Phyllanthus Niruri

Introduction:
Phyllanthus niruri originated in India, usually occurring as a winter weed throughout the hotter parts. The Phyllanthus genus contains over 600 species of shrubs, trees and annual or biennial herbs distributed throughout the tropical and subtropical areas. Phyllanthus niruri is a herb of Euphorbiaceae family that grows upto 60 cm. Phyllanthus means “leaf and flower” because the flower, as well as the fruit, seem to become one with the leaf.

Phyllanthus niruri L., (Syn. P. fraternus Webster), Euphorbiaceae, is a common kharif (rainy season) weed found in both cultivated fields and wastelands. Recently it has attracted the attention of researchers, because of its hepatoprotective properties. No effective specific therapy is available for viral hepatitis but P. niruri has shown clinical efficacy in viral Hepatitis B .It is known for its liver healing properties so used in Chinese medicine for treatment of liver diseases.

Botanical Description1 -
The annual herb is 30-60 cm high, quite glabrous, stem often branched at the base.
Leaves: Numerous, sbsessile distichous often imbricating, elliptic oblong obtuse. Stipules present, very acute.

Flowers: Yellowish, very numerous, axillary. The male flowers are one to three in number while the female flowers are solitary in nature.

Capsules: 2.5mm in diameter, depressed globose, smooth scarcely lobed.
Pharmacological Uses –
I.Hepatoprotective Effect –
1.Hepatitis B is one of the major diseases inflicting human population. Conventional treatment with interferon – alpha is very expensive and has many serious side effects. Alternative herbal medicine using extracts of Phyllanthus niruri and Phyllanthus urinaria have been reported to be effective against Hepatitis B and other viral infections. A study reports quantitative determination of the anti viral effect of these herbs in well-defined in vitro systems. 3

2.Phyllanthus niruri has been reported to exhibit marked antihepatitis B virus surface antigen activity in in-vivo and in-vitro studies. Infectious hepatitis is due to the inability of the bodies’ immune system to eliminate the virus from the liver cells: hence the “carrier state”. An infection with the virus is documented by detectable levels of various viral antigens in the blood, including HbaAg (the surface antigen of the virus) as well as antibodies to the core of virus (HBc antibodies). In one study, 37 patients with chronic viral hepatitis B were treated with a daily dose of 600mg of Phyllanthus niruri for 30 days. 59% of the patients lost the HBsAg two weeks after the end of the treatment. Furthermore, none of the cases followed for up to 9 months had any symptoms of HBsAg. The authors postulated that Phyllanthus niruri might inhibit proliferation of the virus by inhibiting replication of the genetic material of the virus. 4

3.Hepatoprotective effect of an ayurvedic medicine; herbal preparation HPN – 12 (containing Glycirrhiza glabr, Pichorhiza kurroa, Berberis aristata, Piper longum, Phyllanthus niruri, Solanum dulcamara, Zingiber officinale, Curculigo orchioides, Elettaria cardamomum, Tinospora cordifolia, Desmodium trifolium and Sacchrum officinarum) orally administered to male albino rats at 1ml/100g body weight was found to be effective against liver damage. 5

4.Animals with Carbon Tetrachloride induced hepatopathy were treated with catliv (contains extracts of Swertia chirata, Eclipta alba, Fumaria vaillanti, Picorrhiza kurroa, Andrographis paniculata and Phyllanthus niruri) at 25ml twice daily orally for six days starting at 48 hours after administration of Carbon tetrachloride. On basis of result obtained it was concluded that the ingredients in catliv, effectively helped in regeneration of hepatic cells and is an effective liver tonic for calves.6

5.Research in Japan and India in the 1980's has demonstrated the liver -healing properties of Phyllanthus niruri. The primary compounds responsible are phyllanthin, hypophyllanthin and triacontanal. Glycosides found in Phyllanthus niruri demonstrated Aldose reductase (AR) inhibitory activity in studies conducted by a Japanese research group in 1988 and 1989.7

II.HIV Replication Inhibition–
1.Aqueous extract of Phyllanthus niruri is reported to have inhibitory effect on human immunodeficiency virus. The investigation examines the anti-HIV effects of the alkaloidal extract of Phyllanthus niruri in human cell lines. The inhibitory effect on HIV replication was monitored in terms of inhibition of virus induced cytopathogenecity in MT-4 cells. The alkaloidal extract of Phyllanthus niruri showed suppressing activity on strains of HIV-1 cells cultured on MT-4 cell lines. The CC50 for the extract was found to be 279.85μgmL-1 whereas the EC50 was found to be 20.98μgmL-1. Interestingly the Selectivity Index (SI) was found to be 13.34, which showed a clear selective toxicity of the extract for the viral cells. The alkaloidal extract of Phyllanthus niruri was thus found to exhibit sensitive inhibitory response on cytopathic effects induced by both the strains of human immunodeficiency virus on human MT-4 cells in the tested concentrations.8

2.Extracts of five medicinal plants: Aristolochia indica, Cassia occidentalis, Phyllanthus niruri, Withania somnifera and Tinospora cordifolia were administered to 10 HIV infected patients for a period of six months to one year. The clinical status of the patient and their CD4 cell counts were periodically monitored. The results indicate that in seven of the ten patients, their CD4 count increased and the patients remained either asymptomatic or their clinical well being improved. There was no change in the CD4 cell count in one of the patient and the other two progressed to full blown AIDS.9

III. Lipid Lowering Activity -
1.Lipid lowering activity of Phyllanthus niruri alcoholic extracts in triton induced hyperlipidaemia was examined in rats. It was observed that administration of triton in rat caused increase in serum cholesterol by 3.5 fold, phospholipid 2 fold and triglyceride 1.2 fold. Administration of Phyllanthus niruri at the dose of 200mg/kg simultaneously with triton lowered the level of total cholesterol, phospholipid and triglyceride by 27, 25 and 24 percent respectively. In an experiment with cholesterol fed rats, Phyllanthus niruri at a dose of 100 mg/kg lowered the elevated level of low-density lipoprotein lipids in hyperlipidemic and drug fed animals.10

IV.Anti – Diabetic Activity –
1.An alcoholic extract of Phyllanthus niruri was found to reduce significantly the blood sugar in normal rats and in alloxan diabetes rats. In normal rats, administration of Phyllanthus niruri 200mg/kg body weight reduced the blood sugar by 34.5 percent and to 47.4 percent at the concentration of 1000mg/kg by weight at 1 hour. However at 6th hour, values are almost similar to normal value. Continuous administration of the drug produced significant reduction in normal blood sugar in rats, which on 15th day was also found to reduce the blood sugar in alloxan diabetic rats. In short term experiment, drug was found to reduce the blood sugar at 4th hour by 6.07 percent at dose level of 200mg/kg by weight and 18.7 percent at concentration of 1000mg/kg by weight. Continuous administration of drug produced significant reduction in blood sugar in alloxan diabetic rats. On 15th day values were almost similar to normal in the group taking 1000mg/kg by weight. Plant extract did not produce any toxicity as seen from liver and kidney function test and in hematological parameters. The results indicate potential antidiabetic action of Phyllanthus niruri.11

V. Anti Malarial Activity –
1.The ethanolic, dichloromethane and lyophilized aqueous extracts of Cassia occidentalis root bark, Morinda morindoides leaves and whole plants of Phyllanthus niruri were evaluated for their antimalarial activity in vivo, in 4-day, suppressive assays against Plasmodium berghei ANKA in mice. No toxic effect or mortality was observed in mice treated, orally, with any of the extracts as a single dose, of 500 mg/kg body weight, or as the same dose given twice weekly for 4 weeks (to give a total dose of 4 g/kg). No significant lesions were observed, by eye or during histopathological examinations, in the hearts, lungs, spleens, kidneys, livers, large intestines or brains of any mouse. At doses of 200 mg/kg, all the ethanolic and dichloromethane extracts produced significant chemosuppressions of parasitaemia (of > 60% for C.occidentalis root bark and Phyllanthus niruri whole plant, and of 30% for M.morindoides leaves) when administered orally. The most active ethanolic extract, that of Phyllanthus niruri, reduced parasitaemia by 73%. The dichloromethane extracts of M.morindoides and Phyllanthus niruri produced similar reductions (74% and 72% chemosuppression, respectively), whereas that of C.occidentalis was slightly less active (60% chemosuppression). Each lyophilized aqueous extract was less active than the corresponding ethanolic extract.12

VI.Activity Against Filarial Mosquito (Culex quinquefasciatus) –
1. 18 plants were evaluated for juvenile hormone analogue activity against Culex quinquefasciatus. Of these acetone extracts of 8 plants namely Commelina benghalensis , Ageratum conyzoides , Achyranthus aspera, Sida acuta, Euphorbia pulcherrina, Rivinia humilis, Ruellia tuberosa and Phyllanthus niruri possessed significant juvenile hormone activity. The LC50 values of 5 most active plants namely Phyllanthus niruri, Amaranthus spinosus, Antegonon leptopus, Corchorus aestuans, Corchorus benghalensis were determined to be 13,16,17,17,14ppm respectively.13

VII.Anti- spasmodic activity –
1.Research done in Brazil at the Federal University of Santa Catarina in 1984 on Phyllanthus niruri revealed an alkaloid (phyllanthoside) in the leaves and stem with strong antispasmodic activity. It served as a relaxing agent for smooth muscles and they concluded that its spasmolytic action probably accounted for the efficacy of Phyllanthus niruri in expelling stones.14

VIII. Analgesic activity –
1.Methanol extract of dried callus tissue at a concentration of 10mg/kg, administered intraperitonially to mice was active vs. acetic acid induced writhin and vs. formalin – induced pedal edema. The extract, at 50mg/kg was inactive vs tail flick response to radiant heat. Ethanol/ water (1:1) extract of dried entire plant at a dose of 50mg/kg, administered intragastric to male mice was active. The extract also administered intraperitonially to male mice at a dose of 0.3mg/kg was active. In both cases antinociceptive effects were demonstrated using 5 different models of nociception. 15

IX. Chromosome Aberration Inhibition –
1. Water extract of dried fruit and leaves, at a dose of 685.0 mg/kg, administered to mice by gastric incubation was active vs. chromosome damage induced by lead nitrate and aluminium sulphate in bone marrow chromosomes. Dosing was for 7 days. 16

Worldwide Traditional Medicinal Uses-

Bimini
Hot water extract of the entire plant is administered orally, to reduce fevers, and as a laxative.17

Dominican Republic
Hot water extract of leaves is administered orally as a popular fever remedy.18

Fiji
Decoction of dried leaves and roots is taken orally for fever, and for good health.

Dried entire plant, grounded in buttermilk is administered orally for jaundice. Fresh leaf juice is used externally for cuts and bruises. For eye diseases the juice is mixed with castor oil and applied to the eye. Infusion of dried leaves is administered orally for dysentery and diarrhea. Infusion of green root is taken orally to treat heavy menstrual periods.19

French Guyana
Hot water extract of leaves is administered orally as a cholagogue.20

Haiti
Decoction of dried leaves is taken orally for or used in bath for fever, and orally for indigestion.21

Hot water extract of dried entire plant is administered orally as a spasmolytic and is also against fever.22

India
Fresh plant juice is taken orally for genito urinary disorders .23

The fruit is used externally for tubercular ulcers, scabies and ringworm .24

Hot water extract of dried entire plant is administered orally for diabetes .25

For asthma in ayurvedic medicine .26

Papau-New Guinea
Fresh leaf juice or fresh root juice are taken orally for venereal diseases. Decoction of dried entire plant is administered orally to treat venereal diseases.27

Decoction of dried leaf when taken orally is a treatment for diarrhea. A cupful of leaf decoction is drunk daily.28

Philippines
Decoction of dried entire plant is used as a bath for newborns. It is believed to remove disease-causing elements from the skin. Orally the decoction is used for coughs in infants.29

Puerto Rico
Hot water extract of leaf and stem is taken orally for fevers .30

Tanzania
Hot water extract of fresh entire plant is administered orally for gonorrhea .31

Thailand
Hot water extract of commercial sample of the entire plant, is administered orally as an antipyretic .32

Hot water extract of dried aerial parts administered orally is used as a diuretic, as an antipyretic, and for malaria. 33

Hot water extract of dried entire plant is administered orally as an anti-inflammatory agent. 34

Virgin Islands
Hot water extract of the plant is taken orally to increase the appetite.35

West Indies
Hot water extract of roots together with hot water extract of Citrus aurantifolia roots is taken orally to increase appetite. Hot water extract of entire plant administered orally, is taken for malarial fever. The plant is boiled and the tea taken. Water extract of the leaves and roots is taken orally for diabetes, and as a diuretic .36

Phyllanthus niruri is used as a diuretic in dropsical affection, gonorrhoea and other troubles of genito urinary tract. Herb is bitter, astringent, diuretic and febrifuge, antiseptic. Fresh root is a remedy for jaundice. Infusion of young shoots given in dysentery. Leaves are popular remedy against fever. It can be used to increase the appetite and locally to relieve inflammations. It can also be used in case of anorexia.

In – Vitro Studies –
1.Role Of Calcium Oxalate Crystals – Alexander.H.Campos and Nestor Schor investigated the in vitro effect of an aqueous extract of Phyllanthus niruri L on the model of calcium oxalate crystals endocytosis by Madin-Darby canine kidney cells; the extract exhibited a potent and effective non concentration dependent inhibitory effect on the calcium oxalate crystals internalization. This response was present even at high (pathologic) calcium oxalate concentration and no Phyllanthus niruri L. –induced toxic effect could be detected. Biochemical analysis of culture media containing Phyllanthus niruri L did not provide any clues for the elucidation of the cellular pathways affected by this natural product. Although further studies are necessary for better understanding of the role of Phyllanthus niruri L. in urolithiasis, their findings show that this natural product could be an attractive alternative for the treatment of urinary stone.37

Uses Of Isolated Phytochemical Constituents-
1.Bioassay – guided fractionation of boiled aqueous extracts from the whole plant of Phyllanthus niruri (Euphorbiaceae) led to the isolation of 1-o-galloyl-6-o-luteoyl-a-D-glucose (1), which IC50 values of 4.7mg/ml against Babesia gibsoni and 1.4mg/ml against Plasmodium falciparum invitro. The known compounds b glucogallin (2), quercetin 3-o-b-D-glucopyranosyl-(2 to 1)-o-b-D- xylopyranoside(3), b-sitosterol and gallic acid were isolated. Structures of these compounds were elucidated on the basis of their chemical and spectroscopic data.38

General Features–
Comparative pharmacognostic studies of 3 Phyllanthus species –

The detailed pharmacognostic evaluation of the 3 species of Phyllanthus namely Phyllanthus amarus Schum & Thonn or Phyllanthus maderaspatensis Linn or mixture of Phyllanthus amarus, Phyllanthus fraternus Webster and Phyllanthus maderaspatensis has been carried out with the aim to establish the identification markers of this important hepatoprotective agents (effective in Hepatitis B too). The study concluded that the 3 species can be differentiated on the micro and macroscopic characters, physicochemical values, HPTLC fingerprint profile and the detection of phyllanthin and hypophyllanthin as marker components. Besides, an interesting conclusion can be drawn that phyllanthin and hypophyllanthin said to protect the hepatocytes against CCl4 and galactose amine induced toxicity may not be exclusively responsible for hepatoprotective activity as these are present in Phyllanthus amarus while Phyllanthus fraternus and Phyllanthus maderaspatensis also possess significant hepatoprotective activity.39

Chemical Constituents40–
Rt – Rt culture

Pl – Plant

Lf – Leaf

Sd – Seed

Ol – Oil

Aer – Aerial plant

EO – Essential oils

1. Kaempferol-4-o-alpha-L-rhamnoside, Aer 0.9%, Rt

2. (-) Limonine, Lf EO 4.5%

3. Ascorbic acid, Lf 0.41%

4. Cymene, Lf EO 11%

5. Hypophyllanthin, Pl 0.05-0.17%

6. Geranin, Pl .23%

7. Linoleic acid, Sd Ol 21%

8. Linolenic acid, Sd Ol 51.4%

9.Ricinoleic acid, Sd Ol 1.2%

10.Phyltetralin, Pl, Lf 0.14%

11.&Phyllanthin, Lf, Aer

Following are parts of the plant

1. (-)-Nor-secrurinine, Pl

2. 4-Hydroxy-sesamin, Pl

3. Corilagin, Pl

4. Ellagic acid, Pl

5. Estradiol, Pl

6. Fisetin-41-O-beta-D-dlucoside, Pl

7. Hinokinin, Pl

8. Iso-lintetralin, Pl

9. Nirurin, Pl

10.Nirurinetin, Pl

11.Phyllanthus, Pl

12.Trans-phytol, Pl

13.Repandusinic acid A, Pl

Following are parts of the roots:

1. (+)-Catechin, Rt cult

2. (+)-Gallocatechin, Rt Cult

3. (-)-Epi-catechin, Rt Cult

4. (-)-Epi-catechin-3-gallate, Rt Cult

5. (-) Epi-gallocatechin, Rt Cult

6. Gallic acid, Rt cult

7. (-)-Epi-gallocatechin-3-O-gallate, Rt

8. Eriodictyol-7-o-alpha-L-rhamnoside, Rt

9. Fisetin-41-O-alpha-L-rhamoniside, Rt

10.Lupeol acetate, Rt

11.Lupeol, Rt

12.Nor-securinine, Rt

Following are parts of the Leaves:

1. 4-Hydroxy-lintetralin, Lf

2. 2,3-dimethoxy-iso-lintertralin, Lf

3. Astragalin, Lf

4. Beta sitosterol, Lf

5. Demethylenedioxy niranthin, Lf

6. Hydroxy niranthin, Lf

7. Hypophyllanthin, Lf Aer

8. Iso-quercitin, Lf

9. Linnanthin, Lf

10.Lintetralin, Lf

11.Niranthin, Lf

12.Quercitrin, Lf

13.Salicylic acid methyl ester, Lf EO

14.Seco-4-hydroxy-lintetralin, Lf

Following are parts of the aerial plant:

1.24- Isopropyl Cholestrol, Aer

2.Dotriacontanoic acid, Aer

3.Nirphyllin, Aer

4.Nirurine, Aer

5.Phyllanthenol, Aer

6.Phyllantheol, Aer

7.Phyllester, Aer

8.Phyllinurin, Aer

9.Phylltetrin, Aer

10.Triacontan-1-al, Aer

11.Triancontan-1-ol, Aer

Following are present in all leaf, stem, aerial plant, roots

1.Nirtetralin, Pl, Lf

2.4-Methoxy-nor-securinine, Aer, Rt, St

3.Rutin, Pl, Lf

4. Phyllanthine, Rt, Lf, St

5. Phyllochrysine, Lf, St

6. Quercetin, Lf, Pl

Conclusions–
1.Many times Phyllanthus niruri is adulterated with Phyllanthus amarus and vice versa.

2.Many researchers have concluded that Phyllanthus niruri and Phyllanthus amarus are same due to their similar chemical constituents and pharmacological action. But it is not so as they belong to different species

3.Phyllanthus niruri has variegated uses like hepatoprotective effect, inhibition of HIV replication, lipid lowering activity, anti diabetic activity, anti malarial, antifungal, antispasmodial activity, etc.

4.Due to all these applications we also get Phyllanthus niruri as marketed preparation by some prominent companies. In the marketed preparations Phyllanthus niruri is added in everyday used medicines like chyawanprash of many prominent companies. Phyllanthus niruri powder is also available for use.

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