EP1194155A1 - Synergistic compositions containing lycopene and silymarin for treatment of liver disease - Google Patents
Synergistic compositions containing lycopene and silymarin for treatment of liver diseaseInfo
- Publication number
- EP1194155A1 EP1194155A1 EP00937159A EP00937159A EP1194155A1 EP 1194155 A1 EP1194155 A1 EP 1194155A1 EP 00937159 A EP00937159 A EP 00937159A EP 00937159 A EP00937159 A EP 00937159A EP 1194155 A1 EP1194155 A1 EP 1194155A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- accordance
- lycopene
- composition
- silymarin
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 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
- -1 coatings Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 235000013399 edible fruits Nutrition 0.000 claims description 4
- 235000012041 food component Nutrition 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 239000007903 gelatin capsule Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 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
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 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
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 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
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 8
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 8
- 229960003180 glutathione Drugs 0.000 description 8
- 229940118019 malondialdehyde Drugs 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000010586 diagram Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 3
- 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
- 108010053070 Glutathione Disulfide Proteins 0.000 description 3
- 101000833181 Schizosaccharomyces pombe (strain 972 / ATCC 24843) Glycerol dehydrogenase 1 Proteins 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 3
- 231100000304 hepatotoxicity Toxicity 0.000 description 3
- 230000003859 lipid peroxidation Effects 0.000 description 3
- 108010024636 Glutathione Proteins 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- 230000002292 Radical scavenging effect Effects 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- 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
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 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
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 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
- 241001465754 Metazoa Species 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 101150085390 RPM1 gene Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 108010073976 UDP-GlcNAc-undecaprenyl phosphate N-acetylglucosaminyl 1-phosphate transferase Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
- 230000003035 anti-peroxidant effect Effects 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 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
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
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- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000004149 ethanol metabolism Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000003473 lipid group Chemical group 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000587 neutral red assay Toxicity 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 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
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003134 recirculating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 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
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
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
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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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL13055699 | 1999-06-20 | ||
| IL13055699A IL130556A0 (en) | 1999-06-20 | 1999-06-20 | Synergistic compositions for treatment of liver diseases |
| PCT/IL2000/000352 WO2000078325A1 (en) | 1999-06-20 | 2000-06-16 | Synergistic compositions containing lycopene and silymarin for treatment of liver disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1194155A1 true EP1194155A1 (en) | 2002-04-10 |
Family
ID=11072942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00937159A Withdrawn EP1194155A1 (en) | 1999-06-20 | 2000-06-16 | Synergistic compositions containing lycopene and silymarin for treatment of liver disease |
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| Country | Link |
|---|---|
| EP (1) | EP1194155A1 (en) |
| AU (1) | AU5244300A (en) |
| IL (1) | IL130556A0 (en) |
| WO (1) | WO2000078325A1 (en) |
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| 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 |
| 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 |
| 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 |
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| IT1265312B1 (en) * | 1993-12-21 | 1996-10-31 | Indena Spa | FORMULATIONS CONTAINING CAROTENOIDS AND PRO-CAROTENOIDS ASSOCIATED WITH POLYPHENOLS IN THE PREVENTION OF DAMAGES FROM ABNORMAL PRODUCTION OF |
| 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 |
| AT407821B (en) * | 1998-03-24 | 2001-06-25 | Franz Dr Stueckler | MEDIUM BASED ON NATURAL SUBSTANCES |
| AU4217499A (en) * | 1998-05-29 | 1999-12-13 | 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 AU AU52443/00A patent/AU5244300A/en not_active Abandoned
- 2000-06-16 EP EP00937159A patent/EP1194155A1/en not_active Withdrawn
- 2000-06-16 WO PCT/IL2000/000352 patent/WO2000078325A1/en not_active Application Discontinuation
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| See references of WO0078325A1 * |
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| IL130556A0 (en) | 2000-06-01 |
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