US20100120914A1 - Medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis - Google Patents

Medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis Download PDF

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Publication number
US20100120914A1
US20100120914A1 US12/593,053 US59305308A US2010120914A1 US 20100120914 A1 US20100120914 A1 US 20100120914A1 US 59305308 A US59305308 A US 59305308A US 2010120914 A1 US2010120914 A1 US 2010120914A1
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medicament
medicament according
prophylactic
hepatic steatosis
therapeutic treatment
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US12/593,053
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Yuji Yoshikawa
Megumi Yamamoto
Naoto Ishibashi
Mami Seki
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Kowa Co Ltd
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Kowa Co Ltd
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Assigned to KOWA COMPANY, LTD. reassignment KOWA COMPANY, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ISHIBASHI, NAOTO, SEKI, MAMI, YAMAMOTO, MEGUMI, YOSHIKAWA, YUJI
Publication of US20100120914A1 publication Critical patent/US20100120914A1/en
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis. More specifically, the present invention relates to a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis, which comprises a polyprenyl compound as an active ingredient, preferably a medicament comprising (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid.
  • hepatic steatosis in which a lot of fats deposit in the liver, has recently been frequently observed, and some of hepatic steatosis advance at some future to non-alcoholic steatohepatitis, cirrhosis, and hepatoma (Gastroenterology, 116, 1413-1419 (1999)).
  • the aforementioned diseases are based on the different onset mechanisms, and accordingly, a medicament suitable for prophylactic and/or therapeutic treatment of each disease is needed.
  • fibrate agents As a therapeutic agent of hepatic steatosis, polyenephosphatidylcholine has been clinically used. Further, fibrate agents, of which typical examples include clofibrate as an antihyperlipidemic agent, have also been clinically used as therapeutic agents for hepatic steatosis. It is considered that the fibrate agents improve lipid metabolism by acting on enzymes for fatty acid ⁇ -oxidation system in the liver (Ann. N.Y. Acad. Sci., 386, 111-135 (1982)).
  • (2E,4E,6E,10E)-3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid which is one of polyprenyl compounds and has a chemical structure totally different from those of polyenephosphatidylcholine and the fibrate agents mentioned above, is a acyclic retinoid having affinity for retinoic acid binding proteins and retinoic acid receptors, and actions thereof for inducing differentiation and inducing apoptosis in hepatocellular carcinoma are known.
  • (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid significantly inhibited recurrence of hepatoma after radical treatment thereof by long-term administration for one year, and thus suppressing action thereof on the recurrence of hepatoma was suggested.
  • liver function failure or other adverse effects, those caused by retinoids, were not substantially observed during the administration thereof, and therefore the compound was revealed to be a safe medicament (N. Eng. J. Med., 334, 1561-1567 (1996)).
  • polyprenyl compounds had prophylactic and therapeutic effectiveness on hepatic steatosis or non-alcoholic steatohepatitis.
  • Non-patent document 1 Gastroenterology, 116, pp. 1413-1419 (1999)
  • Non-patent document 2 Ann. N.Y. Acad. Sci., 386, pp. 111-135 (1982)
  • Non-patent document 3 Atherosclerosis, 92, pp. 31-40 (1992)
  • Non-patent document 4 N. Eng. J. Med., 334, pp. 1561-1567 (1996)
  • An object of the present invention is to provide a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis. More specifically, the object of the present invention is to provide a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis with reduced side effects.
  • the inventors of the present invention conducted various researches to find a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis. As a result, it was found that polyprenyl compounds reduced an amount of lipids in the liver. The present invention was accomplished on the basis of the above finding.
  • the present invention thus relates to the followings.
  • a medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis which comprises a polyprenyl compound as an active ingredient.
  • the polyprenyl compound is a polyprenylcarboxylic acid.
  • the polyprenyl compound is 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid.
  • a method for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis which comprises the step of administrating a prophylactically and/or therapeutically effective amount of a polyprenyl compound to a mammal including human.
  • FIG. 1 is a graph showing the amounts of H-TG (mg/g liver) and the amounts of H-T-chol (mg/g liver) observed for the groups in Example 1.
  • the symbol * means a significant difference (P ⁇ 0.05) compared with the normal control group.
  • FIG. 2 is a graph showing the hepatic steatosis scores and the O.R. positive areas (mm 2 /mm 2 ) observed for the groups in Example 1.
  • the symbol * means a significant difference (P ⁇ 0.05) compared with the normal control group.
  • FIG. 3 is a graph showing the S-TG concentrations (mg/dL) and S-T-chol concentrations (mg/dL) observed for the groups in Example 1.
  • the symbol * means a significant difference (P ⁇ 0.05) compared with the normal control group.
  • FIG. 4 is a graph showing the S-ALT concentrations (U/L) and the S-AST concentrations (U/L) observed for the groups in Example 1.
  • the symbols * and # mean a significant difference (P ⁇ 0.05) compared with the normal control group and the control group, respectively.
  • FIG. 5 is a graph showing the S-TG concentrations (mg/dL) observed for the groups in Example 2.
  • the symbol * means that a significant difference (P ⁇ 0.05) compared with the control group.
  • FIG. 6 is a graph showing the testis weights (mg) observed for the groups in Example 2.
  • the symbol * means a significant difference (P ⁇ 0.05) compared with the control group.
  • the polyprenyl compounds used for the medicament of the present invention mean compounds having several linear isoprene units in the chemical structure.
  • Preferred compounds include polyprenylcarboxylic acids having carboxy group at the end, and a particularly preferred compound includes (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (henceforth referred to as NIK-333).
  • polyprenyl compounds include conjugated polyprenylcarboxylic acids (polyprenoic acids) such as 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and esters thereof described in Japanese Patent Publication (Kokoku) No. 63-34855, and the like.
  • polyprenoic acids conjugated polyprenylcarboxylic acids
  • the polyprenyl compounds used in the present invention can be synthesized by a known method (Japanese Patent Publication No. 63-32058; J. Chem. Soc. (C), 2154 (1966)).
  • polyprenyl compounds When used for the medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis of the present invention, said compounds can be administered by an appropriate administration method such as oral administration or parenteral administration.
  • forms for oral administration include, for example, tablets, granules, capsules, soft capsules, pills, powders, solutions, and the like.
  • forms for parenteral administration include, for example, injections, suppositories, and the like.
  • These preparations can be prepared by a conventional method using a polyprenyl compound or a pharmacologically acceptable salt thereof and one or more kinds of ordinary pharmaceutical carriers.
  • desired administration forms can be prepared by using excipients such as lactose, glucose, corn starch and sucrose, disintegrating agents such as carboxymethylcellulose calcium and hydroxypropylcellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol and hydrogenated oil, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin and gum arabic, and moistening agents such as glycerin and ethylene glycol, as well as surfactants, flavoring agents and the like as required.
  • excipients such as lactose, glucose, corn starch and sucrose
  • disintegrating agents such as carboxymethylcellulose calcium and hydroxypropylcellulose
  • lubricants such as calcium stearate, magnesium stearate, talc
  • polyethylene glycol and hydrogenated oil such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin and gum
  • diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, agar and tragacanth gum as well as dissolving aids, suspending agents, emulsifiers, stabilizers, buffers, isotonic agents, preservatives, soothing agents and the like can be used as required.
  • a dose may be 1 to 2,000 mg, preferably 20 and 800 mg, in terms of the compounds used for the present invention, per day for an adult in the case of oral administration.
  • the compounds are administered at a dose in the range of 1 to 1,000 mg, preferably in the range of 10 to 100 mg. Desired therapeutic effects can be expected by administering the compounds 1 to 3 times per day as divided portions of the aforementioned doses.
  • HFD32 (Clea Japan) was used for the high fat diet group
  • CE-2 (Clea Japan) was used for the normal control group.
  • the feeding was restricted to 25 ⁇ 3 g for both of the groups.
  • the feed ingredients are shown in Table 1.
  • Administration of NIK-333 was started at the same time as the start of the loading of the high fat diet, and the drug was given once a day for 8 weeks by forcible continuous oral administration. After completion of the test, each liver was extracted, and triglyceride (H-TG) amount and cholesterol (H-T-chol) amount in the liver were measured. The results are shown in FIG. 1 .
  • Hematoxylin-eosin (H.E.) and Oil Red O (O.R.) staining samples were prepared from the extracted liver, and histopathological examination was performed. Degree of fatty degeneration of the liver was graded into five categories on the basis of the examination of the H.E. staining sample, and scores were assigned. Further, from the O.R. staining sample, O.R. positive area in the liver sample area was calculated by using an image analyzer. The results are shown in FIG. 2 . Furthermore, triglyceride (S-TG), total cholesterol (S-T-chol), alanine aminotransferase (S-ALT), and aspartate aminotransferase (S-AST) levels in serum were measured. The results are shown in FIGS. 3 and 4 .
  • NIK-333 decreased the amount of lipids in the liver, and therefore, it was revealed that the compound has effectiveness on prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis. It can be also understood that NIK-333 decreases the amount of lipids in the liver without affecting lipid concentration in blood as shown in FIG. 3 . Generally, retinoids are pointed out to have a problem of inducing hypertriglyceridemia as a side effect in clinical use (N. Engl. J. Med., 313, 981-985 (1985)). However, NIK-333 does not show such increase in lipid concentration in blood.
  • NIK-333 has an suppressing effect on the increase of blood transaminase as shown in FIG. 4 , and has an action of protecting the liver. From the above, it is clearly understood that NIK-333 has effectiveness on prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis.
  • mice 7-Week old C57BL/6N mice (Charles River Japan) were given with NIK-333 or ATRA once per day for 2 weeks by forcible continuous oral administration. After completion of the test, S-TG concentrations and testis weights of individual mice were measured. The results are shown in FIGS. 5 and 6 , respectively. To the control group, soybean oil was administered.
  • ATRA increases the S-TG concentration, whilst NIK-333 does not affect the concentration. It can be also recognized that ATRA markedly decreases testis weight, whilst NIK-333 does not affect the weight as shown in FIG. 6 . It was observed that ATRA decreased testis weight in mice (Fundam. Appl. Toxicol., 8, 517-530 (1987)) and rats (Toxicology, 30, 115-124 (1984)), whilst the aforementioned action is not observed for NIK-333. From the above results, it is clearly understood that toxicity of NIK-333 for S-TG and testis is lower than that of ATRA.
  • the medicament of the present invention is useful as a novel medicament for use in prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis.
  • the medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis provided by the present invention has an action of decreasing lipid amount in the liver and improving liver functions.
  • the medicament has less effect on triglyceride (S-TG) concentration in blood serum and testis weight as compared with all-trans-retinoic acid (henceforth abbreviated as ATRA) as a cyclic retinoid, and thus a medicament with reduced side effects.
  • S-TG triglyceride
  • ATRA all-trans-retinoic acid

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US12/593,053 2007-03-30 2008-03-27 Medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis Abandoned US20100120914A1 (en)

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JP2007090114 2007-03-30
JP2007-090114 2007-03-30
PCT/JP2008/000760 WO2008126363A1 (ja) 2007-03-30 2008-03-27 脂肪肝又は非アルコール性脂肪性肝炎の予防及び／又は治療のための医薬

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US (2) US20100120914A1 (de)
EP (1) EP2143430B1 (de)
JP (2) JP5341749B2 (de)
KR (1) KR101461252B1 (de)
CN (1) CN101652134B (de)
ES (1) ES2555782T3 (de)
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WO (1) WO2008126363A1 (de)

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JP5725491B2 (ja) * 2010-04-14 2015-05-27 国立大学法人鳥取大学 レチノイン酸受容体リガンドによるインスリン抵抗性改善作用
JP5304939B1 (ja) * 2012-05-31 2013-10-02 大日本印刷株式会社 光学積層体、偏光板、偏光板の製造方法、画像表示装置、画像表示装置の製造方法及び画像表示装置の視認性改善方法
GB201301626D0 (en) * 2013-01-30 2013-03-13 Dignity Sciences Ltd Composition comprising 15-OHEPA and methods of using the same
EP2808031A1 (de) * 2013-05-30 2014-12-03 Fundació Hospital Universitari Vall d' Hebron - Institut de Recerca Sexualhormonbindendes Globulin zur Verwendung als Medikament

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US4655973A (en) * 1980-12-24 1987-04-07 Eisai Co., Ltd. Conjugated polyprenylcarboxylic acids and their derivatives
US4917829A (en) * 1980-04-07 1990-04-17 Eisai Co., Ltd. 3,7,11,15-Tetramethyl-2,4,6,10,14,-hexadecapentaendic acid
US5922345A (en) * 1990-12-07 1999-07-13 Scotia Holdings Plc Nutrition
US20050250671A1 (en) * 2000-04-24 2005-11-10 Yoshihiro Shidoji Activators of peroxisome proliferator-activated receptor
US20060094784A1 (en) * 2002-05-17 2006-05-04 Masataka Kagawa Tgf-alpha expression inhibitors
US20080021105A1 (en) * 2004-02-25 2008-01-24 The University Of Tokyo Medicine Capable of Inhibiting Activation of Transcription Factor Klf5

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JPS6332058A (ja) 1986-07-22 1988-02-10 株式会社　梅彦 石材の床張り方法
GB9026648D0 (en) * 1990-12-07 1991-01-23 Efamol Holdings Nutrition
JPH09194362A (ja) * 1996-01-19 1997-07-29 Bizen Kasei Kk ドコサヘキサエン酸及びエイコサペンタエン酸含有リン脂質を含む組成物
JP2002104965A (ja) 2000-09-27 2002-04-10 Kanegafuchi Chem Ind Co Ltd 脂肪肝予防・改善機能を有する組成物
JP2004290821A (ja) 2003-03-27 2004-10-21 Aichi Electric Co Ltd 混合装置
JP2006232711A (ja) 2005-02-24 2006-09-07 Tohoku Univ 血中中性脂肪低下作用および肝臓中性脂肪合成抑制作用および血小板凝集抑制作用を有する油脂
JP5099808B2 (ja) * 2006-05-29 2012-12-19 独立行政法人農業・食品産業技術総合研究機構 脂質代謝改善用組成物
JP2008150307A (ja) * 2006-12-15 2008-07-03 Kenko Tsusho Kk 体脂肪の蓄積に起因する疾患の治療剤

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
US4917829A (en) * 1980-04-07 1990-04-17 Eisai Co., Ltd. 3,7,11,15-Tetramethyl-2,4,6,10,14,-hexadecapentaendic acid
US4988732A (en) * 1980-04-07 1991-01-29 Eisai Co., Ltd. 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid composition and use for treating papillomata
US4655973A (en) * 1980-12-24 1987-04-07 Eisai Co., Ltd. Conjugated polyprenylcarboxylic acids and their derivatives
US5922345A (en) * 1990-12-07 1999-07-13 Scotia Holdings Plc Nutrition
US20050250671A1 (en) * 2000-04-24 2005-11-10 Yoshihiro Shidoji Activators of peroxisome proliferator-activated receptor
US20060094784A1 (en) * 2002-05-17 2006-05-04 Masataka Kagawa Tgf-alpha expression inhibitors
US20080021105A1 (en) * 2004-02-25 2008-01-24 The University Of Tokyo Medicine Capable of Inhibiting Activation of Transcription Factor Klf5

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HK1138200A1 (en) 2010-08-20
US20120259015A1 (en) 2012-10-11
KR20100015986A (ko) 2010-02-12
US8673976B2 (en) 2014-03-18
CN101652134B (zh) 2015-07-15
CN101652134A (zh) 2010-02-17
EP2143430A1 (de) 2010-01-13
EP2143430A4 (de) 2010-12-29
WO2008126363A1 (ja) 2008-10-23
EP2143430B1 (de) 2015-09-23
KR101461252B1 (ko) 2014-11-12
JPWO2008126363A1 (ja) 2010-07-22
ES2555782T3 (es) 2016-01-08
JP2013216679A (ja) 2013-10-24
JP5341749B2 (ja) 2013-11-13

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