Bhumyamalaki (Phyllanthus niruri, Phyllanthus amarus)

Bhumyamalaki (Phyllanthus niruri, Phyllanthus amarus)
By
Dr. Hemant Vinze M. S.


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 people 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 Bhumyamalaki (Bhumamalaki). 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 P. amarus / P.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, P. amarus 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, urinary tract infection (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 is Phyllanthus. [7]

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. [8]

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. [9], [10]  

Other Names

Taxonomic: Phyllanthus niruri L. Phyllanthus fraternus Webster
          Phyllanthus amarus, Phyllanthus urinaria
Sanskrit: Bhumyamalaki (Bhumamalaki), 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  [11], [12]

Taxonomic classification

Kingdom:  Plantae
(Unranked): Angiosperms
(Unranked): Eudicots
(Unranked): Rosids
Phyllum:       MAG/agnoliphyta
Division:     MAG/agnoliophyta – Flowering plants
Class:         MAG/agnoliopsida – Dicotyledons
Order:        Malpighiales, Euphorbiales, Tubiflorae
Family:      Phyllanthaceae, Euphorbiaceae – Spurge family [13], [14]

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 that P. amarus has larger leaves than the other two and its fruit is wart-like.

Geographical distribution

 This annual plant is a widespread tropical and subtropical plant commonly found as a weed in coastal areas and sandy regions. 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 rainforests of Amazon. [15], [16] 

Plant Morphology


   

Bhumyamalaki Phyllanthus amarus Leaves and  Plant



Bhumyamalaki  Phyllanthus niruri/Phyllanthus amarus  Flowers


Bhumyamalaki  Phyllanthus niruri/Phyllanthus amarus  Fruits

Macroscopic Characteristics

This is a small, glabrous and erect annual herb. It grows 10 to 70 cm tall.

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.

Bark: is smooth and light green. Younger parts are rough.

Leaf:  Leaves are numerous. 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; greenish brown in color.

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

Fruits:  are tiny, 1.8 mm in diameter, rounded smooth capsules.

Seeds: about 0.9 mm long, triangular, with 6-7 longitudinal ribs and many transverse striations on the back [18], [19], [20], [21], [22]

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. The 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. The vessels are mostly simple pitted with a few show spiral thickenings. The 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. The 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. The 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. The lamina shows a dorsi-ventral structure, with mesophyll differentiated into palisade and spongy parenchyma. The 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. [23], [24], [25]


Parts Used

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

Phytochemistry

The phytochemical constituents are:

 1. Flavonoids: Rutin, Quercetin, Quercitrin, Astragalin, Catechin, Prenylated flavone glycoside, Nirurin, Niruriflavone,

2. Terpenes: Linonene, p-chymene, Lupeol, Lupeol acetate

3. Coumarins: Ellagic acid, Methylbrevifolincarboxylate,

4. Major lignans:  Phyllanthin and Hypophyllanthin, Phylltetralin,
Niranthin, Hdroxyniranthin, Dimethylenedioxyniranthin, Nirtetralin, Isolintetralin, Lintetralin.

5. Minor lignans: Phyllanthusiin D, Amariin, Amarulone, Amarinic acid.

6. Tannins: Repandusinic acid, Geranin, CorilAG/agin.

7. Saponins: Diosgenin

8. Alkaloids: Norsecurinines, Nirurine, Phyllanthine, Phyllochrysine,
Sobubbialine, Epibubbialine, Diarylbutane, Nyrphyllin and alkaloids of the quinazolidine type.

9. Other compounds: Beta-glucogallin, Linear and complex hetero xylans, Nirurisise

10. Hydrocarbons: Triacontanal, Triacontanol

11. Common lipids

12. Phytosterols 

Table 1. Phytochemicals of Phyllanthus niruri/ Phyllanthus amarus 

Flavonoids
Rutin, quercetin, quercitrin, astragalin, catechin, prenylated flavone glycoside, nirurin, niruriflavone
Terpenes
Linonene, p-chymene, lupeol, lupeol acetate
Coumarins
Ellagic acid, methylbrevifolincarboxylate
Major lignans
Phyllanthin and hypophyllanthin, phylltetralin, niranthin, hdroxyniranthin, dimethylenedioxyniranthin, nirtetralin, isolintetralin, lintetralin
Minor lignans
Phyllanthusiin D, amariin, amarulone, amarinic acid
Tannins
Repandusinic acid, geranin, corilagin
Saponins
Diosgenin
Alkaloids
Norsecurinines, nirurine, phyllanthine, phyllochrysine, sobubbialine, epibubbialine, diarylbutane, nyrphyllin and alkaloids of the quinazolidine type
Other compounds
Beta-glucogallin, linear and complex hetero xylans, niruriside
Hydrocarbons
Triacontanal, triacontanol
Common lipids
 Exact information not available
Phyosterols
 Exact information not available

 [26] 


Table 2. Phytochemicals in Various Parts oPhyllanthus niruri/ Phyllanthus amarus          


The whole plant
Rutin, Quercetin, Quercitrin, Prenylated flavone glycoside, Nirurin, Ellagic acid, Hypophyllanthin, Repandusinic acid, Geranin, Corilagin, Diosgenin, Norsecurinines, Beta-glucogallin, Linear and complex hetero xylans, Nirurisise

Leaf
Quercitrin, Astragalin, p-chymene, Phyllanthin, Niranthin, Hdroxyniranthin, Dimethylenedioxyniranthin, Nirtetralin, Isolintetralin, Lintetralin. Phyllanthine

Root
Catechin, Lupeol, Phyllanthine

Stem
Phyllanthine         

Aerial parts
Nirurine, Triacontanal, Triacontanol

 
[29], [30]

Identity, Purity and strength Tests
(1)
Foreign matter: Not more than 2 percent
Total ash: Not more than 16 percent
Acid-insoluble ash: Not more than 7 percent
Alcohol-soluble extractive: Not less than 3 percent
Water-soluble extractive: Not less than 13 percent [31]

(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, Method B (20 ppm).

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. [32], [33]

Color Tests for identification

Observed colors after treating the solution of P. amarus ( 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 P. amarus. [34]

Various assays are also available to establish the identity of P. amarus [35]

Cytological Identification

The no of chromosomes in Phyllanthus amarus  (Schumach & Thonn) is 7  [36]

Genetic Identification
Although above-mentioned tests are useful to identify P.niruri genetic identification method is gold standard.
Recently SCAR markers are developed for the correct identification of Phyllanthus species. [37]

Purity Tests (Accepted Internationally)

Foreign Matter: Not more than 2%
Ash content:
Total Ash: Not more than 9%
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 0.5mg/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 105cfu/g
Total yeast and mould count:                     Not more than 104cfu/g
Bile tolerant gram negative bacteria:         Not more than 104cfu/g

Specific Pathogens:

Salmonella spp:                        Absent in 25 g
Escherichia coli:                     Absent in 1g   
Staphylococcus aureus:         Absent in 1g          
Pseudomonas aeruginosa:     Absent in 1g  [38]

Specific Pathogens: (as per international guidelines)
Salmonella species:                Absent in 25 g /none
Escherichia coli:                     Absent in 1g / maximum 102 to 104 per gram 
Staphylococcus aureus:         Absent in 1g          
Pseudomonas aeruginosa:     Absent in 1g
Shigella species:                                      
Enterobacter species:            maximum 104 per gram 
Other enterobacteria:            maximum 103 per gram
Aerobic bacteria:                  maximum 105 to 107 per gram   
Mould propagules:               maximum 103 to 105 per gram     
Yeasts and Mould:               maximum 103 to 104 per gram [38a], [38b]  
  

Aflatoxins (as per international guidelines)

Aflatoxin B1, Aflatoxin B2, Aflatoxin G1, Aflatoxin G2                      

Preferably Aflatoxins should be below detectable limits (BLD) [38c], [38d]

Pesticide residues (as per international guidelines)
In recent times various pesticides are used to protect and preserve the food and medicinal values of plants.
To avoid toxicity of herbal medicine, International Society for Standardization of Drugs and World Health Organization (WHO) have laid the guidelines for permissible levels of pesticides in herbal medicines.
In general, the pesticide contamination in any herbal medicine should be less than 1 percent of total intake from all sources, including food and drinking water.
Aldrin and dieldrin are broad spectrum pesticides commonly used in agriculture. The recommended maximum limit of these pesticides is Not more than 0.05 mg/kg. [38e], [38f]
Radioactive residues (as per international guidelines)
A certain amount of exposure to ionizing radiation of plants cannot be avoided since there are many sources, including radionuclides occurring naturally in the ground and the atmosphere.
The World Health Organization (WHO), in close collaboration with several international organizations, has developed guidelines for permissible and acceptable limits for radioactive residues in herbal medicines.

The amount of radiation in plants depends on intake of radionuclides. Significant risk is associated only with consumption of quantities over 20 kg of plant material per year so that the risk to health is most unlikely to be encountered given the amount of medicinal plant materials need to be ingested. Additionally, the level of contamination might be reduced during the manufacturing process. Therefore World Health Organization (WHO) has not proposed strict limits regarding the acceptability for radioactive contamination. [38g]
Properties and Pharmacology

Ayurvedic Properties

Ganas (Classical Categories)

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 [39]

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)


Deepana: Appetizer 
KaphAG/aghna: Allays catarrhal inflammations
KushthAG/aghna: Antileprotic and useful in skin disorders
Krimighna: Anthelmintic and anti microbial
JwarAG/aghna: Anti-pyretic
Mootrala: Diuretic
Paachana:  Digestive (Digestant)
Rakta-Pradara: Allays menorrhagia
Rakta pitta shaamaka: Allays rakta pitta (innate haemorrhage, internal bleeding)
Rakta shodhaka:  Blood purifier   
Shweta pradara: Relieves leucorrhea
Wranaropana: Vulnerary (Wound healer)   
Yakruduttejaka: Stimulates the functions of the liver [40], [41]

According to Ayurvedic system of medicine it is considered alexipharmic (acting as antidote to poisons) and vulnerary.
  
 Modern View

Some recent studies show that P. amarus is febrifuge, antiseptic, astringent, stomachic and diuretic.

The fresh plant extract and the methanol extract show antioxidant activity.

Some therapeutic properties of P. amarus include anti-hepatotoxic, anti-lithic, anti-hypertensive, anti-HIV and anti-hepatitis B activity. [42]

Given orally to mice the whole plant extract shows marked radioprotective activity by decreasing the damage to intestinal cells, decreasing the percentAG/age 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 P. amarus 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). [43]

To study the protective effect of the extract of P. amarus AG/against the damage induced following radiation, 250mg/kg and 750mg/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 P. 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. amarus extract increases the antioxidant defense mechanism in mice and thereby protects the animals from damage induced by radiation. [44]

Administration of 75% methanolic extract of P. 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. [45]

When given orally to male mice the aqueous crude extract causes varying degrees of decline 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 P. 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. [46]

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 [47]

Quercetin

Molecular formula: C15H10O7
Strucural formula: 

[48]

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. [49]

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. [50]

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. [51]

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. [52]

Quercetin AG/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. [53], [54]

Quercetin AG/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. [55], [56]

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 [57]


Catechin

Molecular formula: C15H14O6

Structural formula:



Catechin has been found to be the most powerful antioxidant and free radical scavenger among different members of the different classes of flavonoids. [58]

Lupeol

Molecular Formula: C30H50O
Structural Formula of Lupeol:


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, antiprotozoal, antitumor and chemoprotective properties. In laboratory models it inhibits prostate and skin cancers. [59]

Phyllanthin and Hypophyllanthin:

Molecular formula: Phyllanthin C24H34O6

Structural formula: Phyllanthin

  [60]

Phyllanthin



Molecular formula: Hypophyllanthin C24H30O7                  

Structural formula: Hypophyllanthin

  [61] 


Hypophyllanthin

Phyllanthin and Hypophyllanthin are major 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. [62]

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 P. amarus.  [63]

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 vitro assay 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.  [64]

These lignans show activity AG/against Ehrlich ascites carcinoma in mice. They have protective effect in doxorubicin induced toxicity. [65]

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 P. amarus 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 antAG/agonistic 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 P. amarus the hexane extract and lignans; phyltetralin, nirtetralin, niranthin isolated from P. 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 AG/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. [66], [67], [68]

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. [69]

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. [70]

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 capsase-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. [71]

Phenylpropanoids (Niruriside)

 Molecular formula: C38H42O17      

Structural formula: 


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 these, 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 P. amarus is attributed to repandusinic acid 11, a tannin and niruriside a phenylpropanoid. [73]

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 AG/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. [74], [75]

Alkaloids

The alkaloids in P. amarus exhibit very potent antifungal, 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. [76]




Geraniin and 1346TOGDG

They are very potent antiviral AG/agents. At the dose 5 mg/kg geraniin shows antihypertensive activity by lowering systolic and diastolic BP. [77]

Arabinogalactan (AG/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. 

Arabinogalactan (AG/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/ ag is a soluble, fermentable fiber found in high concentrations in P. amarus, North American larch trees, leeks (Allium fistulosum Linn, Vilaayati lasoona or Marathi: Khorat), carrots, radishes, pears, wheat, red wine, tomatoes and many flowering plants.

The non-absorbed fiber of AG/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/ 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/ 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/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/ag may therefore benefit patients with liver disease.

AG/ag is a potent immunomodulator. In immunological studies conducted in several universities and at major US institutions, AG/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/ag also potentiates the complement system. Antioxidants, such as vitamin C, may enhance its activity. AG/ag thus helps the body to fight infections.

Recent scientific studies have shown that AG/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/ag and fucoidan in vitro. At concentrations of 10 to 100 microgram/ml of AG/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. [78], [79], [80]

A study conducted by Desai et al. concluded that mice pretreated with AG/ag were protected against endotoxin-induced sepsis. In these mice, there was complete protection against lipopolysaccharide-induced mortality. AG/ag exhibits similar actions in patients with septic shock. [81]
                                                                                                
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/ag promotes the growth of ‘health friendly’ bacteria, retards the growth of intestinal pathogens and activates immune system, AG/ag is recommended to preserve and promote health. AG/ag is approved by FDA as dietary fiber and food additive. In July 2009, the Australian Authorities approved AG/ag as a therapeutically active ingredient for oral use.

AG/ag has been shown to block the metastasis of tumor cells in the liver and to stimulate Natural Killer cell (NK cell) cytotoxicity. AG/ag has been shown to reduce tumor cell colonization and increase survival time of subjects with various cancers. Hence AG/ag may be important in cancer treatment.

Some testimonials from modern research

Antioxidant and Detoxification Activity

The methanolic extract of P. 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 P. amarus 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. [82]

P. amarus is effective for detoxification of toxicities induced by paracetamol, nimesulide, cyclophosphamide and many other drugs and chemicals.    

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 of P. 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.

P. amarus exhibits anti-inflammatory activity by inhibition of iNOS, COX2 and cytokines via NF-kappa B pathway. [83]

Further study suggested that anti-inflammatory and antiallodynic (countering allodynia i.e. neuropathic pain) actions of P. amarus are probably mediated through its direct antagonistic action on the PAF receptor binding sites. [84]

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.)

Antimicrobial Activity/ Antiviral Activity

S. P. Thyagarajan et al treated hepatitis B virus carriers with P. 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. [85]

To study the mechanism of action of P. amarus in controlling hepatitis B infection transgenic mice were used as animal model. When P. amarus was administered to transgenic mice hepatic HBsAg,  mRNA levels decreased. In cell culture P. amarus inhibited hepatitis B virus polymerase activity, decreased hepatitis B virus DNA content and suppressed virus release into culture medium. P. amarus also suppressed hepatitis B virus mRNA expression after glucocorticoid stimulation. [86]

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. [87]

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. [88]

Extracts of P. 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. [89]

In a study conducted by Liu et al., 88 patients with chronic hepatitis B were given P. amarus (Quebra pedra) in powder form. There was a substantial increase in antibodies to the hepatitis virus, which is a positive step in the recovery of host defense.

Seven species of Phyllanthus with different formulations and additives showed their ability to inhibit hepatitis B virus DNA replication (i.e. the HbsAg and HbeAg expression). This inhibition occurs at both the HBV DNA synthesis level and translation of viral mRNA. [90]

Mehrotra et al. conducted a study, in which the whole plant material of P. amarus was dried, powdered, and extracted with ethanol. This extract was subsequently fractionated in hexane, chloroform, butanol, and water. All fractions were tested for in vitro effects on HbsAg, HbeAg, and HBV-DNA in serum samples positive for HBV antigens, followed by screening of respective antigens by ELISA. The extracts were effective against HBV antigens, the butanol extract being the most potent of them. [91]

A study conducted by Xia et al. used various combinations of Phyllanthus, interferon-α, lamivudine, adefovir dipivoxil, thymosin, vidarabine and conducted 16 trials and included 1326 patients in the study. They concluded there is no evidence to prove that Pyllanthus can be used in the management of chronic HBV infection. Phyllanthus with an antiviral drug may help better than just the antiviral drug. However, the validity of the 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. [92], [93], [94], [95]

The author 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.”  [96], [97], [98], [99]

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 amarus at 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.  [100], [101]

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. [102]

Yeh et al. designed a study to evaluate the role of P. amarus in the treatment of hepatitis B virus infection. HepA2 cell line was transfected with tandemly arranged HBV DNA, which initiated synthesis and secretion of HbsAg and HbeAg. Aqueous extract of P. amarus resulted in reversible inhibition of cellular proliferation and suppression of HbsAg production, but HbeAg production in HepA2 cells was not affected. HbsAg gene expression was suppressed at mRNA level in a time-dependent manner and the HbsAg gene promoter-driven CAT activity was selectively abolished. This study concludes that specific components in P. amarus suppress the HbsAg gene expression in human hepatoma cells, which contributes to antiviral activity of Phyllanthus amarus in vivo. [103]
 
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. [104]


The polyprotein processing and viral RNA replication necessitate the presence of viral enzymes NS3 protease and NS5B RNA-dependent RNA polymerase. Methanolic extract of P. amarus root inhibited HCV-NS3 protease enzyme significantly, whereas methanolic extract of P. amarus leaf inhibited NS5B considerably in in vitro assays. Besides, monocistronic replicon RNA and HCV H77S viral RNA were effectively inhibited in HCV cell cultural system. Furthermore, P. amarus root extract with IFN inhibited HCV RNA replication. [105]

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.  [106]

[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)

A replicon is a DNA molecule or RNA molecule, or a region of DNA or RNA that replicates from a single origin of replication] [107]

Nikam et al. studied the hepatoprotective property of P. amarus. The study included 50 patients with hepatitis C infection in the age group of 20–60 years, and they were treated with P. amarus.  The plasma LPO levels were significantly decreased, whereas the activity of SUPEROXIDE DISMUTASE (SOD), GPx, catalase, vitamin E, and vitamin C were significantly increased after 5 and 10 weeks of the treatment. Oxidative stress due to hepatitis C is responsible for hepatocellular damage. The treatment with P. 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. [108]

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. After Phyllanthus 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 damAG/age. 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. [109]      

Hepatoprotective Activity

Phyllanthin and Hypophyllanthin are said to protect hepatocytes against carbon tetrachloride and galactosamine induced toxicity. The crude extract of P. amarus has a significant regenerative activity on the hepatocytes following alcohol induced liver damage. The ethanolic extract of P. 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 P. amarus. The increased levels of all these were brought back to normal on administration of powder of P. amarus.

At doses of 35mg/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 P. amarus at the dosage of 0.66g/kg showed hepatoprotective activity against CCl4 induced hepatocyte damage.

In summary phyllanthin, hypophyllanthin, niranthin and nirtetralin, are said to possess anti-hepatitis B activity. 

For more details see above.

Mechanism of Hepatoprotection

The hepatoprotective mechanism of this plant is neither related to inhibition on cytochrome p450, 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. [110]

Actions on Metabolism

In two clinical trials diabetic, mild hypertensive and dyslipidemic patients were treated with the preparation of the whole plant of P. 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 hydroalcoholic extracts of P. 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 histopathological damage of the liver induced by high lipid levels. [111]

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 200mg/kg administration of P. amarus lowered their levels by 27, 25, and 24 percent respectively. At dose 100mg/kg P. amarus 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. [112]

In one study the ethanolic extract (1 or 10 microgram/ml) of P. urinaria (P. amarus) exhibited antioxidant and cytoprotective effects against doxorubicin induced cardiotoxicity. [114]

Culinary uses

Not used as food.

Toxicity

At a dose more than 800 mg/kg body weight, P. amarus is toxic. Histologically, there were protein casts in the kidney 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. [115]

Contraindications/ Drug-interactions

P. amarus may be contraindicated in individuals on medications for heart ailments. At high dosages, it has been considered abortifacient as well as menstrual promoter, hence, it should be contraindicated during pregnancy. It is also contraindicated for people with diabetes, especially if they are on insulin therapy and in various other medical conditions where diuretics are not advised. The doctor has to be consulted before consuming P. niruri for longer than 3 months.

No drug interactions have been reported till date.

Medicinal Actions and Uses

Traditional Uses

Phyllanthus plants have been used in folk medicine to treat a wide number of diseases. In Ayurvedic medicine, various Phyllanthus species are known as bhuiamla. The name was previously assigned to P. amarus 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 P. amarus has been recommended for more or less same afflictions as in Ayurveda.

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. [116]

Usages in Modern Medicine

After extensive research P. amarus 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 for 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) [117] 

Tincture: 1 - 4 ml / daily.

Infusion: One cup/day

P. amarus 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 [118], [119]

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. [120], [121]

In many parts of India, it is commonly used for the treatment of snake bite.



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