: Kapha, Pitta 
Actions on Dhaatus (Tissues): Asthi (Bones: Healing fractures), Rasa (Lymphatics), Rakta (Blood)
Actions on Srotas (Systems): Annawaha (Gastro-Intestinal Tract), Raktawaha (Hemopoetic System), Mootrawaha (Urinary System)
Ayurvedic Actions
Deepana: Appetizer 
Kaphaghna: Allays catarrhal inflammations
Kushthaghna: Antileprotic and useful in skin disorders
Krimighna: Anthelmintic and anti microbial
Jwaraghna: Anti-pyretic
Mootrala: Diuretic
Paachana:  Digestive (Digestant/ Digestive)
Rakta-Pradara: Allays menorrhagia
Rakta pitta shaamaka: Allays rakta pitta
Rakta shodhaka:  Blood purifier   
Shweta pradara: Relieves leucorrhea
Wranaropana: Vulnerary (Wound healer)   
Yakruduttejaka: Stimulates the functions of the liver.  [46], [47]
According to Ayurvedic system of medicine it is considered alexipharmic (acting as antidote to poisons) and vulnerary
Modern View 
Some recent studies show that Phyllanthus niruri is febrifuge, antiseptic, astringent, stomachic and diuretic
The fresh plant extract and the methanol extract show antioxidant activity
Some therapeutic properties of Phyllanthus niruri include anti-hepatotoxic, anti-lithic, anti-hypertensive, anti-HIV and anti-hepatitis B activity. [47 A]
Given orally to mice the whole plant extract shows marked radioprotective activity by decreasing the damage to intestinal cells, decreasing the percentage of chromosomal aberration, decreasing the lipid peroxidation levels and by elevating the levels of antioxidant enzymes in the intestines, liver and blood.
Radioprotective activity of Phyllanthus niruri is attributed to ellagitannins (amariin, 1-galloyl-2, 3-dehydrohexahydroxydiphenyl (DHHDP)-glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin D) and flavonoids (rutin, and quercetin 3-O-glucoside). [48]
To study the protective effect of the extract of Phyllanthus amarus against the damage induced following radiation, 250 mg/kg and 750 mg/kg of the extract were administered orally to mice for five days prior to and for one month after 6 Gy whole body radiations. Treatment with Phyllanthus amarus extract significantly increased the total white cell count in the blood, cellularity of the bone marrow and alpha-esterase activity as compared to untreated animals exposed to radiation. The treatment also increased the activity of Superoxide Dismutase (SUPEROXIDE DISMUTASE (SOD)), Catalase (CAT), Glutathione-S-Transferase (GST), Glutathione Peroxidase (GPX), and Glutathione Reductase (GR), both in the blood and in the tissues, which were reduced by radiation treatment. There was also a significant increase in the glutathione (GSH) levels of blood and tissues. Lipid peroxidation levels, which were increased after radiation, were significantly reduced by the treatment, both in serum and liver. These results indicate that P. amarusextract increases the antioxidant defense mechanism in mice and thereby protects the animals from damage induced by radiation. [49]
Administration of 75% methanolic extract of Phyllanthus amarus at doses 250 and 750 mg/kg body weight significantly reduced the myelosuppression caused by cyclophosphamide. It improved the WBC count, bone marrow cellularity and the number of maturing monocytes. It reinstated glutathione levels.  When administered simultaneously with cyclophosphamide it did not interfere with anticancer activity of cyclophosphamide but reduced its toxic effects thus exhibiting chemoprotective activity. [50]
When given orally to male mice the aqueous crude extract causes varying degrees of declining in fertility. When given orally to female rats at the dose of 100 mg/kg bodyweight for 30 days, the alcoholic extract of the whole plant shows significant contraceptive effect.
The methanol extract of the leaves of Phyllanthus amarus (Dose: 50 to 800 mg/kg) caused a significant decrease in the elevated levels of total cholesterol, AST, ALT, urea, uric acid, alkaline and acid phosphatases, thus exhibiting cardioprotective, hepatoprotective and nephroprotective properties. [51]
Rutin
Molecular formula:  C27H30O16 
Structural formula:

Other names:  Rutoside, Phytomelin, Sophorin, Birutan, Eldrin and many more.
Rutin is the glycoside between the flavonol quercetin and the disaccharide rutinose. Its chemical structure is very much similar to that of quercetin.  
Rutin is a plant pigment found in fruits and vegetables and contributes to the antibacterial properties of the plants.
Rutin is anti-inflammatory, stronger anti-oxidant than quercetin. Rutin inhibits platelet aggregation, decreases capillary permeability and improves circulation. It inhibits vascular endothelial growth factor, thus inhibiting angiogenesis in tumors.
In rats rutin increases iodine uptake by thyroid without raising serum T3 T4. [52]

Quercetin
Molecular formula: C15H10O7
Strucural formula:


Quercetin is a flavonoid (plant pigment)
Quercetin is found in fruits, vegetables, leaves, grains and various types of honey. It is found in red wine, onions, green tea, apples, berries, Ginkgo biloba and St. John’s wort
It is used in beverages and as a food supplements. [54]
Quercetin is anti-inflammatory (hence used in fibromyalgia rheumatoid arthritis and gout). It is anti-oxidant. It is anti-microbial and anti-viral. It inhibits reverse transcriptase, part of the replication process of retrovirus. It is anti-allergic hence is used in hay fever, bronchial asthma and eczema. It is used to treat diabetes and metabolic syndrome. It is Monoamine-Oxidase (MAO) inhibitor. It is used in treating dyslipidemia and atherosclerosis. It is also used to boost immunity, increase endurance and improve athletic performance
Quercetin competitively binds to bacterial DNA gyrase. Hence it is contraindicated with some antibiotics especially fluoroquinolones. [55]

Quercetin and Alcoholic Liver Disease

Disorder of lipid metabolism and oxidative stress are the important factors in the pathogenesis and progression of Alcoholic Liver Disease (ALD). The mitochondria compartment of the hepatocytes is the main target of this oxidative stress. Therefore antioxidants and free radical scavengers should counter this damage
In animals pretreated with quercetin, ethnol-stimulated mitochondrial dysfunction was ameliorated. [56]
Quercetin downregulates the ethanol-induced expression of glutathionine peroxidase 4 (GPX4). Quercetin reduces the ethanol-induced expression of SUPEROXIDE DISMUTASE (SOD)2 to downregulate the expression of Gadd45b which can damage DNA of hepatocytes which in turn culminates in ALD. [57]

Quercetin against HCV Infection

Quercetin and its five derivatives have shown selective anti-HCV activity. These molecules by inhibiting NS3 and heat shock proteins suppress the replication of hepatitis C virus. (Heat shock proteins are essential for HCV replication). Quercetin has a direct inhibitory action on HCV NS3 protease. The inhibition of NS3 by quercetin is dose dependent. [58], [59]

Quercetin against HBV Infection 

The flavone glucoside in the structure of quercetin plays an important role in exhibiting anti-hepatitis B activity. In addition, substitution of acyl group on glucoside may be important for anti-HBV activity. Quercetin does not show activity against HBeAg secretion. This is due to the absence of saccharide group in the structures of quercetin. [60], [61]
For more information about quercetin ref. to Aamalakee (Emblica officinalis)

Quercitrin 
Molecular formula: C21H20O11
Structural formula:


Quercitrin is a glycoside formed from quercetin and rhamnose. It is anti-inflammatory. It exhibits antioxidant and free radical scavenging activity probably via some different mechanism hitherto not clearly understood [62]

Catechin
Molecular formula: C15H14O6
Structural formula:

Catechin has been found to be the most powerful anti-oxidant and free radical scavenger among different members of the different classes of flavonoids. [63]

Lupeol
Molecular Formula: C30H50O 
Structural Formula:


Lupeol is a pharmacologically active triterpenoid. It is anti-inflammatory. It decreases IL4 production by T-helper type 2 cells. Lupeol has complex pharmacological actions in humans, displaying antimicrobial, anti-protozoal, anti-tumor and chemoprotective properties. In laboratory models it inhibits prostate and skin cancers.  [64]

Phyllanthin and Hypophyllanthin:
Molecular formula: Phyllanthin C24H34O6
Structural formula: Phyllanthin 
             [65]

Molecular formula: Hypophyllanthin C24H30O
Structural formula: Hypophyllanthin

                                       [66]

Phyllanthin and Hypophyllanthin are major bioactive lignans. They inhibit DNA polymerase and reverse transcriptase of hepatitis B virus, Woodchuck hepatitis virus and retroviruses. Thus they arrest their replication.
Phyllanthin and hypophyllanthin present in P. amarus inactivate hepatitis B virus, both in vitro and in vivo. [67]
Chanca piedra (Phyllanthus amarus) lowers blood cholesterol, low density lipoprotein and very low density lipoprotein by reducing the ability of the liver to synthesize cholesterol and by increasing the fecal (faecal) bile acid excretion. These effects on blood and liver were attributed to phyllanthin and hypofhyllanthin found in Phyllanthus niruri.  [68]
KB cell culture is a cell line derived from a human carcinoma of the nasopharynx. Since 1960 it has been used by the National Cancer Institute (NCI) as an anti tumor assay for screening antitumor activity of plant extracts. This in vitroassay is more sensitive than in vivo assay. It is less expensive, requires less test material and less time. Phyllanthin and Hypophyllanthin enhance the cytotoxic response mediated by vinblastine with multidrug-resistant KB cells.  [69]
These lignans show activity against Ehrlich ascites carcinoma in mice. They have protective effect in doxorubicin induced toxicity. [70]
Along with phyllanthin and hypophyllanthin the hexane extract contains nirtetralin, niranthin. They exert cytotoxic effects on 2 human leukemia cell lines. They reverse the multidrug resistance of many cancer cells as well.
The ethanolic extract of Phyllanthus niruri is valuable in preventing BPH in rats
Phyllteralin, Nirtetralin, Niranthin
Phyllteralin, Nirtetralin, Niranthin are lignans. They exhibit anti-inflammatory and anti-allodynic actions. Of these nirtetralin is the strongest one. These actions are probably mediated through their direct antagonistic actions on the PAF binding receptor sites. (Allodynia means ‘other pain’ i.e. pain due to a stimulus which normally does not provoke it. It can be static or moving or migrating. It can be perceived in areas other than the one stimulated. This is not ‘referred’ or ‘radiating’ as it is not perceived along a dermatome.)
In studies conducted by Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina (UFSC), Florianopolis, SC, Brazil, to study anti-inflammatory effects of Phyllanthus amarus the hexane extract and lignans; phyltetralin, nirtetralin, niranthin isolated from Phyllanthus amarus were given orally to experimental animals. These lignans inhibited carrageenan induced paw edema, neutrophil influx and interleukin-1 beta tissue levels. They also significantly inhibited paw edema induced by bradykinin (BK), platelet activating factor (PAF) and endothelin-1 (ET-1); while the edema induced by histamine and substance P was unaffected.
Nirtetralin and niranthin are reported to possess hepatoprotective action. Cytotoxic actions of nirtetralin, niranthin, and phyllanthin on two human leukemia cell lines, K-562 and Lucena-1, suggest that they may be MDR reversing agents in the realm of chemotherapy of malignancies. 
Nirtetralin and nirtetralin A and B effectively suppress the secretion of HBV antigens in a dose-dependent manner
In summary phyllanthin, hypophyllanthin, niranthin and nirtetralin, are said to possess anti-hepatitis B activity.  [71], [72], [73] 
Diosgenin
Molecular formula: C27H47O3
Structural formula: 

Diosgenin a steroid sapogenin is the product of hydrolysis by acids, strong bases or enzymes of saponins.
Diosgenin is the precursor for the semi synthesis of progesterone which in turn was used in early combined oral contraceptive pills. The unmodified steroid has estrogenic activity. It can reduce the serum cholesterol levels.
Diosgenin is used for the commercial synthesis of cortisone, pregnenolone, progesterone and many other steroid products. [74]
In obesity, adipocyte hypertrophy and chronic inflammation in adipose tissue cause insulin resistance and type-2 diabetes. Diosgenin decreases the size of adipocytes and reduces inflammation of the adipose tissue by inhibiting macrophage infiltration of the adipocytes. Thus diosgenin ameliorates diabetes. [75]
The steroidal saponin diosgenin induces apoptosis in HT-29 human colon cancer cells (at least in part) by inhibition of bcl-2 and by induction of caspase-3 protein expression. It also inhibits azomethane-induced aberrant crypt foci (ACF) formation in F344 rats or preneoplastic colonic lesions. Further detailed studies show that, in rats, diosgenin prevents azoxymethane-induced colon carcinogenesis during initiation and promotion stages. Thus diosgenin seems to have potential as a novel colon cancer preventive agent. [76]
Phenylpropanoids (Niruriside)
Molecular formula: C38H42O17  
Structural formula: 

      [77]

Phenylpropanoids are a group of natural products with a wide range of biological and pharmacological importance. They show anti-inflammatory activity by inhibiting cyclo-oxygenase enzymes. Of the two, Cox 2 is inhibited more than Cox 1. They also possess free radical scavenging property. They exhibit smooth muscle relaxant, antispasmodic and analgesic properties.
The Rev protein of HIV is sequence specific RNA binding protein required for viral replication. Niruriside shows specific inhibitory activity against binding of Rev Protein. The anti-HIV activity of Phyllanthus niruri is attributed to repandusinic acid 11, a tannin and niruriside a phenylpropanoid. [78]

Polyphenols, ellagitannins, flavonoids

Some principal constituents of P. amarus namely amariin, 1-galloyl-2,3-dehydrohexahydroxydiphenyl (DHHDP)-glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin D, rutin and quercetin 3-O-glucoside  exhibit very strong antioxidant and free radical scavenging activity. Amariin, repandusinic acid and phyllanthusiin D show higher degree of antioxidant activity among the ellagitannins and were comparable to flavonoids, rutin and quercetin 3-O-glucoside.

In addition, they protect rat liver mitochondria and pBR322 plasmid DNA against radiation damage. The protection conferred is probably due to their efficient hydroxyl radical scavenging activity. The inhibitory effect of ellagitannins on lipid peroxidation in liver mitochondria was due to their efficient superoxide radical-scavenging ability. [79], [80] 

Alkaloids
The alkaloids in Phyllanthus niruri exhibit very potent anti-fungal, antimicrobial, anti-inflammatory and analgesic activity. The analgesic activity seems to be unrelated to the activation of opioid mechanism. Some of the alkaloids also show anti-malarial actions.  
The alkaloid phyllanthoside is smooth muscle relaxant. Its spasmolytic action helps to expel urinary calculi. [81]

Geraniin and 1346TOGDG

Molecular formula: C41H28O27
Structural formula:

               [82 A]

They are very potent antiviral agents. At the dose 5 mg/kg geraniin shows antihypertensive activity by lowering systolic and diastolic BP. [82]

Aarabinogalactan (AG) 

The aqueous extract of the whole plant contains acidic arabinogalactan. This molecule can furnish ample material for a ‘Monograph’. The author does not intend to write one though, he would certainly write all that really matters in the present context.
Aarabinogalactan (AG) is a biopolymer. It consists of two monosaccharides arabinose and galactose. In nature two classes of arabinogalactan found are: plant arabinogalactan and microbial arabinogalactan. In plants, it is a major constituent of gums such as gum Arabic.
AG, is a soluble, fermentable fiber found in high concentrations in Phyllanthus niruri, North American larch trees, leeks (Allium fistulosum Linn, Vilaayatee lasoona or Marathi: Khorat), carrots, radishes, pears, wheat, red wine, tomatoes and many flowering plants.
The non-absorbed fiber of AG is eagerly fermented by the fiber avid microflora of the distal gut. This increases the production of short-chain fatty acids (SCFAs), mainly butyrate and propionate. SCFAs are important to the health of the colon as they are the principal energy source for the colonic epithelial cells. AG works in the colon by activating immune cells. By fermenting fibers, it promotes growth of probiotic bacteria (such as Pet Flora) in the colon and contributes to healthy microflora levels. AG furnishes food supply to ‘gut friendly’ bacteria such as bifidobacteria and lactobacillus. It controls the acid balance in the large bowel. It thus acts as prebiotic and probiotic. It also eliminates some pathogens. (The author regrets his inability to find exactly which pathogens!)
Some studies have shown that AG reduces ammonia generation in the colon. Because ammonia has damaging effects on the colonic cells, reduction of ammonia is significant for the health of the colon. The patients with liver disease cannot detoxify ammonia which results in hepatic encephalopathy. AG may therefore benefit patients with liver disease.
AG is a potent immunomodulator. In immunological studies conducted in several universities and at major US institutions, AG was found to stimulate SUPEROXIDE DISMUTASE (SOD) production, activate immune cells especially killer cells and macrophages, promote cytokine production and communication and signaling compounds of immune cells. A recent, randomized 4-week trial in healthy adults showed that AG also potentiates the complement system. Antioxidants, such as vitamin C, may enhance its activity. AG thus helps the body to fight infections.
Recent scientific studies have shown that AG blocks invading bacteria and viruses from attaching to cell membranes in the liver and other organs. In Yonsei University, Seoul, South Korea, the researchers investigated the immunomodulating effects of AG and fucoidan in vitro. At concentrations of 10 to 100 microgram/ml of AG and fucoidan, the activated mouse spleen lymphocytes became cytotoxic to tumor cells. The data suggests that arabinogalactan and fucoidan are activators of lymphocytes and macrophages. This property may contribute to their effectiveness in the immunoprevention of cancer. [83], [84], [85]

A study conducted by Desai et al. concluded that mice pretreated with AG were protected against endotoxin-inducedsepsis. In these mice, there was complete protection againslipopolysaccharide-induced mortality. AG exhibits similaractionipatients with septic shock. [86] 
The Royal Society of Medicine of Great Britain is of the opinion that ninety percent of chronic diseases are caused by unhealthy intestinal tract. Since AG promotes the growth of ‘health friendly’ bacteria, retards the growth of intestinal pathogens and activates immune system, AG is recommended to preserve and promote health. AG is approved by FDA as dietary fiber and food additive. In July 2009, the Australian Authorities approved AG as a therapeutically active ingredient for oral use.
AG has been shown to block the metastasis of tumor cells in the liver and to stimulate Natural Killer cell (NK cell) cytotoxicity. AG has been shown to reduce tumor cell colonization and increase survival time of subjects with various cancers. Hence AG may be important in cancer treatment.

Pharmacology at a glance

Group 1: Flavonoids
 
Phytochemical
Part of the Plant
                            Pharmacology
Rutin
Whole plant
Anti-inflammatory, anti-oxidant, anti-platelet aggregation, decreases capillary permeability, inhibits vascular endothelial factor, inhibits angiogenesis
Quercetin
Whole plant
Anti-inflammatory, anti-oxidant, antibacterial, antiviral, antif-ungal, antiseptic, immunomodulator, anti-platelet aggregation, anti-allergic, increases endurance, anti-diabetic, hepatoprotective, anticancer
Quercetrin
Leaf
Anti-inflammatory, anti-oxidant, antiprotozoal, antileishmanial, antinociceptive, anti-diarrheal
Astragalin
Leaf
Anti-inflammatory, diuretic
Catechin
Root
Anti-oxidant, anti-tumor
Prenylated flavone glycoside
Whole plant
Anti-oxidant
Nirurin
Whole plant
Anti-oxidant
Niruri flavone
Whole plant
Anti-oxidant

Group 2: Terpenes

Phytochemical
Part of the Plant
                     Pharmacology
Limonene

Anti-tumor
p-Cymene
Leaf
Anti-inflammatory, anti-oxidant, anti-bacterial
Lupeol, Lupeol acetate
Root
anti-inflammatory, anti-microbial, anti-protozoal, anti-tumor, chemoprotective

Group 3: Coumarins
 
Phytochemical
Part of the Plant
                      Pharmacology
Ellagic acid
Whole plant
Anti-inflammatory, anti-oxidant, anti-bacterial, anti-viral, anti-tumor 
Methyl brevifolincarboxylate
Whole plant
Vasorelaxant, hypotensive

Group 4: Lignans
 
Phytochemical
Part of the Plant
                        Pharmacology
Phyllanthin
Root, stem, Leaf,
Anti-genotoxic, anti-viral, hepatoprotective, lowers cholesterol, anti-diabetic, anti-cancer
Hypophyllanthin
Whole plant
Anti-genotoxic, anti-viral, anti-allodynic, hepatoprotective, lowers cholesterol, anti-diabetic, anti-cancer
Niranthin, Hydroxyniranthin,
Demethylene-dioxy-niranthin
Leaf
Anti-inflammatory, anti-viral, anti-allodynic, hepatoprotective
Phylltetralin
Leaf
Anti-inflammatory, anti-viral, anti-allodynic, hepatoprotective, anti-cancer
Nirtetralin
Leaf
Anti-inflammatory, anti-viral, anti-allodynic, hepatoprotective, anti-cancer
Lintetralin and Isolintetralin
Leaf
Anti-inflammatory, anti-viral, anti-allodynic, hepatoprotective, anti-cancer

Group 5: Tannins

Phytochemical
Part of the Plant
                        Pharmacology
Repandusinic
acid
Whole plant
Anti-inflammatory, anti-oxidant, anti-viral, hepatoprotective
Geraniin
Whole plant
Anti-inflammatory, anti-oxidant, anti-viral, hepatoprotective, anti-hypertensive
Corilagin
Whole plant
Anti-inflammatory, anti-oxidant, anti-viral, anti-fungal, inhibits plasminogen activator,  hepatoprotective

Group 6: Saponins

Phytochemical
Part of the Plant
                    Pharmacology
Diosgenin
Whole plant
Anti-inflammatory,anti-obesity,  hypolipidemic, anti-diabetic, hepatoprotective, anti-GI-cancer

Group 7: Alkaloids

Phytochemical
Part of the Plant
                    Pharmacology
Norsecuranine
Whole plant
Anti-microbial, anti-fungal, anti-nociceptive, muscle relaxant, anti-spasmodic  
Nirurin
Whole plant
Anti-oxidant
Phyllanthine
Root, stem,
leaf
Anti-genotoxic, anti-viral, hepatoprotective, lowers cholesterol, anti-diabetic, anti-cancer
Phyllochrysine
Stem, leaf
Nervous system stimulant

Group 8: Hydrocarbons

Phytochemical
 Part of the Plant
                    Pharmacology
Triacontanal
Aerial parts
Hepatoprotective
Tricontanal
Aerial parts
Hepatoprotective

Group 9: Other compounds 

Phytochemical
Part of the Plant
                    Pharmacology
β-glucogallin
Whole plant
Effective in hematopoetic disorders
1-O-galloyl-6-O-
Leuteolyl-α-D-glucose
Whole plant
Effective in hematopoetic disorders
Linear and complex hetero xylans
Whole plant
Immunomodulator
Niruriside
Whole plant
Anti-viral, hepatoprotective
Arabinogalactans
Whole plant
Anti-microbial, immunomodulator, anti-sepsis, hepatoprotective, health promotor


Some testimonials from modern research

General Pharmacology
Actions on Chromosome Aberration
To evaluate anti-chromosome aberration activity of Phyllanthus niruri, chromosome damage in bone marrow was induced in mice by administering lead nitrate and aluminium sulphate. Subsequently the mice were treated with aqueous extract of leaves and fruit of Phyllanthus niruri by administering a dose of 685.0 mg/kg body weight for seven days. The result showed anti-chromosome damage activity of the extracts of the plant. [87]
Oral administration of 750 mg/kg body weight of the plant extract of Phyllanthus amarus to BALB/c mice for five days prior to whole body radiation (6Gy) showed radioprotective effect. The plant extract significantly increased W. B. C. count, bonemarrow cellularity, activity of various antioxidant enzymes and α-esterase activity. [88]

Anti-oxidant and Detoxification Activity

The methanolic extract of Phyllanthus  amarus and dried powder of the whole plant; exhibit free-radical scavenging and strong antioxidant activity    
The liver is the largest chemical factory responsible for detoxification of substances detrimental to the body. Glutathione is the prime antioxidant helping the liver in this process. Rising levels of toxins result in depletion of glutathione causing oxidative damage to the liver. The protein fraction of Phyllanthus niruri reinstates the levels of glutathione, boosts the levels of SUPEROXIDE DISMUTASE (SOD) and CAT thereby neutralizing the excessive amounts of free radicals and various toxins to provide hepatoprotection. [89]
Phyllanthus niruri is effective for detoxification of toxicities induced by paracetamol, nimesulide, cyclophosphamide and many other drugs and chemicals. 
DPPH (2, 2- dophenyl-1-picrylhydrazyle) is a dark colored crystalline powder composed of stable free-radical molecule. The ability of herbs scavenge DPPH is a measure of antioxidant property of phytochemicals. In an experimental study Phyllanthin shows maximum antoxidant activity at a concentration of 20 mol/ml and Phyllanthus amarus extract at 300g/ml.
In another study, it has been found that fresh extract of Phallanthus amarus in boiling water has better antioxidant activity than the microwave assisted extract of the plant. [90], [91]

Anti-Inflammatory Activity 

Methanol and aqueous extracts inhibit all phases of inflammation in experimental rats.
When given orally, the hexane extract, the lignan-rich fraction or the lignans phyltetralin, nirtetralin, niranthin ofPhyllanthus amarus inhibited carrageenan induced paw edema and neutrophil influx. They also inhibited the increase of IL1-β tissue levels induced by bradykinin; PAF and endothelin-1 induced paw edema.
Phyllanthus amarus exhibits anti-inflammatory activity by inhibition of iNOS, COX2 and cytokines via NF-kappa B pathway. [92]
Further study suggested that anti-inflammatory and antiallodynic (countering allodynia i.e. neuropathic pain) actions of Phyllanthus amarus are probably mediated through its direct antagonistic action on the PAF (Platelet-Activating Factor) receptor binding sites. [93]
In an experimental study the hydro-alcoholic (ethanol-water) extract and hexane extract of Phyllanthus amarus inhibited the lipopolysaccharide-induced production of nitric oxide and prostaglandin E2 in Kupffer cells and in macrophages RAW264.7. The extracts also attenuated the secretion of Tumor Necrosis Factor alpha (TNF-α) in macrophages as well as in human whole blood. The extracts also reduced endotoxin-induced nitrous oxide synthase iNOS and cyclooxygenase-2   
DPPH (2, 2- dophenyl-1-picrylhydrazyle) is a dark colored crystalline powder composed of stable free-radical molecule. The ability of herbs scavenge DPPH is a measure of antioxidant property of phytochemicals. In an experimental study Phyllanthin shows maximum antoxidant activity at a concentration of 20 mol/ml and Phyllanthus amarus extract at 300g/ml.
In another study, it has been found that fresh extract of Phallanthus amarus in boiling water has better antioxidant activity than the microwave assisted extract of the plant. [90], [91]
(COX-2). These activities were attributed to lignans (nitranthin, phyltetralin and nirtetralin) present in the plant. These activities were similar to the reference compound Ibuprofen. [94], [95], [96] 

Immunomodulatory Activity

Albino rats treated with 400mg/kg of P. amarus exhibited immunostimulant/ immunebooster activity. (Decrease in ESR, increase in RBC, WBC: TC DC counts etc.)
Phyllanthin and hypophyllanthin present in Phyllanthus amaruus and Phyllanthus urinaria are able to modulate the innate immune response of phagocytes especially on the chemotactic migration of phagocytes, phagocytic ability and on the release of Reactive Oxygen Species (ROS). Phyllanthin exhibits higher activity than hypophyllanthin when investigated individually; but both exhibit a synergistic effect. However more studies are required to elucidate their activities on other mechanisms of immunomodulatory responses. [97]
In other study, the standardized 80% ethanol extract of Phyllanthin amarus was administered to Wister-Kyoto rats ranging from 100 to 400mg/kg body weight for 14 days. The results revealed a significant dose dependent reduction in neutrophil migration. According to researchers the immunomodulatory response was due to phytochemicals phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid and gallic acid present in the plant. This study suggests that Phyllanthus amarus may be useful for the improvement of immune-related disorders. [98]

Anti-bacterial Activity

Pseudomonas aeruginosa infection is a leading cause of morbidity and mortality in burns and immune-compromised patients. The treatment of these patients is a daunting task. Recently researchers have synthesized silver nanoparticles from the aqueous extract of Phyllanthus amarus. The average size of synthesized nanoparticles was 15.7, 24 ± 8 and 29.78 n m by XRD, TEM and DLS respectively. Silver nanoparticles from Phyllanthus amarus aqueous extract exhibited excellent antibacterial potential against multi-drug resistant strains of Pseudomonas aeruginosa infecting burns patients. [99]

M. Ananda Chitra and S. Ramesh of Centralised Instrumentation Laboratory, Tamil Nadu, India, showed that silver nanoparticles (SNP) of 1mg/ml and 5mg/ml of aqueous extract of Phyllanthus amarus exhibited antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Proteus vulgaris, Escherichia coli and Salmonella Typhimurium.  [100] 

In an experimental study phytochemicals and minerals extracted from different parts of Phyllanthus amarus inhibited the growth of Pseudomonas auregenosa, Escherichia col and Staphylococcus aureus. Further study revealed that terpenoids present the leaves, stem, root and seeds of Phyllanthus amarus were responsible for the antibacterial activity.  [101], [102] 

Anti-leptospiral Activity

Aqueous and methanolic extracts of whole plant of Phyllanthus amarus show antileptospiral activity. Antioxidant and DNA damaging properties of the plant are responsible for this effect.  [103]

Anti-viral Activity
S. P. Thyagarajan et al treated hepatitis B virus carriers with Phyllanthus amarus, 600 mg/day for 30 days. When tested 15-20 days after the treatment the carriers lost the surface antigen. Some subjects who have been followed up to 9 months the antigen did not return. [104]
To study the mechanism of action of Phyllanthus  amarus in controlling hepatitis B infection transgenic mice were used as animal model. When Phyllanthus amarus was administered to transgenic mice hepatic HBsAg mRNA levels decreased. In cell culture Phyllanthus amarus inhibited hepatitis B virus polymerase activity, decreased hepatitis B virus DNA content and suppressed virus release into culture medium. Phyllanthus amarus also suppressed hepatitis B virus mRNA expression after glucocorticoid stimulation. [105]
An aqueous extract of Phyllanthus niruri inhibits replication of hepatitis virus. In vitro it inhibits endogenous DNA polymerase of hepatitis B virus and binds to the surface antigen of hepatitis B virus. By same mechanism Phyllanthus niruri inhibits Woodchuck hepatitis virus. [106] 
A flavonoid molecule isolated from Phyllanthus urinaria showed anti hepatitis B activity. It was identified as ellagic acid. Ellagic acid blocks HBeAg secretion in HepG2 2.2.15 cells. Since HBeAG is involved in immune tolerance during hepatitis B infection ellagic acid may be a new therapeutic agent against immune tolerance in HBV-infected individuals. [107]
Extracts of Phyllanthus  amarus have been shown by B. S. Blumberg and many other research workers to inhibit the DNA polymerase of HBV and woodchuck hepatitis virus (WHV) in vitro. These activities are attributed to a virucide hitherto unnamed. [108] 
In a study conducted by Liu et al., 88 patients with chronic hepatitis B were given Phyllanthus niruri (Phyllanthus amarus) ipowder form. There was a substantial increase in antibodies to the hepatitis virus, which is a positivestep in the recovery ohost defense.
Seven species oPhyllanthus with different formulations anadditiveshowed their abilittinhibihepatitis B virusDNA replication (i.e. the HbsAg and HbeAg expression). This inhibition occurs at both the HBV DNA synthesis leveland translation oviral mRNA. [109]
R. Mehrotra et al. conducted a study, in which thwholplanmaterial oPhyllanthus  amaruwas driedpowdered,and extracted with ethanol. This extract was subsequently fractionated in hexane, chloroform, butanol, and water. Allfractions were tested for in vitro effects on HbsAg, HbeAg, and HBV-DNA in serum samples positive for HBV antigens, followed bscreening of respective antigens bELISAThe extracts were effective against HBV antigensthebutanol extract beinthmost potent of them. [110]
A study conducted by Xia et al. used various combinations of Phyllanthus amarusinterferon-α, lamivudine, adefovirdipivoxilthymosinvidarabine and conducted 16 trials and included 1326 patients in the study. They concluded there isno evidence to prove that Pyllanthus amarus can be used in the management of chronic HBV infection. In the management HBV infection Phyllanthus amarus with an antiviradrug may be better than just the antiviral drug.However, thvalidity othe study conclusions depends on heterogeneity, systemic errors, and random errors. Some more clinical trials should be conducted with bigger sample size and low risk.  In future, the trials should also report the species and dose at which it is effective.
[111], [112], [113], [114]
The author of this article is very much impressed by the conclusions of the researchers Xia Y et al. They used various combinations of Phyllanthus, interferon alpha, lamivudine, adipovir, dipivoxil, thymosin, vidarabine; conducted 16 trials and included 1326 patients in their study. Their conclusions: 
“There is no convincing evidence that Pyllanthus compared with placebo benefits patients with chronic HBV infection.Phyllanthus plus an antiviral drug may be better than the same antiviral drug alone. However, heterogeneity, systemic errors, and random errors question the validity of the results. Clinical trials with large sample size and low risk of bias are needed to confirm our findings. Species of Phyllanthus should be reported in future trials, and a dose-finding design is warranted.”  [115], [116], [117], [118]
The human hepatoma cell line, PLC/PRF/5, also known as Alexander cell line was shown to produce hepatitis B surface antigen. This cell line has the property of secreting HbsAg (surface antigen) in the supernatant tissue culture medium. The supernatant was used to study the antiviral property of Phyllanthus amarus. It was found that Phyllanthus amarusat 1mg/ml concentration on a single dose inhibited the secretion of HbsAg for a period of 48 hours. This experiment proved the anti hepatitis B virus property of Phyllanthus amarus at cellular level and further confirmed its beneficial use in the treatment of acute and chronic hepatitis B infections and also in eradicating HBV from healthy carriers. [119], [120]
Transfection is the process of deliberately introducing nucleic acids into cells. In animal cells, the term transfection is used to refer to progression to a cancerous state (carcinogenesis) in these cells. Transfection can result in unexpected morphologies and abnormalities in target cells. [121]
A study was designed to evaluate the role of Phyllanthus amarus in the treatment of hepatitis B virus infection. HepA2 cell line had been transfected with tandemly arranged HBV DNA and continued to synthesize and secrete both HbsAg and HbeAg. Aqueous extract of Phyllanthus amarus reversibly inhibited cellular proliferation and suppressed HbsAg production but not HbeAg production in HepA2 cells. Phyllanthus amarus suppressed HbsAg gene expression at mRNA level in a time-dependent manner, and selectively abolished the HbsAg gene promoter driven CAT activity. This shows that Phyllanthus amarus contains some active components which can supress the HbsAg gene expression in human hepatoma cells. Such suppression may contribute the antiviral activity of Phyllanthus amarus in vivo. [122]
The viral enzymes NS3 protease and NS5B RNA dependent RNA polymerase are essential enzymes polyprotein processing and viral RNA replication. Methanolic extract of Phyllanthus amarus root showed significant inhibition of HCV-NS3 protease enzyme and methanolic extract of Phyllanthus amarus leaf showed considerable inhibition of NS5B in the in vitro assays. Further, both these extracts significantly inhibited monocistronic replicon RNA and HCV H77S viral RNA in HCV cell cultural system. Furthermore, the extract of Phyllanthus amarus root together with IFN-alpha showed additive effect in the inhibition of HCV RNA replication.  [123]
[Note: Monocistronic is a term used in biochemistry to describe the capacity of eukaryotes to code one gene per one mRNA, as opposed to many genes or sometimes all genes (polycistronic)
replicon is a DNA molecule or RNA molecule, or a region of DNA or RNA that replicates from a single origin of replication].  [124] 
In one study 50 patients with hepatitis-C infection ranging between age groups 20-60 were selected for the treatment with Phyllanthus amarus. The study was also aimed at hepatoprotection offered by Phyllanthus amarus. AfterPhyllanthus amarus therapy (dose not mentioned) for 5 and 10 weeks, the plasma LPO levels were significantly decreased and activity of SUPEROXIDE DISMUTASE (SUPEROXIDE DISMUTASE (SOD)), GPx, catalase, vitamin E and vitamin C were significantly increased. Hepatitis-C increases oxidative stress that is responsible for hepatocellular damage. The therapy with Phyllanthus amarus increases antioxidant levels in the liver, reduces lipid peroxidation of hepatic cell membranes and protects the liver from free radical insult caused by hepatitis-C virus. [125]
Recent Study shows that Phyllanthus amarus has antiviral activity against Herpes Simplex Virus type -1 and type-2 in early stage of infection. [126]
The alkaloidal extract of Phyllanthus niruri was found to inhibit Human Immunodeficiency Virus-1. [127] 
Notka F et al investigated anti HIV activity of hydro-alcoholic extract of Phyllanthus amarus. They found that the extract blocks the attachment and the HIV-1 enzymes integrase, reverse transcriptase, and protease to different degrees. A gallotannin containing fraction and the isolated ellagitannins geraniin and corilagin were shown to be the most potent mediators of these antiviral activities. [128]
Anti-fungal Activity 
Phytochemicals and minerals extracted from different parts of Phyllanthus amarus exhibit anti-fungal activity especially against Candida albicans. [129]
Antiprotozoal Activity 
Petroleum ether fraction of Phyllanthus amarus exhibited a pronounced anti-plasmodial activity (IC50 <3 activity="" attributed="" etc.="" flavonoids="" font="" g="" is="" lignans="" ml="" of="" phytosteroids="" presence="" terpenes="" the="" this="" to="">
Anti-Malarial Activity 
The ethanolic, dichloromethane and lyophilized aqueous extracts of whole plant of Phyllanthus niruri showed antimalarial activity against Plasmodium berghei ANKA strain in mice. In the experiments on mice when administered orally at doses of 200 mg/kg body weight all extracts of Phyllanthus niruri reduced parasitemia by 73 percent. At a very high dose of 500 mg/kg bodyweight, administered orally as a single dose, twice a week for four weeks none of the extracts showed any toxicity; even on histo-pathological studies.
Unfortunately no data on human studies is available. [131]
Activity against Filarial Mosquito (Culex quinquefasciatus)
Acetone extract of of Phyllanthus niruri possed significant activity against Culex quinquefascinatus that causes filariasis. [132]

Actions on the Skin 

Corilagin, furosin, geraniin and many flavonoids found in aqueous extract of various Phyllanthus species (includingPhyllanthus amarus) stimulate the proliferation of keratinocytes and dermal fibroblasts. Of these geraniin is the dominant compound in this regard. This activity helps rapid wound healing [133] 

Wound healing
See above 
Actions on Hematopoietic System

The albino rats treated with the aqueous extract prepared from the whole plant of Phyllanthus amarus showed decrease in ESR (Erythrocyte Sedimentation Rate) and PCV (Packed Cell Volume). This effect was dependent on the dose used. In rats treated with 100mg/kg body weight by the aqueous extract of the plant, total WBC (White Blood Cell) and Neutrophil count increased significantly. [134], 135], [136]

Actions on Nervous System
In experimental studies scopolamine and diazepam are used to induce amnesia. Subsequently the efficacy and utility of any drug to restore memory is tested. In one such study the aqueous extract of leaves of Phyllanthus amarus exhibited improvement in cognitive function and antiamnestic activity as evidenced by reduction in brain cholinesterase activity. The study shows hope for improving memory and its role in Alzheimer’s disease. [137], [138]
To assess antinociceptive property of drugs, in experimental study chemicals such as acetic acid, formalin are used to induce pain. Subsequently the drug to be assessed for antinociceptive property is administered and its pain relieving response is observed by ‘writhing test’. In one such study, the hydro-alcoholic extract of Phyllanthus amarusadministered at the dose of 0.3mg/kg body weight   intraperitoneally produced significant inhibition of acetic acid-induced abdominal constrictions. It was also observed that the extract administered intraperotineally was more efficacious than when administered orally. The extract also elicited significant reduction in in the capsaicin-induced pain. [139], [140]
In occurrence of recurrent seizures two mechanisms proposed to be involved are:
1. Alterations in the voltage-dependent ion channels (reduction in inhibitory GABA-mediated drive), or
2. Increase in excitatory glutamate mediated inputs.
In one study pentylenetetrazole (PTZ) and electro-shocks were used to induce seizures in Swiss albino rats. Aqueous and ethanolic extract of leaves of Phyllanthus amarus administered to these animals significantly abolished seizures showing anticonvulsant property of Phyllanthus amarus. [141], [142]    
According to some researchers antinociceptive activity of the plant is due to the ability of geraniin to inhibit neurotransmitter processes that relay and receive pain signals in the brain. It is this pain relieving effect is probably why the patients with urinary lithiasis use for quick relief before the plant actually break down and expel renal calculi. [143]

Actions on the eye

To investigate the effect of Phyllanthus niruri on the development of cataract on rats, Phyllanthus niruri was administered to rats at 75, 150 and 300 mg/kg body weight. Lenses of the experimental animals were subjected to osmotic stress by incorporating 30 mmol/L of galactose in the culture medium. The results showed that the dose of 75 mg/kg body weight of Phyllanthus niruri significantly delayed the onset and progression of cataract in rats. [144] 

Actions on CVS 
Traditionally Phyllanthus niruri has been in vogue for the treatment of hypertension. However till 1952 the mechanism of hypotensive effect of the plant remained unknown. The study on dogs in that year revealed that the plant exerts diuretic effect leading to lowering of blood pressure. [145]
In a study in 1988, the hypotensive effects were attributed to the phytochemical geraniin. [146]
In 1995 Indian researchers used powder of Chanca piedra (Phyllanthus niruri) leaves to treat hypertension. Their study showed that the plant induced significant dieresis and markedly lowered systolic blood pressure. Interestingly the diuretic effect of the plant was scientifically recorded in India as far back as 1992. [147], [148], [149] 
Actions on GI System 
To evaluate smooth muscle relaxing property of Phyllanthus niruri, a research was done in 1984 at the Federal University of Santa Catarina, Brazil. The alkaloid phyllanthoside of the plant was found to express smooth muscle relaxant (spasmolytic) activity.  [150]
Alcohol increases oxidative stress in intestine. It is dependent upon the dose of alcoh0l. Toyin Yemisi Faremi et al administered Phyllanthus amarus to rats at 250 mg/kg and 500 mg/kg body weight for four weeks. The researchers found that the plant successfully attenuated the ill effects of oxidative stress induced by alcohol [151]

Actions on the Pancreas

Phyllanthus amarus administered orally to rats with pancreatic cancer at daily doses of 100, 150, 200mg/kg body weight inhibited pancreatic carcinogenesis by modulating lipid peroxidation and antioxidant status. Thus Phyllanthus amarus may thus act as a chemopreventive agent for pancreatic carcinogenesis. [152]
In cancer, cell proliferation occurs. In pancreatic cancer this leads to more enzyme secretion. In one study, pancreatic cancer was induced in Wister rats by intraperitoneal injection of azaserine at a dose of 5 mg/kg body weight for 21 days. For experimental study purpose animals were divided in groups. Administration of 500 mg/kg body weight ofPhyllanthus amarus extract  did not show toxicity in animals. But for the study, aqueous and alcoholic extracts were administered orally at doses of 200 mg/kg body weight and 400 mg/kg body weight for 21 days. The results revealed that administration of extracts of Phyllanthus amarus brought about a significant change in pancreatic amylase, lipase, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activity. This suggested that Phyllanthus amarus possessed choemoprotective activity against azaserine-induced pancreatic cancer in Wistar rats [153]    
Actions on Hepato-biliary System
Traditionally Chanca piedra (Phyllanthus niruri) was used for the treatment of gall stones without specific valid data. In a study in 2002 Indian researchers reported choleretic and lipid lowering activity of the plant. This possibly explains the activity of the plant in the treatment of gall stones [154]
Hepatoprotective Activity
Phyllanthin and Hypophyllanthin are said to protect hepatocytes against carbon tetrachloride and galactosamine induced toxicity. The crude extract of Phyllanthus amarus has a significant regenerative activity on the hepatocytes following alcohol induced liver damage. The ethanolic extract of Phyllanthus amarus administered orally to rats has a significant protective effect on aflatoxin B-1 induced liver damage.   
In one experiment albino rats were treated with oral administration of ethanol for 30 days to induce alcoholic damage. As expected triglyceride, cholesterol and phospholipid deposits were found in liver, brain, kidney and heart. They were then treated with 200 mg. per day for 45 days with powder of the whole plant of Phyllanthus amarus. The increased levels of all these were brought back to normal on administration of powder of Phyllanthus amarus.
At doses of 35 mg/kg and 70 mg/kg the biochemical parameters were restored to normal within 48 hours in jaundiced calves.
In another study in rats the powder of the whole plant of Phyllanthus amarus at the dosage of 0.66 g/kg showed hepatoprotective activity against CCl4 induced hepatocyte damage. [155]
Hepatoprotective effect of aqueous extract of Phyllanthus amarus was evaluated on ethanol inuced hepatic injury in rats. The results reveal that the plant extract brought recovery in the damaged liver cells. [156]
Chanca piedra (Phyllanthus niruri) has been shown to protect the liver even during viral infection especially in Hepatitis B-viral infection. [157]

Mechanism of Hepatoprotection

The hepato-protective mechanism of this plant is neither related to inhibition on cytochrome p 450, nor induction on sulfate and glucuronide conjugation pathways of paracetamol, but partly due to the antioxidant activity and the protective effect on the decrease of hepatic reduced glutathione. [158]

Actions on Metabolism
In two clinical trials diabetic, mild hypertensive and dyslipidemic patients were treated with the preparation of the whole plant of Phyllanthus amarus for 10 days. Their elevated sugar and lipid levels decreased and mild diuretic action of the herb helped control hypertension. However the sample size was too small (9 and 25 patients) and the duration of treatment was too short (only 10 days) to declare the herb to be a trustworthy remedy for diabetes, dyslipidemia and hypertension!
The hydro-alcoholic extracts of Phyllanthus amarus at doses of 300 and 500 mg/kg possess significant hypolipidemic activity against cholesterol rich diet induced hyperlipidemia in Wister rats. These extracts also reverse the morphological and histo-pathological damage of the liver induced by high lipid levels. [159]
During one study administration of triton WR- 1339 in rats caused increase in cholesterol 3.5 folds, phospholipids 2 folds and triglyceride 1.2 fold. At dose 200 mg/kg administration of Phyllanthus niruri lowered their levels by 27, 25, and 24 percent respectively. At dose 100 mg/kg Phyllanthus niruri lowered elevated levels of cholesterol and LDL in rats fed with high cholesterol diet. 
The Lipid lowering activity (LLA) is mediated through hepatic cholesterol synthesis, increased faecal excretion of bile acids and enhanced plasma lecithin: cholesterol acyltransferase activity. [160], [161]
In one study the ethanolic extract (1 or 10 microgram/ml) of Phyllanthus urinary (Phyllanthus niruri) exhibited antioxidant and cytoprotective effects against doxorubicin induced cardiotoxicity. [162]
Many studies have confirmed the beneficial effects of lowering cholesterol and triglyceride levels by Chanca piedra(Phyllanthus niruri) in rats. [163], [164]

Antidiabetic activity
Dotriacontanyl docosanoate a phytochemical was isolated from hexane extract of Phyllanthus amarus. Researchers showed that dotriacontanyl docosanoate had α-amylase inhibitory properties. [165]
In 1995 researchers reported a significant hypoglycemic activity of Chanca piedra (Phyllanthus niruri) in human subjects.
Two other studies on rabbits also documented hypoglycemic effect of Chanca piedra (Phyllanthus niruri)
Yet another study documented Aldose Reductase Inhibition (ARI) by Chanca piedra (Phyllanthus niruri)
Aldose reductase inhibitors (ARIs) are substances that act on nerve endings exposed to high blood sugar concentrations. They protect the nerves from this imbalance. Thus Aldose reductase inhibitors (ARIs) protect diabetics from diabetic neuropathy. This Aldose reductase inhibitor (ARI) activity of Chanca piedra (Phyllanthus niruri) is attributed to ellagic acid found in Chanca piedra (Phyllanthus niruri). [166], [167], [168], [169], [170] 

Actions on Urinary System

In 1990, the Paulista School of Medicine in Sao Paulo, Brazil, researchers validated the use of Chanca piedra(Phyllanthus niruri) for expulsion of kidney stones. They used Chanca piedra (Phyllanthus niruri) tea for 1-3 months that eliminated stones.   
They also reported significant dieresis and increased excretion of sodium and creatinine. In 1999 in an in vitro study, the extract of Chanca piedra (Phyllanthus niruri) was shown to be effective in prevention of formation of calcium oxalate stones. Similar results were demonstrated in an in vivo study on rats conducted in 2002 on urolithiasis in urinary bladder. [171], [172], [173], [174], [175], [176], [177]   
To evaluate smooth muscle relaxing property of Phyllanthus niruri, a research was done in 1984 at the Federal University of Santa Catarina, Brazil. The alkaloid phyllanthoside of the plant was found to express smooth muscle relaxant (spasmolytic) activity. It is this spasmolytic activity probably accounts for the efficacy of the plant in expelling urinary calculi.  [178]
In diabetic subjects oxidative stress induced byhyperglycemia is responsible for renal damage. Hypoglycemic, hypolipidemic and antioxidant activities of Phyllanthus amarus are well known.
In one study aqueous extract of leaves of Phyllanthus amarus administered to male, streptozotocin-induced diabetic rats at doses of 200mg/kg and 400 mg/kg for 28 days prevented the diabetic nephropathy. This activity was said to be due to polyphenols present in the plant. The polyphenols show more potent antioxidant activity than ascorbic acid.  [179], [180]

Actions on Male Reproductive System
A. W. Obianime and F. I. Uche found that methanol extract of leaves of Phyllanthus amarus administered to male guinea pigs at doses of 50 to 500 mg/kg body weight caused a decrease in sperm count and reduction in motility of sperms. The effects were time and dose dependent. [181]
In another study, researchers found that the crude aqueous extract of Phyllanthus amarus administered to male albino rats caused varying degrees of testicular degeneration and reduction in the mean diameter of seminiferous tubules. [182]

Actions on Female Reproductive System

Researchers studied the effect of aqueous extract of leaves of Phyllanthus amarus on pregnancy in rodents. They administered the extract at 0.2 mg kg body weight to rodents from 4th day of pregnancy. The results showed that the extract hastened the implantation. The time frame for the hormonal changes that occur during pregnancy was reduced. However the pregnancy was not sustained after 8th day as the animals aborted. Robaki et al in 1988 showed that the flavonoids present in the plant have an abortifacient property. [183]
Alcohol extract of the whole plant of Phyllanthus amarus administered orally at a dose of 100mg/kg body weight for 30 days to female mice had antifertility effect. While on treatment these females when cohabited with normal male mice were unable to conceive. The antifertility effect was reversible upon withdrawal of the plant extract. [184]

Anti-tumor activity
Aqueous extract of Phyllanthus amarus exhibited potent anticancer activity against 20-methylcholanthrene-induced sarcoma. The extract was also found to prolong the life span of mice bearing Dalton’s Ascites Lymphoma and Ehrlich Ascites Carcinoma and reduced the volume load of transplanted solid tumors. The anti-tumor and anticancer activity ofPhyllanthus amarus may be due to inhibition of metabolic activation of carcinogen as well as the inhibition of cell cycle regulators and DNA repair. [185]
The anticancer activity of extracts of Phyllanthus urinaria against various cancers is due to induced apoptosis of cancer cells as evidenced by DNA fragmentation and increased caspase-3 activity through both intrinsic and extrinsic pathways. The plant also down-regulates telomerase activation and induces apoptotic process. The plant also exhibits anti-angiogenic activity. [186]
In one study, aqueous extract of Phyllanthus urinaria decreased the number of Lews lung cancer cells in a dose dependent manner without exertingcytotoxic effect on endothelial and liver cells. The extract directly induces apoptosis in Lews lung carcinoma cells. [187]
In another study aqueous extract of Phyllanthus urinaria was found induce apoptosis in HL-60 without harming the normal cells. The apoptosis is HL-60 cells is mediated through a ceramide-related pathway. [188] 
A study by Huang ST et al showed that the polyphenol compounds of Phyllanthus urinaria reduced viability of nasopharyngeal carcinoma cells. Furthermore treatment of nasopharyngeal carcinoma with Phyllanthus urinaria led to inhibition of human telomerase reverse transcriptase, human telomerase-associated protein-1, c-myc mRNA expression and telomerase activity. [189]
Culinary uses
Not used as food
Toxicity 
At a dose more than 800 mg/kg bodweight, Phyllanthus niruri is toxic. Histologically, there were protein casts in thkidney tubules with tubular necrosis, lymphocytic infiltration at the portal areas of the liver and marked testicular degeneration with severe disorganization of the seminiferous tubules, which were devoid of spermatic cells. [190], [191]
Bakare A. A. et al investigated the toxic effects of aqueous extract of Phyllanthus amarus in rats. The researchers used five concentrations: 100, 200, 400, 800 and 1600 mg /kg body weight. The extracts were dministered orally. The extracts induced the circulation of micronucleated polychromic erythrocytes, leucocytosis, lymphocytosis and sperm abnormalities. There were pathological changes in the liver, kidney and testis. The toxicity was due to tannins, resins, phenols and cardiac glycosides present in the plant. They are also capable of causing DNA damage in mouse and rat. [192]
To investigate acute toxic effects of Phyllanthus niruri George Awaku Asare administered aqueous extract of leaf of Phyllanthus niruri at very high doses from 2000 to 5000 mg/kg body weight to female Sprague-Dawley rats for 14 days. On 15th day the animals were sacrificed for toxicological study. The researchers did not observe any toxicity.  [193]
Contraindications
Phyllanthus niruri mabe contraindicated in individuals on medicationfor heart ailments. At high dosagesit has beenconsidered an abortifacient as well as menstrual promoter; hence, ishould be contraindicatedurinpregnancy. It is also contraindicated for people with diabetes, especially if they are on insulin therapy and ivariouother medical conditionwherediuretics are not advised. The doctor has to be consulted before consuming Phyllanthus niruri  for longer than 3months.
Drug-interactions
May potentiate the action of insulin and antidiabetic drugs
Phytochemical geraniin present in plant is a potent hypotensive agent which may potentiate the action of other hypotensive agents such as angiotensin converting agents, β-blockers
May potentiate other diuretics [194]
Medicinal Actions and Uses
Traditional Uses
Phyllanthus plants have been used in folk medicine to treat a wide number of diseases. In Ayurvedic medicine, variousPhyllanthus species are known as bhuiamla. The name was previously assigned to Phyllanthus niruri only. Bhuiaamla is recommended for jaundice, gonorrhea and diabetes; skin ulcer, scabies and other skin afflictions as well as for poultices for abscesses.
World over uses of Phyllanthus niruri/ Phyllanthus amarus are more or less same as described in Ayurveda. The uses are:  
Analgesic, antipyretic, antibacterial, antiviral, antimalarial, antifilarial, carminative, dyspepsia, appetite stimulant, dysentery, jaundice, laxative, vermifuge, cardioprotectant, hypertension, dropsy,  hepatoprotectant, cholegogue, gall stones, antidiabetic,   urolithiasis, contraceptive, abortifacient
Usages in Ayurveda
It is used to quench thirst, to treat bronchitis, tuberculosis, asthma, biliousness, hiccups, leprosy, anemia, urethral discharge and as diuretic.
It is recommended to treat jaundice and hepatic disorders, acid peptic disease, many GI disorders, bleeding disorders, metabolic disorders and leucorrhea. [195]

Usages in Modern Medicine

After extensive research Phyllanthus niruri is used to prevent and treat hepatitis B infection

Preparations and dosages

Paste prepared from the leaves crushed with salt is used to treat fractures, applied on wounds, applied on edematous surfaces and to treat dermatitis. For this it is used as external applications 
Powder of the whole plant given with rice water is useful in menorrhagia, leucorrhoea, dysuria, diabetes and some skin disorders
Root mixed with sugar is instilled in nose to treat hiccups
Whole plant: Dosage of whole plant decoction is 10-20 ml
Powder:  3-6gm., 600-900mg (recommended by some experts) [196]
Tincture: 1 - 4 ml / daily
Infusion/ Tea: One cup/day
Phyllanthus niruri is administered in the form of infusion or tincture or capsules for the treatment of chronic dysentery
Phyllanthin and Hypophyllanthin are major components of many popular liver tonics 
In India, a cupful of the leaf decoction is drunk daily to cure diarrhea
Fruits useful for tubercular ulcers, wounds, sores, scabies and ring worm [197], [198]
The fresh root is believed to be an excellent remedy for jaundice      
Poultice of the leaves with salt cures scabies and without salt is applied on bruises and wounds. The milky juice is a good application to offensive sores
The infusion of the root and leaves is a good tonic and diuretic when taken in repeated doses. [199], [200] 
In many parts of India, it is commonly used for the treatment of snake bite 


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