WO2023119167A1 - Pharmaceutical composition based on glutathione thioester and oleuropein for use in the treatment of non-alcoholic steatohepatitis - Google Patents
Pharmaceutical composition based on glutathione thioester and oleuropein for use in the treatment of non-alcoholic steatohepatitis Download PDFInfo
- Publication number
- WO2023119167A1 WO2023119167A1 PCT/IB2022/062566 IB2022062566W WO2023119167A1 WO 2023119167 A1 WO2023119167 A1 WO 2023119167A1 IB 2022062566 W IB2022062566 W IB 2022062566W WO 2023119167 A1 WO2023119167 A1 WO 2023119167A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glutathione
- oleuropein
- composition according
- ole
- liver
- Prior art date
Links
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Natural products OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title claims abstract description 38
- RFWGABANNQMHMZ-UHFFFAOYSA-N 8-acetoxy-7-acetyl-6,7,7a,8-tetrahydro-5H-benzo[g][1,3]dioxolo[4',5':4,5]benzo[1,2,3-de]quinoline Natural products CC=C1C(CC(=O)OCCC=2C=C(O)C(O)=CC=2)C(C(=O)OC)=COC1OC1OC(CO)C(O)C(O)C1O RFWGABANNQMHMZ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 title claims abstract description 33
- 229960003180 glutathione Drugs 0.000 title claims abstract description 29
- HKVGJQVJNQRJPO-UHFFFAOYSA-N Demethyloleuropein Natural products O1C=C(C(O)=O)C(CC(=O)OCCC=2C=C(O)C(O)=CC=2)C(=CC)C1OC1OC(CO)C(O)C(O)C1O HKVGJQVJNQRJPO-UHFFFAOYSA-N 0.000 title claims abstract description 21
- RFWGABANNQMHMZ-HYYSZPHDSA-N Oleuropein Chemical compound O([C@@H]1OC=C([C@H](C1=CC)CC(=O)OCCC=1C=C(O)C(O)=CC=1)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RFWGABANNQMHMZ-HYYSZPHDSA-N 0.000 title claims abstract description 21
- 235000011576 oleuropein Nutrition 0.000 title claims abstract description 21
- RFWGABANNQMHMZ-CARRXEGNSA-N oleuropein Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)C(=CC)[C@H]1CC(=O)OCCc3ccc(O)c(O)c3 RFWGABANNQMHMZ-CARRXEGNSA-N 0.000 title claims abstract description 21
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title claims abstract description 17
- 108010024636 Glutathione Proteins 0.000 title claims abstract description 15
- 238000011282 treatment Methods 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- -1 glutathione thioester Chemical class 0.000 title abstract description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 230000002503 metabolic effect Effects 0.000 claims abstract description 5
- 206010019668 Hepatic fibrosis Diseases 0.000 claims abstract description 4
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 14
- FVRWSIPJNWXCEO-YUMQZZPRSA-N S-acetylglutathione Chemical compound OC(=O)CNC(=O)[C@H](CSC(=O)C)NC(=O)CC[C@H](N)C(O)=O FVRWSIPJNWXCEO-YUMQZZPRSA-N 0.000 claims description 13
- 108700017742 S-acetylglutathione Proteins 0.000 claims description 13
- JUUBCHWRXWPFFH-UHFFFAOYSA-N Hydroxytyrosol Chemical class OCCC1=CC=C(O)C(O)=C1 JUUBCHWRXWPFFH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 claims description 3
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 claims description 3
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims description 3
- 229940012843 omega-3 fatty acid Drugs 0.000 claims description 3
- 150000007970 thio esters Chemical class 0.000 claims description 3
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 2
- 230000002443 hepatoprotective effect Effects 0.000 claims description 2
- 229960004488 linolenic acid Drugs 0.000 claims description 2
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims 2
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 claims 1
- 206010073069 Hepatic cancer Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 201000002250 liver carcinoma Diseases 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 210000004185 liver Anatomy 0.000 description 9
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 7
- 108010082126 Alanine transaminase Proteins 0.000 description 7
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 7
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 4
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 4
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 4
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 4
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229940090949 docosahexaenoic acid Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 235000003248 hydroxytyrosol Nutrition 0.000 description 2
- 229940095066 hydroxytyrosol Drugs 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000006372 lipid accumulation Effects 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000007863 steatosis Effects 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- MQTAHPDMMDYVPZ-DECRLCMHSA-N C(CCCCCCC\C=C/C\C=C/C\C=C/CC)(=O)SC[C@H](NC(CC[C@H](N)C(=O)O)=O)C(=O)NCC(=O)O Chemical compound C(CCCCCCC\C=C/C\C=C/C\C=C/CC)(=O)SC[C@H](NC(CC[C@H](N)C(=O)O)=O)C(=O)NCC(=O)O MQTAHPDMMDYVPZ-DECRLCMHSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- FIKLMMHLPVXWJN-WRWORJQWSA-N Elenolic acid Chemical compound COC(=O)C1=CO[C@@H](O)C(=CC)[C@@H]1CC(O)=O FIKLMMHLPVXWJN-WRWORJQWSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 244000179886 Moringa oleifera Species 0.000 description 1
- 235000011347 Moringa oleifera Nutrition 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000002725 Olea europaea Nutrition 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- 238000011713 fatty liver animal model Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- RFWGABANNQMHMZ-ZCHJGGQASA-N oleuropein Chemical compound O([C@@H]\1OC=C([C@H](C/1=C\C)CC(=O)OCCC=1C=C(O)C(O)=CC=1)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RFWGABANNQMHMZ-ZCHJGGQASA-N 0.000 description 1
- BIWKXNFEOZXNLX-BBHIFXBUSA-N oleuropein aglycone Chemical compound COC(=O)C1=CO[C@@H](O)\C(=C\C)[C@@H]1CC(=O)OCCC1=CC=C(O)C(O)=C1 BIWKXNFEOZXNLX-BBHIFXBUSA-N 0.000 description 1
- DEBZOPZQKONWTK-KWCYVHTRSA-N oleuropein aglycone Natural products COC(=O)C1=CO[C@H](C)[C@@H](C=O)[C@@H]1CC(=O)OCCc1ccc(O)c(O)c1 DEBZOPZQKONWTK-KWCYVHTRSA-N 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 208000012237 paracetamol poisoning Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Definitions
- the present invention refers to the field of pharmaceutical preparations comprising organic active ingredients, in particular it refers to the combination of Glutathione (GSH) thioester and Oleuropein (Ole) for use in the prevention and/or treatment of hepatic steatosis forms of metabolic origin such as NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis) and their evolution into hepatic fibrosis, liver cirrhosis and liver cancer.
- Glutathione Glutathione
- Oleuropein Oleuropein
- NAFLD is a complex and severe degenerative liver disease characterized by oxidative stress, inflammation and injury following metabolic stress. NAFLD and its evolution into NASH involve a number of processes, including lipid accumulation, insulin resistance, inflammation and fibrogenesis, closely associated with complications such as obesity, diabetes and steatohepatitis with possible evolution into severe liver fibrosis and cancer. Recent attempts to establish effective therapies for NAFLD and NASH have identified potential micronutrients with antioxidant power that may reduce ROS accumulation and ultimately ameliorate the disease.
- Glutathione or GSH is a tripeptide with antioxidant properties, consisting of cysteine and glycine, linked by a normal peptide bond, and glutamate, which is instead linked to cysteine with an isopeptide bond between the carboxy group of the glutamate side chain and the amino group of cysteine.
- GSH is used as a direct and “fast” antidote in paracetamol poisoning.
- Glutathione is only to a small extent bioavailable to humans; its introduction into the body using external sources is, in fact, poorly effective in increasing its plasma and/or intracellular concentration.
- bioavailable derivatives of glutathione have been synthesized and studied, which have shown to be able to increase the intracellular levels of this peptide (A. Pensalfini et al. Free Radical Biology & Medicine 44 (2008) 1624-1636).
- GSH glutathione
- ALT alanine transaminase
- gGT g-glutamyl transpeptidase
- AST aspartate transaminase
- HbA1c glycohemoglobin
- Oleuropein is the main secoiridoid polyphenol in the olive tree.
- Secoiridoids are structural derivatives of iridoids (where there is a cyclopentane ring most often fused with an oxygencontaining six-membered heterocycle ring) in which the cyclopentane ring is open upon oxidation and breaking of a carbon-carbon bond.
- the oleuropein aglycone metabolism leads to the formation, inter alia, of hydroxytyrosol, a polyphenol with strong antioxidant power, and elenolic acid.
- AST aspartate aminotransferase
- yGT Gamma-glutamyl transferase
- GSH glutathione
- HbA1c glycosylated hemoglobin
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- DHA docosahexaenoic acid
- the present invention addresses the aforementioned problems by means of a pharmaceutical composition comprising an S-acyl-Glutathione and oleuropein for use in the treatment and/or prophylaxis of hepatic steatosis forms of metabolic origin such as NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis) and related diseases, such as their evolution into hepatic fibrosis, liver cirrhosis and liver cancer.
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- related diseases such as their evolution into hepatic fibrosis, liver cirrhosis and liver cancer.
- S-acyl-glutathione is selected from bioavailable S-acyl-derivatives, such as for example S-acetyl-glutathione (SAG) or thioesters of omega- 3 fatty acids such as linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
- SAG S-acetyl-glutathione
- thioesters of omega- 3 fatty acids such as linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
- oleuropein is glycated oleuropein or in the form of an aglycone or metabolites thereof, such as for example hydroxytyrosol.
- composition according to the present invention is preferably in the form of formulations for oral administration, preferably capsules, tablets, or in another form which can be administered parenterally, inhaled or transcutaneously.
- the composition according to the present invention comprises 10-500 mg, more preferably 50-200 mg, of Ole and 30-1000 mg, more preferably 100-500 mg, of S-acyl- GSH.
- the composition of the present invention is preferably to be taken once or twice a day.
- composition of the present invention may obviously include excipients suitable for its formulation for oral, parenteral, inhalation or transcutaneous use.
- composition of the present invention may also comprise one or more other substances with hepatoprotective activity such as, for example, N-acetyl cysteine, choline, phosphatidylcholine, Moringa oleifera extract, Silybum marianum extract, and other hepatoprotectors known to those skilled in the art.
- substances with hepatoprotective activity such as, for example, N-acetyl cysteine, choline, phosphatidylcholine, Moringa oleifera extract, Silybum marianum extract, and other hepatoprotectors known to those skilled in the art.
- liver enzymes alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and Gamma-glutamyl transferase (yGT)
- ALT lanine aminotransferase
- AST aminotransferase
- yGT Gamma-glutamyl transferase
- Table 1 shows the values of the parameters measured at the beginning and at the end of the study.
- mice studied after 56 days of treatment with both substances showed a surprising reduction of lipid deposits in the liver together with strongly improved histopathological characteristics. This protection resulted to be significantly improved compared to that observed in mice treated with glutathione thioester alone (both SAG and SLinG) or with Ole alone.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102021000031985 | 2021-12-21 | ||
| IT102021000031985A IT202100031985A1 (it) | 2021-12-21 | 2021-12-21 | Composizione farmaceutica a base di glutatione tioestere e oleuropeina per l’uso nel trattamento della steatoepatite non alcolica |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023119167A1 true WO2023119167A1 (en) | 2023-06-29 |
Family
ID=80625350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2022/062566 WO2023119167A1 (en) | 2021-12-21 | 2022-12-21 | Pharmaceutical composition based on glutathione thioester and oleuropein for use in the treatment of non-alcoholic steatohepatitis |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | IT202100031985A1 (it) |
| WO (1) | WO2023119167A1 (it) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0327612A1 (de) * | 1987-07-09 | 1989-08-16 | Gerhard Dr. med. OHLENSCHLÄGER | Pharmazeutisch therapeutische verwendung von glutathion-derivaten |
| WO2018146621A1 (en) * | 2017-02-08 | 2018-08-16 | Solosale S.R.L. | Pharmaceutical composition for the prevention and treatment of memory and cognitive deficits related to ageing |
| US20200009101A1 (en) * | 2017-02-16 | 2020-01-09 | Valbiotis | Pharmaceutical active ingredient and use thereof, in particular for the prevention and treatment of metabolic disorders in humans and animals |
-
2021
- 2021-12-21 IT IT102021000031985A patent/IT202100031985A1/it unknown
-
2022
- 2022-12-21 WO PCT/IB2022/062566 patent/WO2023119167A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0327612A1 (de) * | 1987-07-09 | 1989-08-16 | Gerhard Dr. med. OHLENSCHLÄGER | Pharmazeutisch therapeutische verwendung von glutathion-derivaten |
| WO2018146621A1 (en) * | 2017-02-08 | 2018-08-16 | Solosale S.R.L. | Pharmaceutical composition for the prevention and treatment of memory and cognitive deficits related to ageing |
| US20200009101A1 (en) * | 2017-02-16 | 2020-01-09 | Valbiotis | Pharmaceutical active ingredient and use thereof, in particular for the prevention and treatment of metabolic disorders in humans and animals |
Also Published As
| Publication number | Publication date |
|---|---|
| IT202100031985A1 (it) | 2023-06-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20240041810A1 (en) | Amino acid compositions and methods for the treatment of liver diseases | |
| JP7458443B2 (ja) | スルホラファン及び／又はスルホラファンの誘導体及びオオアザミ抽出物又は粉末を含む組成物 | |
| ES2510690T3 (es) | Método para extender la esperanza de vida y retrasar la aparición de enfermedad relacionada con la edad | |
| EP2081564B1 (fr) | Utilisation de la citrulline pour le traitement des etats de denutrition | |
| US20240238232A1 (en) | Compositions and methods for the reduction or treatment of insulin resistance and metabolic conditions | |
| EP3310191A1 (en) | Synergistic beverage composition | |
| JP5576484B2 (ja) | アデノシンｎ１−オキシドを有効成分として含有する炎症性疾患治療剤 | |
| JP2001520994A (ja) | 消化管疾患を治療するためにクマリン誘導体を用いる用途 | |
| KR20120125993A (ko) | Ｃ형 간염 바이러스 양성 사람 간경변 환자용 간암 발생·진전 억제제 | |
| Mikhaylovich et al. | Comparison of the effectiveness of various sulphur-containing hepatoprotectors against chronic alcoholization | |
| WO2023119167A1 (en) | Pharmaceutical composition based on glutathione thioester and oleuropein for use in the treatment of non-alcoholic steatohepatitis | |
| KR20100015986A (ko) | 지방간 또는 비알코올성 지방성 간염의 예방 및/또는 치료를 위한 의약 | |
| Nosworthy et al. | Enterally delivered dipeptides improve small intestinal inflammatory status in a piglet model of intestinal resection | |
| Shivashangari et al. | Hepatoprotective potential of lycopene on D-galactosamine/lipopolysaccharide induced hepatitis in rats | |
| JP2022551528A (ja) | カンナビノイドを含む経口医薬組成物およびその製造方法 | |
| JP2009107928A (ja) | パウ・フェロから単離された新規化合物 | |
| JPH08208472A (ja) | 抗肝炎剤 | |
| KR20010076824A (ko) | 도인 추출물 및 이를 함유하는 간 섬유화 억제 조성물 | |
| KR20090105691A (ko) | 흉선 추출물 및 ｌ－카르니틴을 포함하는 조성물의 용도 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22846928 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| ENP | Entry into the national phase |
Ref document number: 2022846928 Country of ref document: EP Effective date: 20240722 |