WO2000078325A1 - Synergistic compositions containing lycopene and silymarin for treatment of liver disease - Google Patents
Synergistic compositions containing lycopene and silymarin for treatment of liver disease Download PDFInfo
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- WO2000078325A1 WO2000078325A1 PCT/IL2000/000352 IL0000352W WO0078325A1 WO 2000078325 A1 WO2000078325 A1 WO 2000078325A1 IL 0000352 W IL0000352 W IL 0000352W WO 0078325 A1 WO0078325 A1 WO 0078325A1
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- accordance
- lycopene
- composition
- silymarin
- group
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- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 title claims abstract description 59
- 229960004999 lycopene Drugs 0.000 title claims abstract description 59
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 title claims abstract description 58
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 title claims abstract description 58
- 239000001751 lycopene Substances 0.000 title claims abstract description 58
- 235000012661 lycopene Nutrition 0.000 title claims abstract description 58
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 title claims abstract description 58
- 239000000203 mixture Substances 0.000 title claims abstract description 41
- 208000019423 liver disease Diseases 0.000 title claims abstract description 18
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 13
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 title claims description 47
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims description 47
- 229960004245 silymarin Drugs 0.000 title claims description 32
- 235000017700 silymarin Nutrition 0.000 title claims description 32
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 121
- 210000004185 liver Anatomy 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 15
- 241000227653 Lycopersicon Species 0.000 claims description 9
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 9
- 239000008601 oleoresin Substances 0.000 claims description 9
- 235000003869 genetically modified organism Nutrition 0.000 claims description 8
- 208000006454 hepatitis Diseases 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 6
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000007894 caplet Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
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- 239000003826 tablet Substances 0.000 claims description 4
- 208000030090 Acute Disease Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 235000007882 dietary composition Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 235000014899 silybin Nutrition 0.000 claims description 3
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- 244000272459 Silybum marianum Species 0.000 claims 9
- 150000001875 compounds Chemical class 0.000 claims 3
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 claims 2
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 claims 2
- 229940043175 silybin Drugs 0.000 claims 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002516 radical scavenger Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 16
- 230000010412 perfusion Effects 0.000 description 12
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 8
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 8
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 8
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- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000132536 Cirsium Species 0.000 description 1
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- CYGIJEJDYJOUAN-UHFFFAOYSA-N Isosilychristin Natural products C1=C(O)C(OC)=CC(C2C3C=C(C4C(C3=O)(O)OCC42)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 CYGIJEJDYJOUAN-UHFFFAOYSA-N 0.000 description 1
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 231100000587 neutral red assay Toxicity 0.000 description 1
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- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 1
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- 230000002000 scavenging effect Effects 0.000 description 1
- 229950000628 silibinin Drugs 0.000 description 1
- 229950004878 silicristin Drugs 0.000 description 1
- 229950004304 silidianin Drugs 0.000 description 1
- BMLIIPOXVWESJG-LMBCONBSSA-N silychristin Chemical compound C1=C(O)C(OC)=CC([C@H]2[C@@H](C3=C(C(=CC(=C3)[C@@H]3[C@H](C(=O)C4=C(O)C=C(O)C=C4O3)O)O)O2)CO)=C1 BMLIIPOXVWESJG-LMBCONBSSA-N 0.000 description 1
- BMLIIPOXVWESJG-UHFFFAOYSA-N silychristin A Natural products C1=C(O)C(OC)=CC(C2C(C3=C(C(=CC(=C3)C3C(C(=O)C4=C(O)C=C(O)C=C4O3)O)O)O2)CO)=C1 BMLIIPOXVWESJG-UHFFFAOYSA-N 0.000 description 1
- CYGIJEJDYJOUAN-JSGXPVSSSA-N silydianin Chemical compound C1=C(O)C(OC)=CC([C@H]2[C@H]3C=C([C@@H]4[C@@](C3=O)(O)OC[C@@H]42)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 CYGIJEJDYJOUAN-JSGXPVSSSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention concerns a composition containing lycopene and sUymarin.
- the present invention more particularly concerns the synergistic mixture of both lycopene and sUymarin and its use in the treatment of acute, subacute and chronic liver diseases,
- Toxic nutritive liver diseases are the most frequent metabolic diseases of the modem world, in particular the alcohol-induced liver diseases like alcohol hepatitis, alcohol-induced fatter liver hepatitis and alcohol-induced liver cirrhosis. Free oxygen radical formation is found to be involved in ethanol-induced hepatotoxicity in experimental models and in man (Younes and Strubelt, 1987).
- Lycopene is a ⁇ -carotinoid with radical-scavenging properties.
- radical-scavengers like thiols or flavonoids
- lycopene is specialized to scavenge singlet-oxygen (Gerster, 1997). This action results in a protection of hepatocytes against carbon tetrachloride induced injury and lipid peroxidation (Kirn, 1995).
- SUymarin is an extract of mild thistle fruits containing three main flavonoids, silibinin, silidianin and silicristin (Wagner et al., 1968), a class of flavonolignanes.
- Yet an additional objective of the present invention is to provide a composition effective in treating liver disorders.
- the present invention provides a synergetic mixture comprising of lycopene and sUymarin. Furthermore, the present invention provides a method for inhibiting or preventing free oxygen radical formation in a subject, wherein said method comprises adrriinistering to a subject a free oxygen radical scavenging effective dose of the synergistic mixture of the present invention. Furthermore, the present invention provides a use of a novel synergistic mixture comprising lycopene and sylimarin in the preparation of a medicament for treating liver diseases. Additionally, the present invention provides a use of a novel synergistic mixture comprising lycopene and sylimarin in the preparation of a dietary composition. Further provided by the present invention is a pharmaceutical composition comprising lycopene and sylimarin. Description of the Drawings
- Fig. 1 is a graph of GPT U I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
- Fig. 2 is a graph of GPT U/I perfusate levels over time and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
- Fig. 3 is a graph of GPT U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
- Fig. 4 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
- Fig. 5 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
- Fig. 6 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
- Fig. 7 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
- Fig. 8 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
- Fig. 9 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
- Fig. 10 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
- Fig. 11 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®..
- Fig. 12 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol
- the following description is illustrative of embodiments of the invention.
- the following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations.
- the present invention is based on the unexpected discovery that there is a surprising synergism between lycopene and silymarin in counteracting the free oxygen radical formation found to be involved in alcohol-induced liver diseases.
- the source of lycopene can be tomato oleoresin, algal, fermented, fungal, genetically modified organism (GMO), synthetic lycopene, and mixtures thereof.
- GMO genetically modified organism
- Lycopene and Lyc-O-mato® were obtained from the Lycored Natural Products Industries Ltd. Silymarin extract was delivered by the Paul Muggenburg Company, Germany. The combination of silymarin and Lyc-O-mato® (the latter a 6% tomato oleoresin) was found to be most effective in counteracting the effects of alcohol-induced liver diseases such as alcohol-induced fatter liver hepatitis, and alcohol-induced liver cirrhosis.
- the relative parts by weight of silymarin to lycopene is from 50: 1 to 1 :250, preferably 30: 1 to 1:30.
- Ethanol hepatotoxicity could be tested in an ex-vivo model because of high ADH-activities which are necessary for the ethanol metabolism and oxygen radical formation (Younes and Strubelt, 1987).
- As a measure of hepatotoxic response to ethanol (3%o) the release of enzymes (LDH, GLDH, GPT) into the perfusate are determined in a time dependent manner and also functional parameters are looked at like perfusion flow, bile flow, oxygen consumption, glucose, lactate and pyruvate release into the perfusate.
- Biochemical parameters at the end of the perfusion in the livers give information on mechanistic aspects like lipid peroxidation (MDA), ATP-depletion or glutathione depletion (GSH/GSSG). Alterations in the liver weight are indicative of general toxicity (hydropic swelling of injure cells).
- composition of the present invention can be used straight or contain dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof.
- composition of the present invention can be contained in a variety of dosage forms such as tablets, caplets, vegecaps, and hard shell gelatin capsules.
- HepG2 a human hepatocellular tumor cell line (ATCC-Nr. HB 8065) was cultured in
- the neutral-red assay was performed as a measure of cell growth according to Borenfreund and Puerrier (1984). Enzyme releases into the medium were a measure of cytotoxicity; LDH, GPT, GPT and GLDH were determined by using commercially available test kits (Boehringer and Sigma, Germany).
- Wistar rats Males Wistar rats (conventional animals, 320-380 gr breeder Winkelrnann, Borchen) were used throughout. They had free access to a standard diet (AJtromin pellets) and tap water.
- reagents used for liver perfusion and biochemical determinations were of analytical grade and obtained from either Sigma Aldrich (Deisenhofen, FRG) or Merck (Darmstadt, FRG).
- the albumin- and serum-free perfusion medium consisted of 259 ml Krebs Henseleit buffer, pH 7.4 (118 mmoVl NaCl, 6 mmol/1 KC1, 1.1 mmol/1 MGSO4 24 mmol/1 CaC-5).
- Sodium taurocholate (36.7 g/1) was infused into the perfusate at a rate of 1.2 ml/h to stimulate bile secretion.
- the perfusion medium was continuously gassed with carbogen (95% O 2 , 5% CO 2 ) yielding an oxygen partial pressure of about 600 rnmHg.
- Perfusion was performed under conditions of constant pressure (240 mmi ⁇ o) throughout the experiment and the perfusion flow rate was initially regulated at 60 ml/min using a tube clamp.
- the experiments were started after a 30-min equilibration period (time 0) by adding ethanol (130.2 mmol/1) to the perfusate before they were finished 120 rnin later.
- Oxygen consumption of the isolated perfused livers was calculated by measuring the differences in oxygen concentrations between the influent and affluent perfusate using a micro pH/blood gas analyzer 1306 (Instrumentation Laboratory).
- Perfusion flow was determined every 30 rnin by damming up the effluent perfusate in a special vial without imp-airing the perfusion flow and measuring the volume after 20 s.
- Bile was sampled every 30 rnin and the rate of bile secretion was calculated in g Uver/min.
- samples of 2 ml were also taken from the perfusate every 30 rnin. Livers were weighed before connecting them to the perfusion system. At the end of the experiments they were frozen in liquid nitrogen until further analysis.
- GPT GPT
- LDH LDH
- GLDH GLDH
- Perfusate enzyme concentrations were distributed normally as checked by the method of Sachs (1978).
- Malondialdehyde (MDA) was measured both in the perfusate and livers by coupling to thiobarbituric acid (Buege and Aust, 1978).
- Total glutathione was determined in liver and perfusate samples according to Brehe and Burch (1976).
- Oxidized glutathione (GSSG) was estimated by the same procedure after blocking GS11 with 2-vinylpyridine (Griffith, 1980).
- ATP ATP
- hepatic tissue was frozen immediately in liquid nitrogen and extracts were prepared according to Williamson and Corkey (1969).
- Adenosine triphosphate (ATP) was assayed enzymatically using a reagent kit from Sigma (Munich, FRG).
- GPT enzyme released into the perfusate is markedly depressed by the combination of silymarin and lycopene:
- MDA is markedly decreased by the combination of silymarin and lycopene or
- GSH depletion is markedly inhibited by the combination of silymarin and lycopene or
Abstract
The present invention provides a novel synergistic composition comprising lycopene and sylimarin and its use in treating liver diseases. The composition of the invention is further effective as a free oxygen radical scavenger, thus the composition of the invention is effective in treating liver diseases induced by free oxygen radical formation.
Description
SYNERGISTIC COMPOS ITIONS CONTAIN ING LYCOP ENE AND SI LYMARIN FOR TREATMENT OF LIVER DISEASE
Field of the Invention
The present invention concerns a composition containing lycopene and sUymarin. The present invention more particularly concerns the synergistic mixture of both lycopene and sUymarin and its use in the treatment of acute, subacute and chronic liver diseases,
Background of the Invention
Toxic nutritive liver diseases are the most frequent metabolic diseases of the modem world, in particular the alcohol-induced liver diseases like alcohol hepatitis, alcohol-induced fatter liver hepatitis and alcohol-induced liver cirrhosis. Free oxygen radical formation is found to be involved in ethanol-induced hepatotoxicity in experimental models and in man (Younes and Strubelt, 1987).
Lycopene is a β-carotinoid with radical-scavenging properties. Among other radical-scavengers like thiols or flavonoids, lycopene is specialized to scavenge singlet-oxygen (Gerster, 1997). This action results in a protection of hepatocytes against carbon tetrachloride induced injury and lipid peroxidation (Kirn, 1995).
SUymarin is an extract of mild thistle fruits containing three main flavonoids, silibinin, silidianin and silicristin (Wagner et al., 1968), a class of flavonolignanes.
Three main mechanisms of hepatoprotection are discussed:
1. Stimulation of RNA-polymerase 1 in the cell nucleus and thereby stimulation of liver cell regeneration (Sonnenbichler and Zetl, 1984)
2. Stabilization of lipid cell membranes
3. Antiperoxidative properties by scavenging free radicals (Feher and co workers, 1987)
Clinical experiences with sUymarin-containing drugs have proven efficacy in the treatment of toxic liver diseases (Ferenci et al., 1989; Fintelmann and Albert, 1980; Floersheim et al.,
1980). Even, adjuvant treatment of chronic viral hepatitis and liver cirrhosis were reported (Kiescwetter et al., 1977; Ferenci et al., 1989).
Objectives It is an objective of the present invention to provide a novel synergetic pharmaceutical composition.
It is a further objective of the present invention to provide a novel synergetic dietary composition.
Yet an additional objective of the present invention is to provide a composition effective in treating liver disorders.
It is a further objective of the present invention to provide a mixture to scavenge free radicals of different origins in order to counteract the inflammation, toxic cell injury and lipid peroxidation involved in the alcohol-induced liver diseases such as alcohol hepatitis, alcohol-induced fatter liver hepatitis, and alcohol-induced liver cirrhosis.
Summary of the Invention The present invention provides a synergetic mixture comprising of lycopene and sUymarin. Furthermore, the present invention provides a method for inhibiting or preventing free oxygen radical formation in a subject, wherein said method comprises adrriinistering to a subject a free oxygen radical scavenging effective dose of the synergistic mixture of the present invention. Furthermore, the present invention provides a use of a novel synergistic mixture comprising lycopene and sylimarin in the preparation of a medicament for treating liver diseases. Additionally, the present invention provides a use of a novel synergistic mixture comprising lycopene and sylimarin in the preparation of a dietary composition. Further provided by the present invention is a pharmaceutical composition comprising lycopene and sylimarin.
Description of the Drawings
Fig. 1 is a graph of GPT U I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
Fig. 2 is a graph of GPT U/I perfusate levels over time and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
Fig. 3 is a graph of GPT U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
Fig. 4 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
Fig. 5 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
Fig. 6 is a graph of LDH U/I perfusate levels over time and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
Fig. 7 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide; and ethanol + silymarine.
Fig. 8 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®.
Fig. 9 is block diagram of GSH levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
Fig. 10 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol + dimethyl sulfoxide + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene + silymarine; and ethanol + Lyc-O-Mato® + silymarine.
Fig. 11 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol + tetrahydrofuran + butylated hydroxytoluene; ethanol + lycopene; and ethanol + Lyc-O-mato®..
Fig. 12 is block diagram of MDA levels in the liver and is a comparison of ethanol; ethanol
+ dimethyl sulfoxide; and ethanol + silymarine.
Detailed Description of the Invention
The following description is illustrative of embodiments of the invention. The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations. The present invention is based on the unexpected discovery that there is a surprising synergism between lycopene and silymarin in counteracting the free oxygen radical formation found to be involved in alcohol-induced liver diseases.
The source of lycopene can be tomato oleoresin, algal, fermented, fungal, genetically modified organism (GMO), synthetic lycopene, and mixtures thereof.
Lycopene and Lyc-O-mato®. (6% tomato oleoresin) were obtained from the Lycored Natural Products Industries Ltd. Silymarin extract was delivered by the Paul Muggenburg Company, Germany.
The combination of silymarin and Lyc-O-mato® (the latter a 6% tomato oleoresin) was found to be most effective in counteracting the effects of alcohol-induced liver diseases such as alcohol-induced fatter liver hepatitis, and alcohol-induced liver cirrhosis.
The relative parts by weight of silymarin to lycopene is from 50: 1 to 1 :250, preferably 30: 1 to 1:30.
Ethanol hepatotoxicity could be tested in an ex-vivo model because of high ADH-activities which are necessary for the ethanol metabolism and oxygen radical formation (Younes and Strubelt, 1987). As a measure of hepatotoxic response to ethanol (3%o) the release of enzymes (LDH, GLDH, GPT) into the perfusate are determined in a time dependent manner and also functional parameters are looked at like perfusion flow, bile flow, oxygen consumption, glucose, lactate and pyruvate release into the perfusate. Biochemical parameters at the end of the perfusion in the livers give information on mechanistic aspects like lipid peroxidation (MDA), ATP-depletion or glutathione depletion (GSH/GSSG). Alterations in the liver weight are indicative of general toxicity (hydropic swelling of injure cells).
The composition of the present invention can be used straight or contain dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof.
The composition of the present invention can be contained in a variety of dosage forms such as tablets, caplets, vegecaps, and hard shell gelatin capsules.
Examples
General
HepG2, a human hepatocellular tumor cell line (ATCC-Nr. HB 8065) was cultured in
RPM1/1640 /Boehringer, Mannheim, Germany) medium supplemented with 5% fetal calf serum and l% L-glutamine.
The neutral-red assay was performed as a measure of cell growth according to Borenfreund and Puerrier (1984). Enzyme releases into the medium were a measure of cytotoxicity; LDH, GPT, GPT and GLDH were determined by using commercially available test kits (Boehringer and Sigma, Germany).
Perfusion of isolated rat livers with ethanol was performed according to published procedures from our lab (Younes and Strubelt, 1987; Deters et al., 1998).
Arithmetic means and their standard errors are given, IC50 value were calculated by graphic interpolation. Until now, checks for statistical significance of differences between means were not performed because of the problems of multiple comparisons.
Males Wistar rats (conventional animals, 320-380 gr breeder Winkelrnann, Borchen) were used throughout. They had free access to a standard diet (AJtromin pellets) and tap water.
Unless otherwise stated, reagents used for liver perfusion and biochemical determinations were of analytical grade and obtained from either Sigma Aldrich (Deisenhofen, FRG) or Merck (Darmstadt, FRG).
Removal of the liver and its connection to a recirculating perfusion system was performed as previously described (Strubelt et al., 1986). After removal of the livers, rats died by exsanguination. The albumin- and serum-free perfusion medium consisted of 259 ml Krebs Henseleit buffer, pH 7.4 (118 mmoVl NaCl, 6 mmol/1 KC1, 1.1 mmol/1 MGSO4 24 mmol/1 CaC-5). Sodium taurocholate (36.7 g/1) was infused into the perfusate at a rate of 1.2 ml/h to stimulate bile secretion. The perfusion medium was continuously gassed with carbogen (95% O2, 5% CO2) yielding an oxygen partial pressure of about 600 rnmHg. Perfusion was performed under conditions of constant pressure (240 mmiπo) throughout the experiment and the perfusion flow rate was initially regulated at 60 ml/min using a tube clamp. The experiments were started after a 30-min equilibration period (time 0) by adding ethanol (130.2 mmol/1) to the perfusate before they were finished 120 rnin later. Oxygen consumption of the isolated perfused livers was calculated by measuring the differences in
oxygen concentrations between the influent and affluent perfusate using a micro pH/blood gas analyzer 1306 (Instrumentation Laboratory). Perfusion flow was determined every 30 rnin by damming up the effluent perfusate in a special vial without imp-airing the perfusion flow and measuring the volume after 20 s. Bile was sampled every 30 rnin and the rate of bile secretion was calculated in g Uver/min. For biochemical determinations, samples of 2 ml were also taken from the perfusate every 30 rnin. Livers were weighed before connecting them to the perfusion system. At the end of the experiments they were frozen in liquid nitrogen until further analysis.
The activities of GPT, LDH and GLDH were assayed using commercial kits from Bochringer Mannheim (Mannheim, FRG). Perfusate enzyme concentrations were distributed normally as checked by the method of Sachs (1978). Malondialdehyde (MDA) was measured both in the perfusate and livers by coupling to thiobarbituric acid (Buege and Aust, 1978). Total glutathione was determined in liver and perfusate samples according to Brehe and Burch (1976). Oxidized glutathione (GSSG) was estimated by the same procedure after blocking GS11 with 2-vinylpyridine (Griffith, 1980). For ATP determination, hepatic tissue was frozen immediately in liquid nitrogen and extracts were prepared according to Williamson and Corkey (1969). Adenosine triphosphate (ATP) was assayed enzymatically using a reagent kit from Sigma (Munich, FRG).
Example 1
GPT enzyme released into the perfusate is markedly depressed by the combination of silymarin and lycopene:
GPT U/I Perfusate
(a) Control 45 (See Fig.1,2,3)
(b) 130.2 mmol/1 ethanol 310
(c) 10 mg/1 Silymarin + (b) 90 (See Fig.1)
(d) 300 mg/1 Lyc-O-mato® + (b) 300 (See Fig.2)
(e) 10 mg/1 Lycopene + (b) 300 (See Fig.2)
10 mg/1 Silymarin + 300 mg/1 Lyc-O-mato® 100 (See Fig.3) + (b) (g) 10 mg/1 Silymarin + 10 mg/1 Lycopene + (b) 80 (See Fig.3)
Example 2
LDH enzyme released into the perfusate is markedly depressed by the combination of silymarin and Lyc-O-mato®
LDH U/I Perfusate
(a) Control 500 (See Fig.4, 5, 6)
(b) 1130.2 mmol/1 ethanol + (b) 3100
(c) 10 mg/1 Silymarin + (b) 1085 (See Fig.4)
(d) 300 mg/1 Lyc-O-mato® + (b) 3000 (See Fig.5)
(e) 10 mg/1 Lycopene + (b) 3000 (See Fig.5)
10 mg/1 Silymarin + 300 mg/1 Lyc-O-mato® 750 (See Fig.6) + (b) (g) 10 mg/1 Silymarin + 10 mg/1 Lycopene + (b) 2600 (See Fig.6)
Exa ple 3
MDA is markedly decreased by the combination of silymarin and lycopene or
Lyc-O-mato®:
MDA nmol/g liver
(a) Control 16.5 (See Fig. lo,:
(b) 130.2 mmol/1 ethanol 22.5
(c) 10 mg/1 Silymarin + (b) 17.5 (See Fig. 10)
(d) 300 mg/1 Lyc-O-mato® + (b) 14 (See Fig. 11)
(e) 10 mg/1 Lycopene + (b) 20 (See Fig. 11)
10 mg/1 Silymarin + 300 mg/1 13 (See Fig. 12) Lyc-O-mato® + (b) (g) 10 mg/1 Silymarin + 10 mg/1 Lycopene + (b) 14 (See Fig. 12)
Example 4
GSH depletion is markedly inhibited by the combination of silymarin and lycopene or
Lyc-O-mato®:
GSH μmol/g liver
(a) Control 3.5 (See Fig. 7, 8, 9)
(b) 130.2 mmol/1 ethanol 2.3
(c) 10 mg/1 Silymarin + (b) 3.6 (See Fig. 7)
(d) 300 mg 1 Lyc-O-mato® + (b) 4.2 (See Fig. 8)
(e) 10 mg/1 Lycopene + (b) 3.3 (See Fig. 8)
10 mg/1 Silymarin + 300 mg/1 Lyc-O-mato® 4.75 (See Fig. 9) + (b) (g) 10 mg/1 Silymarin + 10 mg/1 Lycopene + (b) 4.2 (See Fig. 9)
While embodiments of the invention have been described by way of illustration, it will be apparent that the invention may be carried out with many modifications, variations and adaptations, without departing from its spirit or exceeding the scope of the claims.
Claims
1. A synergistic pharmaceutical or dietary composition which comprises lycopene and silymarin.
2. A composition in accordance with Claim 1 wherein the lycopene is selected from the group consisting of lycopene from tomato oleoresin, algal, fermented, fungal, genetically modified organism (GMO), synthetic lycopene, and mixtures thereof.
3. A composition in accordance with Claim 1 wherein the lycopene is selected from the group consisting of lycopene and tomato oleoresin.
4. A composition in accordance with Claim 1 which comprises synthetic lycopene.
5. A composition in accordance with Claim 1 wherein the sπymarin is extracted from the Silybum marianum plant.
6. A composition in accordance with Claim 1 wherein the sUvmarin is extracted from the fruit of the Silybum marianum plant.
7. A composition in accordance with Claim 1 wherein the silymarin is extracted from the Silybum marianum plant and is standardized on a silybin content between 75% and 90%.
8. A composition in accordance with Claim 1 wherein the relative parts by weight of suymarin to lycopene is from 50:1 to 1 :50 preferably 30:1 to 1 :30.
9. A composition in accordance with any of Claims 1 to 8 wherein the composition contains compounds selected from the group consisting of dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof.
10 A composition in accordance with any of Claims 1 to 9 wherein the composition is contained in dosage forms selected from the group consisting of tablets, caplets, vegecaps and hard shell gelatin capsules.
Use of a synergistic composition containing lycopene and silymarin for the preparation of pharmaceutical compositions for treatment of acute, subacute and chronic liver diseases.
A use in accordance with Claim 1 1 wherein the lycopene is selected from the group consisting of lycopene from tomato oleoresin, algal, fermented, fungal, genetically modified organism (GMO), synthetic lycopene, and mixtures thereof.
A use in accordance with Claim 11 wherein the diseases are selected from the group consisting of alcohol-hepatitis and alcohol-induced fatter liver hepatitis and alcohol induced liver cirrhosis.
A use in accordance with Claim 11 wherein the lycopene is tomato oleoresin.
A use in accordance with Claim 1 1 which comprises synthetic lycopene.
A use in accordance with Claim 1 1 wherein the silymarin is extracted from the Silybum marianum plant.
A use in accordance with Claim 11 wherein the silymarin is extracted from the fruit of the Silybum marianum plant.
A use in accordance with Claim 1 1 wherein the suymarin is extracted from the Silybum marianum plant and is standardized on a sirybin content between 75% and 90%.
A use in accordance with Claim 1 1 wherein the relative parts by weight of silymarin to lycopene is from 50:1 to 1:50 preferably 30:1 to 1 :30.
A use in accordance with any of Claims 11 to 19 wherein the composition contains compounds selected from the group consisting of dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof.
A use in accordance with any of Claims 11 to 20 wherein the composition is contained in dosage forms selected from the group consisting of tablets, caplets, vegecaps and hard shell gelatin capsules.
A method for combating acute, subacute, and chronic liver diseases which comprises contacting the liver with a synergistic mixture of lycopene and silymarin.
A method in accordance with Claim 22 wherein the lycopene is selected from the group consisting of lycopene from tomato oleoresin, algal, fermented, fungal, genetically modified organism (GMO), synthetic lycopene, and mixtures thereof.
A method in accordance with Claim 22 wherein the lycopene is selected from the group consisting of lycopene and tomato oleoresin.
A method in accordance with Claim 22 which comprises synthetic lycopene.
A method in accordance with Claim 22 wherein the silymarin is extracted from the Silybum marianum plant.
A method in accordance with Claim 22 wherein the silymarin is extracted from the fruit of the Silybum marianum plant.
A method in accordance with Claim 22 wherein the silymarin is extracted from the Silybum marianum plant and is standardized on a silybin content between 75% and 90%.
A method in accordance with Claim 22 wherein the relative parts by weight of silymarin to lycopene is from 50: 1 to 1:50 preferably 30: 1 to 1:30. A method in accordance with any of Claims 22 to 29 wherein the composition contains compounds selected from the group consisting of dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof.
A method in accordance with any of Claims 22 to 30 wherein the composition is contained in dosage forms selected from the group consisting of tablets, caplets, vegecaps and hard shell gelatin capsules.
Use of a composition claimed in claim 1 for preventing or inhibiting the free oxygen radical formation found to be involved in alcohol-induced liver diseases.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU52443/00A AU5244300A (en) | 1999-06-20 | 2000-06-16 | Synergistic compositions containing lycopene and silymarin for treatment of liver disease |
| EP00937159A EP1194155A1 (en) | 1999-06-20 | 2000-06-16 | Synergistic compositions containing lycopene and silymarin for treatment of liver disease |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL130556 | 1999-06-20 | ||
| IL13055699A IL130556A0 (en) | 1999-06-20 | 1999-06-20 | Synergistic compositions for treatment of liver diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000078325A1 true WO2000078325A1 (en) | 2000-12-28 |
Family
ID=11072942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IL2000/000352 WO2000078325A1 (en) | 1999-06-20 | 2000-06-16 | Synergistic compositions containing lycopene and silymarin for treatment of liver disease |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1194155A1 (en) |
| AU (1) | AU5244300A (en) |
| IL (1) | IL130556A0 (en) |
| WO (1) | WO2000078325A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011076155A1 (en) | 2009-12-22 | 2011-06-30 | Irel, Spol. S R.O. | Feed supplement based on milk thistle, method of its production and its use |
| WO2011076154A1 (en) | 2009-12-22 | 2011-06-30 | Irel, Spol. S R.O. | Feed supplement based on milk thistle, method of its production and its use |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111543545A (en) * | 2020-05-15 | 2020-08-18 | 内蒙古自治区农牧业科学院 | Feed additive for relieving liver injury of dairy cows, daily ration and application |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0659402A2 (en) * | 1993-12-21 | 1995-06-28 | INDENA S.p.A. | Formulations containing carotenoids and procarotenoids combined with polyphenols in the prevention of the damages due to an abnormal production of free radicals |
| US5895652A (en) * | 1996-07-29 | 1999-04-20 | Longevity Institute International | Method of metabolic adjuvanation and cellular repair |
| US5904924A (en) * | 1997-11-04 | 1999-05-18 | Oncologics, Inc. | Green nutritional powder composition |
| WO1999048386A1 (en) * | 1998-03-24 | 1999-09-30 | Stueckler Franz | Natural substance based agent |
| WO1999061038A1 (en) * | 1998-05-29 | 1999-12-02 | Adams Food Ltd. | Composition having therapeutic and/or nutritionally active substituent |
-
1999
- 1999-06-20 IL IL13055699A patent/IL130556A0/en unknown
-
2000
- 2000-06-16 WO PCT/IL2000/000352 patent/WO2000078325A1/en not_active Application Discontinuation
- 2000-06-16 AU AU52443/00A patent/AU5244300A/en not_active Abandoned
- 2000-06-16 EP EP00937159A patent/EP1194155A1/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0659402A2 (en) * | 1993-12-21 | 1995-06-28 | INDENA S.p.A. | Formulations containing carotenoids and procarotenoids combined with polyphenols in the prevention of the damages due to an abnormal production of free radicals |
| US5895652A (en) * | 1996-07-29 | 1999-04-20 | Longevity Institute International | Method of metabolic adjuvanation and cellular repair |
| US5904924A (en) * | 1997-11-04 | 1999-05-18 | Oncologics, Inc. | Green nutritional powder composition |
| WO1999048386A1 (en) * | 1998-03-24 | 1999-09-30 | Stueckler Franz | Natural substance based agent |
| WO1999061038A1 (en) * | 1998-05-29 | 1999-12-02 | Adams Food Ltd. | Composition having therapeutic and/or nutritionally active substituent |
Non-Patent Citations (2)
| Title |
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| "Bio-C3 complex is a unique synergistic combination of 10 antioxidants from herbal,vitamin and mineral sources", MATOL PRODUCTS, XP002153303, Retrieved from the Internet <URL:www.matol.com/products/antioxidants/product.htm> [retrieved on 20001114] * |
| FLORA K. ET AL: "Milk thistle (Sylibum marianum) for the Therapy of liver disease", AMERICAN JOURNAL OF GASTROENTEROLOGY, vol. 93, no. 2, 1998, pages 139 - 143, XP000965734 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011076155A1 (en) | 2009-12-22 | 2011-06-30 | Irel, Spol. S R.O. | Feed supplement based on milk thistle, method of its production and its use |
| WO2011076154A1 (en) | 2009-12-22 | 2011-06-30 | Irel, Spol. S R.O. | Feed supplement based on milk thistle, method of its production and its use |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5244300A (en) | 2001-01-09 |
| EP1194155A1 (en) | 2002-04-10 |
| IL130556A0 (en) | 2000-06-01 |
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