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MEDICAL RATIONALE OF LIVOKURE, HEPATOPRETECTIVE HERBAL FORMULATION 1 MANAGEMENT OF HEPATIC DISORDERS LIVOKURETM :Corrects liver dysfunction. LIVOKURETM :Is safe and provides anti-viral effect in infective hepatitis. LIVOKURETM : Augments appetite by normalizing liver function. LIVOKURETM : Is ideally suited for long term treatment. LIVOKURETM : Gives protection in metabolic liver disorders. HIGHLY EFFECTIVE IN THE MANAGEMENT OF: Infective Hepatitis, Fatty Infiltration of liver, Anorexia. Alcoholic and Metabolic liver disorders, Constipation etc. Livokure is well-researched and clinically proven herbal formulation to act effectively as a prophylaxis as well as curative drug to any kind of disorder affecting the healthy functioning of the liver, one of the vital organs of the body. In our daily living we can not escape factors like consumption of rich and spicy food, polluted drinking water, toxic medicines or possible attack from hepatitis virus. There is also an increasing trend towards consumption of alcohol. As well these actors continuously jeopardize functioning of the liver, there is every necessity to ensure a complete protective shield for this vital organ, which Livokure ensures in a safe and sound manner. An essential co-prescription with hepato-toxic drugs, such as: Antibiotics, Hypotensives, Oral Hypoglycemics, Analgesics, Guinolones, Anti-Tuberculous etc. COMPOSITION: Each 500 mg. Capsule contains : Phyllanthus niruri (bhuiamla) Picrorhiza kurroa (kutki) Andrographis paniculata ( kalmegh) Holarrhena antidysenterica ( kurchi) Excipient : : : : : 100 mg 150 mg 150 mg 100 mg qs DOSE : ADULTS: 1 to 2 capsules twice daily (before food) or as directed by the physician. CHILDREN: Half of the adult dose. MAINTENANCE DOSE: One Capsule twice daily. ONSET OF ACTION: One to Two hours. 2 Duration of Action: Eight to Twelve hours. SIDE EFFCT / TOXIC EFFECT: Not found in the clinical trial. May safely be continued for a longer period. CONTRAINDICATION : Hypersensitivity to any of the ingredients. PRESENTATION : Strip of 10 capsules. CLINICAL VALIDATION : Successful clinical trial was conducted at J. B. Roy State Ayurvedic Medical College & Hospital, Govt. of West Bengal, Kolkata. Livokure compound has completely antagonized the toxic effects of Paracetamol on certain enzymes in serums as well as in isolated hepatic cells. Andrographolide has been found to be more potent. The plant p. Kurroa has been found to be having hepatoprotective activities against alcohol, ccl4 and aflatoxin b1 induced hepatic damage. (ref.1). Amoebicidal, anti-tuberculous and other anti-protozoal activity of individual alkaloids specially, conessine (kurchi) have been extensively investigated. (ref.2). REFERENCES: 1) 2) Indigenous Drugs Of India (1982), 2nd Edition Academic Publishers, Calcutta; P – 343-344. Cultivation and Utilization Of Medicinal Plants. (1982) Rrl, Jammu-Tawi, P-33. MODE OF ACTION: Livokure contains the mixture of picroside I and kutkoside, which has significant hepatopretective activity and the antiviral effect. Livokure contains the active principle of andrographolide, which acts as a cholagogue, and is used in sluggishness of liver and jaundice. Livokure containing lignans blocks DNA polymerase, the enzyme needed for the hepatitis B virus to reproduce. This is effective in jaundice and also for diarrhoea, dysentery and dyspepsia. 3 CHEMICAL CONSTITUENTS AND PHARMACOLOGICAL ACTIVITIES OF EACH INGREDIENT OF LIVOKURE 4 Andrographis paniculata Nees BOTANICAL NAME : Andrographis paniculata Nees COMMON NAME : Bengali: Kalmeg, English: The Creat; Sanskrit: Kalmegha, Bhunimba FAMILY : Acanthaceae PARTS USED : Leaf HABITAT : It grows abundantly in south eastern Asia, India (and Sri Lanka), Pakistan and Indonesia It grows "serpentine soil," which is relatively high in aluminum, copper and zinc. DESCRIPTION OF PLANT : Andrographis paniculata is an annual - branched, erect - running 1/2 to 1 meter in height. Stem dark green, 0.3 - 1.0 m in height, 2 - 6 mm in diameter, quadrangular with longitudinal furrows and wings on the angles of the younger parts, slightly enlarged at the nodes; leaves glabrous, up to 8.0 cm long and 2.5 cm broad, lanceolate, pinnate; flowers small, in lax spreading axillary and terminal racemes or panicles; capsules linear-oblong, acute at both ends, 1.9 cm x 0.3 cm; seeds numerous, sub quadrate, yellowish brown. (Sing, A., Kapoor, L.D., and Chandra, V., Pharmaco-botanic studies of kalmegh, J. ResIndian Med., 7,93,1972) Photograph 1: whole plant CHEMICAL CONSTITUENTS: The highest concentration of the active components is found just before the plant blooms. The leaves contain the highest amount of andrographolide (2.39%), the most medicinally active phytochemical in the plant, while the seeds contain the lowest. (Sharma, A., L. Krishan, and S.S. Handa. 1992. Standardization of the Indian crude drug Kalmegh by high pressure liquid chromatographic determination of andrographolide. Phytochemical analysis 3:12931). The other medicinal chemicals are also bitter principles: diterpenoids viz. deoxyandrographolide, -19ß-D-glucoside, and neo-andrographolide, all of which have been isolated from the leaves. (Chem Weiming and Liang Xiaotion. Deoxyandrographolide 19ß-D- 5 glucoside from the leaves of A. paniculata, Planta Medica 1982; 15: 245-246.). The primary medicinal component of Andrographis is andrographolide It has a very bitter taste, is a colourless crystalline in appearance, and is called a "diterpene lactone" - other active components include 14-deoxy-11,12- didehydroandrographolide (andrographlide D), homoandrographolide, andrographan, andrographon, andrographosterin, and stigmasterol - the last of which was isolated from an Astrographis preparation (Siripong, P., B. Kongkathip, K. Preechanukool, P. Picha, K. Tunsuwan, and W.C. Taylor. 1992. Cytotoxic diterpenoid constituents from Andrographis paniculata, Nees leaves, J. Sci. Soc. Thailand 18(4):18794.). The roots gave apigenin- 7, 4'- di-O-methyl ether, andrographolide and a new natural flavone, 5hydroxy 7,8,2',3'- tetramethoxy flavone (C19H18O7, mp 150-151˚C; yield, 0.006%). They also contain a monohydroxy trimethyl flavone, andrographin (C18H16O6, mp 190-191˚C) and a dihydroxy-di-methoxyflavone, panicolin (C17H4O6, mp 263-264˚C). The presence of α-sitosterol is also reported. (Chemistry and pharmacology of Andrographis species' by Sudhanshu Saxena et al published in Indian Drugs 35 (8) August 1998). PHARMACOLOGICAL ACTION: Andrographis paniculata, (AP), also known commonly as "King of Bitters," is a member of the plant family Acanthaceae, and has been used for centuries in Asia to treat GI tract and upper respiratory infections, fever, herpes, sore throat, and a variety of other chronic and infectious diseases. It is found in the Indian Pharmacopoeia and is the prominent in at least 26 Ayurvedic formulas. Since ancient times, A. paniculata is used as a wonder drug in traditional Siddha and Ayurvedic systems of medicine as well as in tribal medicine in India and some other countries for multiple clinical applications. The therapeutic value of Kalmegh is due to its mechanism of action which is perhaps by enzyme induction. The plant extracts exhibits antityphoid and antifungal activities. Kalmegh is also reported to possess antihepatotoxic, antibiotic (Gupta et al., 1993), antimalarial, antihepatitic (Jayaram et al., 1989; Ramfi et al., 1992), antithrombogenic, Jaundice (Tomar et al., 1983), anti-inflammatory (Tajuddin et al., 1983; Shen et al., 2000), antisnakevenom, and antipyretic properties to mention a few, besides its general use as an immuno-stimulant agent. A recent study conducted at Bastyr University, USA confirms anti-HIV activity of andrographolide. Liver & Gallbladder Protection: In Ayurvedic medicine (a system used in India), there are 26 different formulations containing AP that are used to treat liver disorders. AP's four related medicinal compounds were tested for a protective effect against liver toxicity produced in mice by giving them carbon tetrachloride (a 6 cleaning solvent), alcohol, or other toxic chemicals. (Kapil, A., I.B. Koul, S.K. Banerjee, and B.D. Gupta. 1993. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochemical Pharmacology 46(1):182-85. ). These chemicals damage the liver by causing lipid peroxidation. This is a process whereby free radicals (reactive molecules) produced by the chemical attack and destroy cellular membranes that surround liver cells. When the AP compounds were given to animals three days before the toxic chemicals, there was a significant protective effect in the liver. This effect was attributed to the antioxidant ability of the AP compounds, which was effective as silymarin (another plant antioxidant from milk thistle). In another study, andrographolide from AP was shown to produce a significant increase in bile flow. (Shukla, B., P.K.S. Visen, G.K. Patnaik, and B.N. Dhawan. 1992. Choleretic effect of andrographolide in rats and guinea pigs. Planta Med. 58:146-48. ). Bile is produced in the liver and stored in the gallbladder and aids in digestion. When a chemical, paracetamol, was given to animals pretreated with andrographolide, the usual decrease in bile production seen with this chemical was prevented. In this case. andrographolide was more potent than silymarin. Infective hepatitis is an acute inflammatory condition of the liver. It is often followed by liver cirrhosis and may progress to a coma and death. In India, where ancient physicians used AP to treat similar liver ailments, a study was conducted to evaluate the effect of AP in infective hepatitis. There was marked improvement in the majority of patients tested, when given a decoction or infusion of AP. Appetite improved on the fifth day of treatment, jaundice (yellow colour of conjunctive of the eye and skin) gradually diminished and completely disappeared within 24 days, and fever subsided after 7 days on average. Other indications of effectiveness of AP included improvement in liver function tests. The researchers concluded that AP was a useful remedy for treatment of infective hepatitis. The andrographolides present in AP are potent stimulators of gallbladder function. In animal experiments, those that received andrographolides for seven consecutive days showed an increase in bile flow, bile salts, and bile acids. These increases are beneficial and result in enhanced gallbladder function. Use of AP might, therefore, decrease the probability of gallstone formation and might also aid fat digestion. The andrographolides also prevented decreases in the amount of bile that are caused by acetaminophen toxicity. (Holt, Stephen M.D., Linda Comac, Miracle Herbs: How Herbs Combine with Modern Medicine to Treat Cancer, Heart Disease, AIDS, and More, Caro Publishing Group, 1998.). 7 REFERENCES: 1. Chem Weiming and Liang Xiaotion. Deoxyandrographolide 19ß-D-glucoside from the leaves of A. paniculata, Planta Medica 1982; 15: 245-246. 2. Chemistry and pharmacology of Andrographis species' by Sudhanshu Saxena et al published in Indian Drugs 35 (8) August 1998 3. Gupta et al., 1993 4. Holt, Stephen M.D., Linda Comac, Miracle Herbs: How Herbs Combine with Modern Medicine to Treat Cancer, Heart Disease, AIDS, and More, Caro Publishing Group, 1998.). 5. Jayaram et al., 1989; Ramfi et al., 1992 6. Kapil, A., I.B. Koul, S.K. Banerjee, and B.D. Gupta. 1993. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochemical Pharmacology 46(1):182-85. 7. Sharma, A., L. Krishan, and S.S. Handa. 1992. Standardization of the Indian crude drug Kalmegh by high pressure liquid chromatographic determination of andrographolide. Phytochemical analysis 3:129-31 8. Shukla, B., P.K.S. Visen, G.K. Patnaik, and B.N. Dhawan. 1992. Choleretic effect of andrographolide in rats and guinea pigs. Planta Med. 58:146-48. 9. Siripong, P., B. Kongkathip, K. Preechanukool, P. Picha, K. Tunsuwan, and W.C. Taylor. 1992. Cytotoxic diterpenoid constituents from Andrographis paniculata, Nees leaves, J. Sci. Soc. Thailand 18(4):187-94. 10. Sing,A.,Kapoor,L.D.,and Chandra, V., Pharmaco-botanic studies of kalmegh, J.ResIndian Med .,7,93,1972 11. Tajuddin et al., 1983; Shen et al., 2000 12. Tomar et al., 1983 8 Holarrhena antidysenterica Wal. SCIENTIFIC NAME : Holarrhena antidysentericaWal. COMMON NAME : Kurchi (Bengali); Ieory tree (English); FAMILY : Apocynaceae. PARTS USED : Bark. HABITAT : It grows throughout India up to an altitude of 4,000 ft. It is especially abundant in the sub-Himalayan tract DESCRIPTION : Kureya (Hindi); A shrub or small tree, glabrous or pubescent, bark with pale. Leaves 10-20 by 5.11 cm from broadly ovate to elliptic, obtuse. Flowen white in terminal corymbose eymes, white. Fruit follicles of 20-38 cm long. A tall perennial woody plant have a main trunk and branches forming a distinct elevated crown; includes both gymnosperms and angiosperms. This is a small tree, glabrous or pubescent, bark with pale colour. Leaves 10-20 by 5.11 cm from broadly ovate to elliptic, obtuse. Flowers white in terminal corymbose eymes, white. Fruit follicles of 20-38 cm long (Ref: Indian Journal of Pharmaceutical Sciences (Scientific Publication of the Indian Pharmaceutical Association) March April 2002 Poonam G. Daswani Tannaz J. Birdi D. S. Antarkar1 and N. H. Antia. The Foundation for Medical Research Mumbai Holarrhena antidysenterica (L). Fig.1 Portion of a flowering twig 9 Photograph-1&2: Whole plant CHEMICAL CONSTITUENTS: 1. Around 30 alkaloids have been isolated from the plant, mostly from the bark. These include conessine, kurchine, kurchicine, holarrhimine, conarrhimine, conaine, conessimine, iso-conessimine, conimine, holacetin and conkurchin. Aminoglycosides are important; the bark also gave nonalkaloids.(Ref: Indian J. Chem., 1981, 20B: 62.). 2. Three new bases isolated from bark are conesi'mine, holarrhine and holarrhimine'. Further, two new alkaloids from the. seeds and bark were isolated -conimine and isoconessimine".The gum resin contains caoutechoue, lettoresinol-A and lettoresinol-B'. The formulation Kutajarishta has been studied for distribution of alkaloids. 3. The principal alkaloid of kurchi is conessine. The other alkaloids reported to be present in the bark are: conamine, conkurchine, connessimine, kurchine, conarrhinine, holarrhinene and isoconcessimine 10 PHARMACOLOGICAL ACTIVITIES: 1. The bark is used as an astringent, anthelmintic, antidontalgic, stomachic, febrifuge, antidropsical, diuretic, in piles, colic, dyspepsia, chest affections and as a remedy in diseases of the skin and spleen. It is a well known drug for amoebic dysentery and other gastric disorders. It is also indicated in diarrhoea, indigestion, flatulence and colic. [Ref: Dictionary of Indian Medicinal Plants, CIMAP, Lucknow (1992) ,Singh, K.P.: Ancient Sci. Life 5:228 (1986) , Selected Medicinal Plants of India, CHEMEXCIL, Mumbai (1982). ] 2. Conessine from the bark killed free living amoebae and also kills Entamoeba histolytica in the dysenteric stools of experimentally infected kittens. It is markedly lethal to the flagellate protozoon. It is antitubercular also. Conkurchine is hydrochloride hypotensive and vasodilator. (Ref: J.Pharm. (London), 1049, 1:340. , 3. Antibacterial activity of Holarrhena antidysenterica [kurchi] Against The Enteric pathogens. The present study was undertaken to find the anti-bacterial activity of the crude aqueous and alcoholic extracts of stem bark of Holarrhena antidysenterica against the known enteric pathogens. Our present work suggests that clinical trial of both aque-ous and alcoholic extracts of the stem bark of H. antidysenterica can be carried out against a battery of enteric pathogens, casuative agents of diarrhea in infants and adults. (Ref: M. BALLAL, D. SRUJAN, K.K. BHAT, A. SHIRWAIKAR, P.G. SHIVANANDA Department of Microbiology, Kasturibai Medical college, Manipal Department of Botany, Poorna Prajna College, Udupi,Department of Chemistry, Kasturibai Medical College, Manipal-576 119.) (Ref: Indian Journal of Pharmacology 2001; 33: 392-393, Brown HC. Holarrhena antidysenterica. Br Med J 1992; 306:903-10). 4. Investigation of the Antidiarrhoeal activity of holarrhena antidysenterica. Holarrhena antidysenterica (L)- Apocyanaceae, well known for its antidiarrhoeal activity was studied for its effect on diarrhoeagenic Escherichia Escherichia coil. Different dilutions of the decoction of the plant were assayed for its effect on the adherence and toxin production of 2 groups of E. coli enteropathogenic (EPEC) and enterotoxigenic (ETEC.) Adherence per se was not affected though disruption of the characteristic `microcolonies' of EPEC on HEp-2 cell line was observed. The decoction was more effective in inhibiting stable toxin production as compared with labile toxin. (Ref: Daswani PG; Birdi TJ; Antarkar DS; Antia NH. Indian Journal of Pharmaceutical Sciences. 2002 Mar-Apr; 64(2): 164-7). 11 5. Chopra and his associates (1972) showed that conessine killed free living amoebae, proteus and limax in dilutions of 1 in 2,80,000. Its action on the vegetative forms of E.histolytica was tested on the dysenteric stools of experimentally infected kittens. In mucus flakes in such stools motile amoebae were killed in dilutions of 1 in 2,80,000 in 8 minutes in the presence of an alkali and in 18 minutes in the absence of alkali, as compared with 1 in 2,00,000 of emetine. (Ref: Chopra, R. N.: Indigenous Drugs of India, Acadernic Publishers, Calcutta (1982). 6. Conessine from the bark kills free living amoebae; it also kills Entamoeba histolytica in dysenteric stools of experimentally infected kittens. Conessine produces little effect on Trichomonas hominis but is lethal to the flagellate protozoon. 7. In a clinical study on 40 cases of amoebiasis and giardiasis, the efficacy of Holarrhena antidysenterica in intestinal amoebiasis was 70%. Good response was also observed in Entamoeba histolytica cyst-passers, when treated with H. antidysenterica bark. (Ref: Encyclopedia of Indian Medicinal Plants – C.P.Khare. Published by Springer-Verlag Berlin Heidelberg, Printed in Germany. REFERENCES: 1. Chopra, R. N.: Indigenous Drugs of India, Acadernic Publishers, Calcutta (1982). 2. Prasad, S. and P. N. Kaul,: Ind. J. Pharm, Oct. 423 (1956). 3. Anandakumar, A. et al.: Ancient Sci. Life 3: 203 (1983).306:903-10. 4. Roy, A. C. and Mukherjee,. J. Sci. Indus. Res. 17A: 158 (1958). 5. Siddiqui, S. and Pillai: Ind. J. Chem. Soc. 9: 553 (1932). 6. Siddiqui, S. et al.: J. Sci. Indus. Res. 25: 20 (1982). 7. Peacock and Choudbury: J. Chem. Soc. 1129 (1935). 8. Singh, K. P.: Ancient Sci. Life 5: 228 (1986). 9. Khorana, M. L. and T. N. Vasudevan: Ind. J. Pharin. 29: 149 (1967). 10. Chopra, R. N.: Indigenous Drugs of India, Acadernic Publishers, Calcutta (1982). Daswani PG; Birdi TJ; Antarkar DS; Antia NH. Indian Journal of Pharmaceutical Sciences. 2002 Mar-Apr; 64(2): 164-7 11. Dictionary of Indian Medicinal Plants,CIMAP, Lucknow(1992) ,Singh, K.P.: Ancient Sci. Life 5:228 (1986) , Selected Medicinal Plants of India, CHEMEXCIL, Mumbai (1982). 12 12. Encyclopedia of Indian Medicinal Plants – C.P.Khare. Published by Springer-Verlag Berlin Heidelberg, Printed in Germany. 13. Indian J. Chem., 1981, 20B: 62. 14. Indian Journal of Pharmacology 2001; 33: 392-393, Brown antidysenterica. Br Med J 1992; J.Pharm. (London), 1049, 1:340. 13 HC. Holarrhena Phyllanthus niruri BOTANICAL NAME : Phyllanthus niruri FAMILY : Euphorbiaceae SYNONYMS : Phyllanthus carolinianus, P, sellowianus, COMMON NAMES : Chanca piedra PART USED : Entire plant HABIT : Shrubs, trees, and annual or biennial herbs HABITAT : Distributed throughout the tropical and subtropical regions of both hemispheres. DESCRIPTION OF PLANT: Phyllanthus niruri is an annual, herb; height varies between 30–60 cm. Stem is angular with numerous distichous, elliptic-oblong leaves. Flowers are yellow and very numerous; monoecious with 1–3 staminate flowers and solitary pistillate flower borne axillary. Fruits capsule, very small, globose, smooth, seeds 3-gonous, longitudinally ribbed on the back. Seed to seed cycle occurs in two or four weeks. The flowering time in Indian conditions is July to August. Keys for identification of different species of Phyllanthus are found in Caius (1986), Agharkar (1991), and Gupta (984). Fig: 1 Portion of Phyllanthus niruri Fig: 2 Inflorescence Photograph: Whole plant 14 CHEMICAL CONSTITUENTS: Alkaloids, astragalin, brevifolin, carboxylic acids, corilagin, cymene, ellagic acid, ellagitannins, gallocatechins, geraniin, hypophyllanthin, lignans, lintetralins, lupeols, methyl salicylate, niranthin, nirtetralin, niruretin, nirurin, nirurine, niruriside, norsecurinines, phyllanthin, phyllanthine, phyllanthenol, phyllochrysine, phyltetralin, repandusinic acids, quercetin, quercetol, quercitrin, rutin, saponins, triacontanal, tricontanol (Ref: Ueno, H., et al. “Chemical and pharmaceutical studies on medicinal plants in Paraguay. Geraniin, an angiotensin-converting enzyme inhibitor from ‘paraparai mi,’ Phyllanthus niruri.” J. Nat. Prod. 1988; 51(2): 357–59. PHARMACOLOGICAL ACTION: Its root, leaves, fruits, milky juice, and whole plants are used as medicine. According to Ayurvedic system of medicine it is considered acrid, cooling, alexipharmic and useful in thirst, bronchitis, leprosy, anemia, urinary discharge, anuria, biliousness, asthma, for hiccups, and as a diuretic. According to Unani system of medicine herb is stomachic and good for sores and useful in chronic dysentery. Fruits useful for tubercular ulcers, wounds, sores, scabies and ring worm (Agharkar 1991; Krishnamurty 1993). The fresh root is believed to be an excellent remedy for jaundice. A poultice of the leaves with salt cures scabby affection and without salt applied on bruise and wounds. The milky juice is a good application to offensive sores. The bark yields a bitter principle phyllanthin. The infusion of the root and leaves is a good tonic and diuretic when taken cold in repeated doses. In different parts of India, specially, in Chhattisgarh state, there is a rich traditional medicinal tradition concerning this weed (Caius 1986; Oudhia and Tiwari 2001). In many parts of India, it is commonly used for the treatment of snake bite. The active compounds phyllanthin and hypophyllanthin have been isolated from leaves. Recently, lignansniranthin, nirtetralin, and phyltetralin have been isolated from leaves. (Rastogi and Mehrotra, 1991) It is a major component of many popular liver tonics in India. Fresh juice and powder of dried plant are used most frequently in Ayurvedic preparations (Sastry and Kavatherkar, 1991). (Ref: Rastogi, R.P. and B.N. Mehrotra. 1991. Compendium of Indian medicinal plants Vol. II. Central Drug Research Institute, Lucknow and publications and Information Directorate, New Delhi). 15 ETHNOBOTANY: India Anemia, asthma, astringent, bronchitis, conjunctivitis, cough, deobstruent, dropsy, diabetes, diarrhea, diuretic, dysentery, fevers, eye disorders, galactagogue, genitourinary disorders, gonorrhea, hepatitis, jaundice, leucorrhea, menorrhagia, oligogalactia, ringworm, scabies, stomachic, thirst, tuberculosis, tumor (abdomen), urogenital tract infections, warts. REFERENCES: 1. Rastogi, R.P. and B.N. Mehrotra. 1991. Compendium of Indian medicinal plants Vol. II. Central Drug Research Institute, Lucknow and publications and Information Directorate, New Delhi 2. Dhar, M. L., et al. “Screening of Indian plants for biological activity: Part I.” Indian J. Exp. Biol. 1968; 6: 232–47. 3. Kitisin, T., et al. “Pharmacological studies. 3. Phyllanthus niruri.” Sirriaj. Hosp. Gaz. 1952; 4: 641– 49. 4. Umarani, D., et al. “Ethanol induced metabolic alterations and the effect of Phyllanthus niruri in their reversal.” Ancient Sci . Life 1985; 4(3): 174–80. 5. Ueno, H., et al. “Chemical and pharmaceutical studies on medicinal plants in Paraguay. Geraniin, an angiotensin-converting enzyme inhibitor from ‘paraparai mi,’ Phyllanthus niruri.” J. Nat. Prod. 1988; 51(2): 357–59. 6. Sreenivasa, R. Y., “Experimental production of liver damage and its protection with Phyllanthus niruri and Capparis spinosa (both ingredients of LIV52) in white albino rats.” Probe 1985; 24(2): 117–19. 7. Prakash, A., et al. “Comparative hepatoprotective activity of three Phyllanthus species, P. urinaria, P. niruri and P.simplex, on carbon tetrachloride induced liver injury in the rat.” Phytother. Res. 1995; 9(8): 594–96. 8. Bhumyamalaki , et al. “Phyllanthus Niruri and jaundice in children.” J. Natl. Integ. Med. Ass. 1983; 25(8): 269–72. 9. Thabrew, M. R., et al. “Phytogenic agents in the therapy of liver disease.” Phytother. Res. 1996; 10(6): 461–67. 10. Wang, M. X., et al. “Observations of the efficacy of Phyllanthus spp. in treating patients with chronic Hepatitis B.” Zhongguo Zhong Yao Za Zhi 1994; 19(12): 750–52. 11. Farouk, A. “Antimicrobial activity of certain Sudanese plants used in folkloric medicine. Screening for antibacterial activity (I). Fitoterapia 1983; 54(1): 3–7. 12. Mesia, L.T.K., et al. “In-vitro antimalarial activity of Cassia occidentalis, Morinda morindoides and Phyllanthus niruri.” Ann. Trop. Med. Parasitol. 2001; 95(1): 47–57. 13. “Antimalarial activity of 20 crude extracts from nine African medicinal plants used in Kinshasa, Congo.” J. Ethnopharmacol. 1999; 68(1/3): 193–203. 14. Rao, M. V., and K. M. Alice. “Contraceptive effects of Phyllanthus amarus in female mice. Phytother. Res. 2001; 15(3): 265–67. 16 Picrorhiza kurroa Royle ex Benth BOTANICAL NAME : Picrorhiza kurroa Royle ex Benth COMMON NAME : Hellbore, Katuka, Katuki, Kurri, Kutki, Katuko, Kuru, Katukarogani. PARTS USED : Dry rhizomes and roots. HABITAT : Found in the Himalayan region growing at elevations of 3,000-5,000 meters DESCRIPTION OF PLANT: Picrorhiza kurroa has a long, creeping rootstock that is bitter in taste, and grows in rock crevices and moist, sandy soil. The leaves of the plant are flat, oval, and sharply serrated. The flowers, which appear June through August, are white or pale purple and borne on a tall spike. Photograph 1: Whole plant 17 PHYTOCHEMISTRY: The active constituents are obtained from the root and rhizomes Kutkin is the active principal of Picrorhiza kurroa and is comprised of kutkoside and the iridoid glycoside picrosides I, II, and III. Other identified active constituents are apocynin, drosin, and nine cucurbitacin glycosides. [Weinges K, Kloss P, Henkels WD. Natural products from medicinal plants. XVII. picroside-II, a new 6-vanilloyl-catapol from Picrorhiza kuroa Royle and Benth. Justus Liebigs Ann Chem 1972;759:173-182. [Article in German]; Stuppner H, Wagner H. New cucurbitacin glycosides from Picrorhiza kurroa. Planta Med 1989;55:559563.] Apocynin is a catechol that has been shown to inhibit neutrophil oxidative burst in addition to being a powerful anti-inflammatory agent, [Simons JM, `t Hart BA, Ip Vai Ching TR, et al. Metabolic activation of natural phenols into selective oxidative burst agonists by activated human neutrophils. Free Radic Biol Med 1990;8:251-258.] while the curcubitacins have been shown to be highly cytotoxic and possess antitumor effects. [Stuppner H, Wagner H. New cucurbitacin glycosides from Picrorhiza kurroa. Planta Medica 1989;55:559.] Kutkin, a bitter glycosidal principle, was reported by Rastogi et al. They also isolated D-mannitol, vanillic acid and some steroids.Kutkin was later shown to be a stable mixed crystal of two C-9 iridoid glycosides-Picroside I and Kutakosid. Apocynin has been isolated from the plant. Picroside II has been isolated and shown to have hepatoprotective activity. With the help of preparative HPLC, larger Quantities of picrosides have been isolated, permitting precise structure identification and biological experiments. ETHNOBOTANY: For thousands of years, the bitter rhizomes of Picrorhiza have been used in India to treat people with indigestion, but it is also a remedy for constipation accompanied with insufficient digestive secretion, and fevers caused by all types of infection. Scientific studies have shown Picrorhiza to have antioxidant properties, particularly in the liver. PHARMACOLOGICAL ACTION: Hepatoprotective, Anticholestatic, Antioxidant, Immune-modulating activity. 18 [Atal CK, Sharma ML, Kaul A, Khajuria A. Immunomodulating agents of plant origin. I: preliminary screening. J Ethnopharmacol 1986;18:133-141.Subedi BP. Plant profile: Kutki (Picrorhiza scrophulariifiora). Himalayan Bioresources 2000;4. 1. Picrorhiza kurroa (Kutaki) Royle ex Benth as a hepatoprotective agent--experimental & clinical studies. Vaidya AB, Antarkar DS, Doshi JC, Bhatt AD, Ramesh V, Vora PV, Perissond D, Baxi AJ, Kale PM Year : 1996 Vol: 42 Issue : 4 Page : 105-8 Picrorhiza kurroa (Pk), a known hepatoprotective plant, was studied in experimental and clinical situtations. The standardization of active principles--Picroside 1 and 2 was done with High Performance Liquid Chromatography. Picroside 1 ranged from 2.72 to 2.88 mg/capsule and picroside 2 from 5.50 to 6.00 mg/capsule. In the galactosamine-induced liver injury in rats, Pk at a dose of 200 mg/kg p.o. showed a significant reduction (p < 0.05) in liver lipid content, GOT and GPT. In a randomised, double-blind placebo controlled trial in patients diagnosed to have acute viral hepatitis (HBsAg negative), Pk root powder 375 mg three times a day was given for 2 weeks (n = 15) or a matching placebo (n = 18) was given. Difference in values of bilirubin, SGOT and SGPT was significant between placebo and Pk groups. The time in days required for total serum bilirubin to drop to average value of 2.5 mg% was 75.9 days in placebo as against 27.44 days in Pk group. The present study has shown a biological plausability of efficacy of Pk as supported by clinical trial in viral hepatitis, hepatoprotection in animal model and an approach for standardizing extracts based on picroside content. 19 2. Hepatic Insult and Damage Numerous animal studies, primarily in rats, have demonstrated that the active constituents of Picrorhiza kurroa are effective at preventing liver toxicity and the subsequent biochemical changes caused by numerous toxic agents. Hepatocytes damaged by exposure to galactosamine, thiocetamide, and carbon tetrachloride were incubated with Picrorhiza constituents. A concentration-dependent restorative effect was observed in regard to normal hepatocyte function. [Visen PK, Saraswat B, Dhawan BN. Curative effect of picroliv on primary cultured rat hepatocytes against different hepatotoxins: an in vitro study. J Pharmacol Toxicol Methods 1998;40:173-179.] A similar effect was seen when 25 mg/kg/day oral Picrorhiza extract was administered to rats poisoned by aflatoxin B1 exposure. Picrorhiza kurroa significantly prevented the biochemical changes induced by aflatoxin B1. [ Rastogi R, Srivastava AK, Rastogi AK. Biochemical changes induced in liver and serum aflatoxin B1-treated male wistar rats: preventive effect of picroliv. Pharmacol Toxicol 2001;88:53-58.] Picrorhiz extract, when given at a dose of 3-12 mg/kg orally for 45 days, was also shown to be effective in reversing ethanol-induced liver damage in rats. [ Saraswat B, Visen PK, Patnaik GK, Dhawan BN. Ex vivo and in vivo investigations of picroliv from Picrorhiza kurroa in an alcohol intoxication model in rats. J Ethnopharmacol 1999;66:263-269.] In an animal model of hepatic ischemia, rats given Picrorhiza orally at 12 mg/kg daily for 7 days, prior to induced ischemia, demonstrated improved hepatocyte glycogen preservation and reduced apoptosis, compared to control animals. [ Singh AK, Mani H, Seth P. Picroliv preconditioning protects the rat liver against ischemia-reperfusion injury. Eur J Pharmacol 2000;395:229-239] Picrorhiza principals have also shown to be effective in treating Amanita mushroom poisoning in an in vivo animal model. [ Dwivedi Y, Rastogi R, Garg NK, et al. Effects of picroliv, the active principle of Picrorhiza kurroa, on biochemical changes in rat liver poisoned by Amanita phalloides. Chung Kuo Yao Li Hsueh Pao 1992;13:197200.] 20 An in vitro study demonstrated Picrorhiza's antioxidant activity by subjecting human Glioma and Hep 3B cells to a hypoxic state. Picrorhiza treatment reduced the cellular damage cause by hypoxia, indicating Picrorhiza constituents may protect against hypoxia/reoxygenation-induced injuries. [ Gaddipati JP, Madhavan S, Sidhu GS, et al. Picroliv -- a natural product protects cells and regulates the gene expression during hypoxia/reoxygenation. Mol Cell Biochem 1999;194:271-281.] REFERENCES: 1. Atal CK, Sharma ML, Kaul A, Khajuria A. Immunomodulating agents of plant origin. I: preliminary screening. J Ethnopharmacol 1986;18:133-141.Subedi BP. Plant profile: Kutki (Picrorhiza scrophulariifiora). Himalayan Bioresources 2000;4. 2. Dwivedi Y, Rastogi R, Garg NK, et al. Effects of picroliv, the active principle of Picrorhiza kurroa, on biochemical changes in rat liver poisoned by Amanita phalloides. Chung Kuo Yao Li Hsueh Pao 1992;13:197-200.] 3. Gaddipati JP, Madhavan S, Sidhu GS, et al. Picroliv -- a natural product protects cells and regulates the gene expression during hypoxia/reoxygenation. Mol Cell Biochem 1999;194:271-281.] 4. Justus Liebigs Ann Chem 1972;759:173-182. [Article in German]; 5. Saraswat B, Visen PK, Patnaik GK, Dhawan BN. Ex vivo and in vivo investigations of picroliv from Picrorhiza kurroa in an alcohol intoxication model in rats. J Ethnopharmacol 1999;66:263-269. 6. Simons JM, `t Hart BA, Ip Vai Ching TR, et al. Metabolic activation of natural phenols into selective oxidative burst agonists by activated human neutrophils. Free Radic Biol Med 1990;8:251-258. 7. Singh AK, Mani H, Seth P. Picroliv preconditioning protects the rat liver against ischemiareperfusion injury. Eur J Pharmacol 2000;395:229-239]. 8. Stuppner H, Wagner H. New cucurbitacin glycosides from Picrorhiza kurroa. Planta Med 1989;55:559-563.]. 9. Stuppner H, Wagner H. New cucurbitacin glycosides from Picrorhiza kurroa. Planta Medica 1989;55:559.]. 10. Vaidya AB, Antarkar DS, Doshi JC, Bhatt AD, Ramesh V, Vora PV, Perissond D, Baxi AJ, Kale PM Year : 1996 Vol: 42 Issue : 4 Page : 105-8. 11. Rastogi R, Srivastava AK, Rastogi AK. Biochemical changes induced in liver and serum aflatoxin B1-treated male wistar rats: preventive effect of picroliv. Pharmacol Toxicol 2001;88:53-58. 12. Weinges K, Kloss P, Henkels WD. Natural products from medicinal plants. XVII. picroside-II, a new 6-vanilloyl-catapol from Picrorhiza kuroa Royle and Benth. 21 QUALITY CONTROL PARAMETERS OF `API’ OF LIVOKURE 22 QUALITY CONTROL PARAMETERS OF `API’ OF LIVOKURE Sl. Extracts No. 01. Phyllanthus niruri Plant parts used Type of form used Organoleptic test Particle size L.O.D.% w/w at 1050C pH of 1% soln. in water Assay Whole plant Dry powder extract with fine granules Brown coloured, aromatic odour and bitter taste passed thru 20# NMT 6% 4.0-7.0 Root Dry powder extract with white specks passed thru 20# NMT 5% 4.0-7.0 Leaf Brown dry powder passed thru 20# NMT 5% 4.0-7.0 Andrograph olides NLT 5% by gravimetry Bark Fine powder extract Dark brown coloured, characteristic odour and bitter taste Dark greenish brown coloured, aromatic odour and bitter taste Brown coloured, aromatic odour and bitter taste By gravimetry. Bitters NLT 2%(d/b) Bitters by gravimetry. NLT 6% (d/b). passed thru 20# NMT 10% 4.0-7.0 Alkaloids by gravimetry NLT 4% (d/b) (Bhuiamla) 02. Picrorhiza kurroa (Kutki) 03. Andrographis paniculata (Kalmegh) 04. Holarrhena antidysenterica (Kurchi) 23 CLINICAL DATA ON LIVOKURE 24 Fig. 1. Effect of the Plant extract of Livokure on lipid content of the liver in rats during CCl4 liver injury (S.E.) Total lipid in mg/kg liver tissue 200 150 Normal 100 CCl4 administered + vehicle CCl4 administered + Livokure 50 0 Groups Sl. No. 1) 2) 3) Group Normal CCl4 administered + Vehicle CCl4 administered + Plant extract No. of animal used 65, * P<0.001 25 Total lipids in mg/kg liver tissue 67.0 2.0 180.5 3.5 71.2 2.5* Fig. 2 Effect of plant extract of Livokure on serum triglyceride level during CCl4 intoxication in rats (+S.E.) 200 180 160 140 Groups 120 Normal 100 80 CCl4 administered + Vehicle 60 40 CCl4 administered + Livocure 20 0 Triglyceride level (mg/100ml) Sl. No. 1) 2) 3) Group Normal CCl4 administered + Vehicle CCl4 administered + Plant extract No. of animal used 65, *P<0.01 26 Total lipids in mg/kg liver tissue 180.5 5.5 135.6 6.2 167.2 3.9* Fig. 3. Effect of Livokure on serum cholesterol in CCl4 induced liver intoxication in rats (S.E) Cholesterol level (mg/100 ml) 60 50 40 Normal 30 CCl4 administered + vehicle CCl4 administered + Livokure 20 10 0 Groups Normal CCl4 administered CCl4 administered Livokure No. of animal used 65, * P<0.02 27 50.2 2.9 41.1 3.2 53.5 3.1 Fig. 4. Effect of Livokure on SGPT and SGOT level of source of rats during the CCl4 treatment (S.E.) 120 Unit/ml serum 100 80 Normal 60 CCl4 administered + vehicle CCl4 administered + Livokure 40 20 0 SGPT Sl. No. 1) 2) 3) SGOT Group Normal CCl4 CCl4 administered + Plant extract No. of animal used 65, * P<1.9 28 SGPT (unit/ml serum) 14.4 0.8 110.0 2.1 15.6 0.9 SGOT (Unit/ml serum) 51.6 2.0 86.2 3.0 52.6 1.9* CLINICAL TRIAL OF LIVOKURE : Clinical trials on effectiveness of Phyllanthus for HBV have been mixed, the picies P.urinaria and P.niruri seem to work better than P.amarus (Ref 8). Clinical trials with hepatitis B patients have been used 900-2700 mg of Phyllanthus per day (Ref. 1.). It completely antagonized the toxic effects of paracetamol on certain enzymes in serums as well as in isolated hepatic cells. Andrographolide was found to be more potent (Ref 2). The plant has found experimentally that it has hepatoprotective activities against alcohol CCl4 and aflatoxin B1 induced hepatic damage (Ref. 3,4). Amoebicidal, antituberculous and other antiprotozoal activity of individual alkaloids specially, conessine have been extensively investigated (Ref 5). References : 1) Meixa W, Haoweei C, Yanjun L, et al. Herbs of the genus Phyllanthus in the treatment of chronic hepatitis B: observation with three preparations from different geographic sites. J Lab Clin Med 1995; 126:350-2. 2) J. Ethnopharmacol 1993 Oct; 40(2):131-136. 3) Ibid., Abstract No. 36. 4) Indigenous Drugs of India (1982), 2nd Ed. Acedemic Publishers, Calcutta, P-242. 5) J. Ethnopharmacol 1999 Dec 15;68(1-3):399-44. 29 A CLINICAL TRIAL REPORT OF `LIVOKURE’ DONE BY “J. B. ROY STATE AYURVEDIC MEDICAL COLLEGE & HOSPITAL” GOVERNMENT OF WEST BENGAL Date : 17.06.2001 The Ayurvedic medicine `LIVOKURE’ [Drug License no. AL-828(M)] manufactured by Herbicure (P) Ltd. Calcutta was supplied to me in capsule form for clinical trial. LIVOKURE was given to the patients (male 11, female 13, age group 10 – 60 years) through p.o. route (dose: One capsule t.i.d.). The patients were suffering from haemolytic jaundice, cirrhosis of liver, hepatitis, alcoholic liver diseases. After 7 days’ consecutive treatment with LIVOKURE, biochemical studies revealed that lipid level was normalised significantly. It was also noted that serum bilirubin level (conjugated & unconjugated) was reduced markedly. Most of the patients were relieved from griping pan and irregular bowel movement and revival of loss of appetite was noticed within a week. SGPT & SGOT levels were normalized after 14 days’ consecutive treatment of LIVOKURE. It is suggested that the Ayurvedic medicine LIVOKURE is very much effective remedy against all sorts of acute and chronic liver disorders. LIVOKURE can also be used as prophylactic medicine to root out liver disorders. It is free from any side effects. 30