WO2003080090A1 - Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450 - Google Patents

Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450 Download PDF

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Publication number
WO2003080090A1
WO2003080090A1 PCT/IB2002/000635 IB0200635W WO03080090A1 WO 2003080090 A1 WO2003080090 A1 WO 2003080090A1 IB 0200635 W IB0200635 W IB 0200635W WO 03080090 A1 WO03080090 A1 WO 03080090A1
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WIPO (PCT)
Prior art keywords
composition
drugs
extract
liver
hepatotoxicity
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Application number
PCT/IB2002/000635
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English (en)
Inventor
Rakesh Kamal Johri
Sheikh Tasaduq Abdullah
Kuldeep Singh
Devinder Kumar Gupta
Bal Krishan Kapahi
Dilip Manikrao Mondhe
Satinder Mohan Jain
Om Parkash Suri
Kasturi Lal Bedi
Ghulam Nabi Qazi
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Council Of Scientific And Industrial Research
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Application filed by Council Of Scientific And Industrial Research filed Critical Council Of Scientific And Industrial Research
Priority to PCT/IB2002/000635 priority Critical patent/WO2003080090A1/fr
Priority to KR10-2004-7015457A priority patent/KR20040101374A/ko
Priority to CNA028290305A priority patent/CN1627955A/zh
Priority to JP2003577916A priority patent/JP2005526792A/ja
Priority to EP02716955A priority patent/EP1490078A1/fr
Priority to AU2002247880A priority patent/AU2002247880A1/en
Priority to CA002480334A priority patent/CA2480334A1/fr
Publication of WO2003080090A1 publication Critical patent/WO2003080090A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • composition comprising an extract from Emblica officinalis and optionally pharmaceutically acceptable additives and use of treating drug induced hepatotoxicity.
  • liver diseases As one among six thrust areas for multidisciplinary study.
  • liver cirrhosis as such accounts amongst the ten top fatal diseases in the world. Exposure of humans to a variety of agents such as chemicals and drugs (xenobiotics), many natural compounds, viral and bacterial pathogens with attendant predisposable conditions, etc. are considered responsible for hepatic insufficiency.
  • liver toxicity There are large group of drugs which on repeated administration produce liver toxicity. These are mediated primarily by bioactivation so that the products of parent drug are toxic. Another class of drugs induce toxicity by causing membrane rupture or DNA damage and by interfering with protein synthesis. One of the important categories of drugs are the anti-TB drugs which when taken regularly cause hepatotoxicity.
  • Tuberculosis is prevelent in all counteries of the world - tropical, subtropical and colder regions.
  • the chemotherapy of tuberculosis is important and challenging, because the disease is often chronic and the toxicity due to anti-TB drugs pose therapeutic problems.
  • the disorders of the liver caused during the treatment of tuberculosis, by known antimicrobial agents range from jaundice to the fibrosis of the liver.
  • Three drugs i.e., rifampicin, pyrazinamide and isoniazid comprise first choice treatment of tuberculosis. These are to be administered for long period of time and produce liver dysfunction leading to toxicity.
  • Emblica officinalis Gaertn. (Hindi : Amla) (Euphorbiaceae)is widespread in India, Ceylon,Malaya and China. The tree is common in mixed deciduous forests of India ascending to4500 ft on the hills , cultivated in gardens and homeyards. It is a small or medium sized deciduous tree, fruits depressed globose, Vi to 1 inch in diameter, fleshy, and contains six trigonows seeds. The fruit is sour and is occasionally eaten raw.
  • the fruit pulp contains (%) ; moistre 81.2, protein 0.5, fat 0.1, mineral matter 0.7, Ca 0.005, Phosphorus 0.02 and Iron 1.2 mg 100 gm, nicotinic acid 0.2 mg/100 gm, vitamin C 600 mg/100 mg.
  • moistre 81.2 protein 0.5, fat 0.1, mineral matter 0.7, Ca 0.005, Phosphorus 0.02 and Iron 1.2 mg 100 gm, nicotinic acid 0.2 mg/100 gm, vitamin C 600 mg/100 mg.
  • the potent vitamin C-like activity has been located in the low molecular weight hydrolysable tannins.
  • Four such compounds emblicanin-A, emblicanin-B, punigluconin and pedunculagin have been isolated from the fresh pericarp.
  • the first two compounds are naturally occurring galloellagi-tannins ( Ghosal, et al, IndJChem, 1996:353 :941-948; Bhattacharya et al, Phytomedicine, 2000: 7: 173-175).
  • the fruit is acrid, cooling, and diuretic. Dried fruit is useful in haemorrhage, diarrhoea and dysentry. It has been extensively use in anemia, liver diseases and dyspepsea. A fermented liquor prepared from the fruits is used in jaundice. Fruits are a reputed Ayurvedic rasayan (revitaliser, biological response modifier) (SharmaPN. Dravyaguna vijnana, Chaukhamba Sanskrit Sansthan, Naranasi, 1978). Several pharmacological properties are also reported.
  • Leaf extracts have been found to be anti-inflammatory (Summanen et al, Planta Medica, 1993:59: 666), antioxidant (Jose.and Kuttan, Clin. Biochem. ⁇ utr, 1995:19:63-70), hypolipidemic (Mathw:eta ⁇ ,JEthnopharmacol, 1996:50 :61-68), cell growth inhibition (Psatima et al, ACS Symp. Ser, 1998, p701). Hepatoprotective activity of Emblica officinalis extracts against a chemical viz., carbon tetrachoride induced liver toxicity has been demonstrated ( Jose JK & Kutten R, J.
  • the Applicants provide protection against hepatotoxicity produced by all such drugs, which are bio-activated by multiple CYP isoforms as indicated by clinical parameters in serum/liver.
  • clinical parameters showing toxicity are reversed even if the symptoms of genotoxicity may not begin to appear.
  • decrease in abnormal rise of serum Bilirubin which may be attributed to a protective effect also due to other cellular factors such as membrane stabilization, as revealed in primary monolayer cultures of liver cells.
  • preparations from Emblica officinalis which are superior so far as their systemic effects are manifested in clinical profile (serum/liver parameters) which correlate to their hepatoprotective profile.
  • the main object of the present invention is to develop a hepatocurative composition against CYP 450 bio-activation hepatotoxicity induced by drugs.
  • Another main object of the present invention is to develop a hepatocurative composition against CYP 450 bio-activation hepatotoxicity induced by anti-TB drugs.
  • Still another object of the present invention is to develop a use of preparing an extract from fruit Emblica officinalis.
  • Still another object of the present invention is to develop a use for treating a subject for CYP 450 and free radical mediated hepatotoxicity caused by drugs using composition comprising an extract from Emblica officinalis.
  • Still another object of the present invention is to develop a use of using hepatocytes to understand the effect of extract from fruit Emblica officinalis.
  • composition comprising an extract from Emblica officinalis and optionally pharmaceutically acceptable additives and use of treating drug induced hepatotoxicity.
  • the present invention relates to a composition useful for hepatocurative effect against CYP 450 bio-activation hepatotoxicity induced by drugs, said composition comprising an extract from Emblica officinalis and optionally pharmaceutically acceptable additives and use of treating drug induced hepatotoxicity.
  • composition useful for hepatocurative effect against CYP 450 bio-activation hepatotoxicity induced by drugs comprising an extract from Emblica officinalis and optionally pharmaceutically acceptable additives.
  • additives are selected from a group of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and or pharmaceutically acceptable carrier, excipient, diluent, or solvent.
  • composition is administered orally.
  • extract and additives are in the ratio ranging between 1 : 1 to 1:10.
  • said additives have no effect on the hepatocurative effect of the said extract.
  • said extract is prepared in a solvent selected from a group comprising aqueous, aqueous-ethanolic, ethanolic, ketonic, ethereal, halogenated solvents.
  • composition shows tanin content in the range of 8.5 to 15%.
  • composition for the oral route is in form of capsule, tablet, syrup, concentrate, powder, granule, aerosol, and/or beads.
  • composition comprising an extract from Emblica officinalis and optionally pharmaceutically acceptable additives, said use comprising steps of adding polar solvent to the fruit Emblica Officinalis to obtain the extract and optionally adding pharmaceutically acceptable additives.
  • composition for the oral route is in form of capsule, tablet, syrup, concentrate, powder, granule, aerosol, and/or beads.
  • composition is not effective against hepatotoxicity which is independent of bio-activation by CYP 450.
  • composition is administered orally.
  • said composition for the oral route is in form of capsule, tablet, syrup, concentrate, powder, granule, aerosol, and/or beads.
  • said composition is useful for treating animals or human beings.
  • said drugs are selected from a group comprising Paracetamol, CC1 4 , and anti-TB drugs.
  • anti-TB drugs are selected from a group comprising Rifampicin, Pyrazinamide, and isoniazid.
  • composition controls abnormal rise in the clinical pathological symptoms revealed by serum/liver markers serving as indices of hepatic damage besides control of high levels of Bilirubin.
  • said drugs is used at cytotoxic levels to produce valid and reproducible results in liver cells.
  • said composition is useful for treating animals or human beings.
  • said composition has no adverse effect on health.
  • composition shows restoration of hepatocyte viability.
  • composition reverses the leakage of glutamate pyruvate transaminase (GPT) from hepatocyte.
  • GPT glutamate pyruvate transaminase
  • composition shows hepatocurative effect of about 96% against combined effect of anti-TB drugs of Rifampicin, isoniazid, and pyrazinamide.
  • composition shows about 94%) hepatocurative effect against rise in lipid Peroxidation (LPO) induced by combination of anti-TB drugs Rifampicin, isoniazid, and pyrazinamide.
  • LPO lipid Peroxidation
  • composition shows about 96% decrease of serum Bilirubin as a hepatocurative effect against combination of anti-TB drugs Rifampicin, isoniazid, and pyrazinamide.
  • dosage of said composition is ranging between 50-250 mg/kg.
  • the applicants provide protection against hepatotoxicity produced by all drugs, which are bio-activated by multiple CYP isoforms as indicated by clinical parameters in serum/hver. Besides, we claim that the clinical parameters showing toxicity are reversed even if the symptoms of genotoxicity may not begin to appear. For example decrease in abnormal rise of serum Bilirubin, which may be attributed to a protective effect also due to other cellular factors such as membrane stabilization, as revealed in primary monolayer cultures of liver cells.
  • Emblica Officinalis cures hepatotoxicity induced by drugs that is restricted to CYP 450 bio- activation hepatotoxicity.
  • compositions and methods of the present invention increase biological defence mechanism of the tissue, improve recovery from dysfunctional states of the liver after prolonged challenge of anti-TB drugs.
  • compositions and use of the present invention contain one of the extracts/ fractions of Emblica officinalis fruit as an essential ingredient. These extracts/ fractions may be obtained from fresh or semi dried fruits of Emblica officinalis.
  • the compositions are formulated with more than one extracts and combined in any weight ratios. The preferred weight ratios include 1:1,1:2,1:1:1:, 1:2:2.2:1:2:, 2:2:1.
  • the present invention is related to preparation and use of products from Emblica officinalis, which restores normal liver function against drug induced toxicity caused as a result of bio-activation of drugs applicable with particular relevance to anti-TB drug(s) induced liver toxicity.
  • the products of the invention comprise aqueous, aqueous-ethanolic, ethanolic, ketonic, ethereal, halogenated solvents extracts/ fractions from Emblica officinalis, obtained either from fresh or semi-dried fruits. These contain 8.5 -15 % of tannin content. It also relates to preparation of compositions of such products in different proportions of more than one ingredient.
  • liver cell (hepatocyte) cultures which ideally provide an insight into the mechanism of a toxin-induced impairment of hepato-biliary dysfunction because this model allows use of a test compounds (such as anti-TB drugs) to be used at cytotoxic level so that a valid and reproducible toxicity is generated.
  • test compounds such as anti-TB drugs
  • the in vitro cell culture model is of significant interest in ascertaining the mechanisms of toxicity and its reversal by protective agents.
  • liver cells are considered as system of choice which have found ample application in the evaluation of cyto- cum geno-toxicity of chemicals and drugs (Nakagawa and Tayama, Arch Toxicol, 1995:69:208) and as such have been used in the evaluation of hepatoprotective profiles of the present invention.
  • the mechanisms are revealed in critical biochemical functions of liver cells which are sensitive indicators of drug (s) toxicity. (Tomasi et al, Toxicol /Ntf/zo/: 15: 178-183).
  • the preparations act in a specific manner. These act against toxicity produced by drugs including anti-TB drugs which require bioactivation by hepatic cytochrome P 450 dependent mixed function oxidases. Cytochrome P450 have been shown to be involved in the liver toxicity (Anundi I, Lindros KO, Pharmacol Toxicol 1992; 70;453-458). Participation of CYP 450 dependent oxidation of drugs including anti-tubercular drugs rifampicin, isoniazid, pyrazinamide in liver is reported ( Ono et al, Biol Pharm Bull 1998:21 :421-425).
  • the metabolic activation of drugs including anti-TB drugs alone or in combination is also accompanied by reactive intermediates which may be free radical/ active metabolites/ free oxy radicals through a variety of cellular oxidative metabolic pathways.
  • Figure 1 shows liver toxicity wherein plant extract attenuates Rifampicin induced hepatotoxicity by restoring liver function to normal (95% effect).
  • the cell toxicity indicators shown in the said Fig. 1 is the leakage of lactate dehydrogenase (LDH) from intact cells after toxin challenge and its reversal by extracts.
  • LDH lactate dehydrogenase
  • Figure 2 shows leakage of glutamate pyruvate transaminase wherein said plant extracts in combination attenuates Rifampicin + isoniazid induced hepatotoxicity by restoring liver function to normal (96%).
  • the cell toxicity indicators shown in Fig 2 is the leakage of glutamate pyruvate transaminase (GPT) from intact cells after toxin challenge and its reversal by the extracts in combination. (Model: primary monolayer cultures of liver cells).
  • FIG. 3 shows leakage of serum glutamate pyruvate transminase (GPT) after toxin challenge and its reversal by Emblica officinalis fraction wherein Emblica officinalis reverses Rifampicin + isoniazid +pyrazinamide induced hepatotoxicity and restores the liver function to normal
  • the cell toxicity indicators shown in Fig 3 is the leakage of serum glutamate pyruvate transminase (GPT) after toxin challenge and its reversal by Emblica officinalis fraction.
  • GPT serum glutamate pyruvate transminase
  • Figure 4 shows protection against cell leakage wherein, Emblica officinalis fractions in combination prevents Rifampicin + isoniazid induced toxicity.
  • Fig. 4 shows that fractions provide 96% protection against cell leakage as measured by serum GPT levels and increases cellular defense. 75% increase in glutathione levels (liver) is observed.
  • Figure 5 shows Emblica officinalis extract reverses Rifampicin + isoniazid + pyrazinamide induced toxicity.
  • Fig 5 shows 94 % protection against rise in lipid Peroxidation
  • Figure 6 shows a flow chart for the preparation of extract from fruit Emblica Officinalis.
  • Table 1 shows that the plant products are effective against paracetamol hepatotoxicity which is mainly dependent against bioactivation mechanisms mediated by CYP 450. % protection is shown as combined effect release of LDH and GPT in serum.
  • Table 2 shows that the preparations of the present invention are not effective against liver toxicity produced by agents where the toxicity is primarily not dependent on bioactivation by
  • CYP 450 Table 2: Effect of plant products against hepatotoxicity produced by galactosamine.
  • Fig. 1 The cell toxicity indicators shown in Fig. 1 is the leakage of lactate dehydrogenase (LDH) from intact cells after toxin challenge and its reversal by extracts. (Model; primary monolayer cultures of liver cells)
  • LDH lactate dehydrogenase
  • Plant extracts in combination attenuates Rifampicin + isoniazid induced hepatotoxicity by restoring liver function to normal (96%).
  • the cell toxicity indicators shown in Fig 2 is the leakage of glutamate pyruvate tiansaminase (GPT) from intact cells after toxin challenge and its reversal by the extracts in combination. (Model: primary monolayer cultures of liver cells).
  • Emblica officinalis reverses Rifampicin + isoniazid +pyrazinamide induced hepatotoxicity and restores the liver function to normal (96%).
  • the cell toxicity indicators shown in Fig 3 is the leakage of serum glutamate pyruvate transminase (GPT) after toxin challenge and its reversal by
  • Emblica officinalis fractions in combination prevents Rifampicin + isoniazid induced toxicity.
  • Fig. 4 shows that fractions provide 96% protection against cell leakage as measured by serum GPT levels and increases cellular defense. 75% increase in glutathione levels (liver) is observed.
  • Emblica officinalis extract reverses Rifampicin + isoniazid + pyrazinamide induced toxicity.
  • Fig 5 shows 94 % protection against rise in lipid Peroxidation (LPO, liver) and 96% decrease of serum Bilirubin in response to treatment with extract of the present invention.

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Abstract

La présente invention concerne une composition utile pour produire un effet hépatocuratif contre l'hépatotoxicité de la bioactivation de CYP 450 induite par des médicaments, ladite composition comprenant un extrait d'Emblica officinalis et éventuellement des additifs pharmaceutiquement acceptables. L'invention concerne également une méthode destinée à traiter une hépatotoxicité induite par des médicaments.
PCT/IB2002/000635 2002-03-26 2002-03-26 Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450 WO2003080090A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PCT/IB2002/000635 WO2003080090A1 (fr) 2002-03-26 2002-03-26 Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450
KR10-2004-7015457A KR20040101374A (ko) 2002-03-26 2002-03-26 시토크롬 ｐ-４５０ 관련된 간독성에 대한 아말라의간치료 효과
CNA028290305A CN1627955A (zh) 2002-03-26 2002-03-26 余甘子对与细胞色素p－450有关的肝毒性的治疗作用
JP2003577916A JP2005526792A (ja) 2002-03-26 2002-03-26 アムラ（Ｅｍｂｌｉｃａｏｆｆｉｃｉｎａｌｉｓ）のチトクロムＰ−４５０に関する肝毒性への肝臓治療効果
EP02716955A EP1490078A1 (fr) 2002-03-26 2002-03-26 Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450
AU2002247880A AU2002247880A1 (en) 2002-03-26 2002-03-26 Hepatocurative effect of emblica officinalis on hepatotoxicity related to cytochrome p-450
CA002480334A CA2480334A1 (fr) 2002-03-26 2002-03-26 Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450

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PCT/IB2002/000635 WO2003080090A1 (fr) 2002-03-26 2002-03-26 Effet hepatocuratif d'emblica officinalis sur l'hepatotoxicite associee au cytochrome p-450

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EP (1) EP1490078A1 (fr)
JP (1) JP2005526792A (fr)
KR (1) KR20040101374A (fr)
CN (1) CN1627955A (fr)
AU (1) AU2002247880A1 (fr)
CA (1) CA2480334A1 (fr)
WO (1) WO2003080090A1 (fr)

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WO2011001441A1 (fr) * 2009-06-29 2011-01-06 Benny Antony Composition d’extrait d’emblica officinalis et son procédé de préparation
CN103772452A (zh) * 2014-01-08 2014-05-07 合肥康龄养生科技有限公司 一种余甘子中单宁酸的提取方法
US8980340B1 (en) 2013-10-08 2015-03-17 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same
US9066911B2 (en) 2013-10-08 2015-06-30 Benny Antony Medicinal composition of extract of seed of Emblica officinalis and method of preparing the same
US9757423B2 (en) 2003-03-03 2017-09-12 Arjuna Natural Extracts, Ltd. Composition to enhance HDL cholesterol and to decrease intima-media thickening in animals and humans and a method for its preparation
US10286022B2 (en) 2013-10-08 2019-05-14 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same

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US8808979B2 (en) * 2008-05-28 2014-08-19 Basf Se Methods related to liver enzyme induction as a predisposition for liver toxicity and diseases or disorders associated therewith
BRPI0912110A2 (pt) * 2008-05-28 2015-10-06 Basf Se métodos para diagnosticar a toxicidade do fígado, para determinar se um composto é capaz de induzir a toxicidade no fígado em um indivíduo, e para identificar uma substância para tratar toxicidade do fígado

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JP3621517B2 (ja) * 1996-07-12 2005-02-16 稲畑香料株式会社 抗アレルギー・抗炎症剤及び抗アレルギー・抗炎症食品

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Cited By (11)

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US9757423B2 (en) 2003-03-03 2017-09-12 Arjuna Natural Extracts, Ltd. Composition to enhance HDL cholesterol and to decrease intima-media thickening in animals and humans and a method for its preparation
US10434129B2 (en) 2003-03-03 2019-10-08 Arjuna Natural Ltd. Composition to enhance HDL cholesterol and to decrease intima-media thickening in animals and humans and a method for its preparation
WO2011001441A1 (fr) * 2009-06-29 2011-01-06 Benny Antony Composition d’extrait d’emblica officinalis et son procédé de préparation
US8980340B1 (en) 2013-10-08 2015-03-17 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same
US9066911B2 (en) 2013-10-08 2015-06-30 Benny Antony Medicinal composition of extract of seed of Emblica officinalis and method of preparing the same
US9775869B2 (en) 2013-10-08 2017-10-03 Benny Antony Medicinal composition of extract of seed of Emblica officinalis and method of preparing the same
US10286022B2 (en) 2013-10-08 2019-05-14 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same
US10485831B2 (en) 2013-10-08 2019-11-26 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same
US10953055B2 (en) 2013-10-08 2021-03-23 Benny Antony Medicinal composition of extract of seed of emblica officinalis and method of preparing the same
US11125130B2 (en) 2013-10-08 2021-09-21 Benny Antony Medicinal composition of extract of seed of Emblica officinalis and method of preparing the same
CN103772452A (zh) * 2014-01-08 2014-05-07 合肥康龄养生科技有限公司 一种余甘子中单宁酸的提取方法

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JP2005526792A (ja) 2005-09-08
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