WO2008153220A1 - Agent prophylactique ou thérapeutique pour une maladie vasculaire - Google Patents

Agent prophylactique ou thérapeutique pour une maladie vasculaire Download PDF

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Publication number
WO2008153220A1
WO2008153220A1 PCT/JP2008/061289 JP2008061289W WO2008153220A1 WO 2008153220 A1 WO2008153220 A1 WO 2008153220A1 JP 2008061289 W JP2008061289 W JP 2008061289W WO 2008153220 A1 WO2008153220 A1 WO 2008153220A1
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WO
WIPO (PCT)
Prior art keywords
dgla
vascular
therapeutic agent
vascular disease
acid
Prior art date
Application number
PCT/JP2008/061289
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English (en)
Japanese (ja)
Inventor
Akiko Tateishi
Hiroshi Kawashima
Mizuo Miyazaki
Shinji Takai
Takao Tanaka
Original Assignee
Suntory Holdings Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Suntory Holdings Limited filed Critical Suntory Holdings Limited
Publication of WO2008153220A1 publication Critical patent/WO2008153220A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • A61K31/202—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 three or more double bonds, e.g. linolenic
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a prophylactic or therapeutic agent for vascular diseases, particularly symptoms or diseases caused by a decrease in vascular endothelial function such as arteriosclerosis and a decrease in vascular elasticity, and also relates to a food or drink provided with these functions.
  • vascular diseases particularly symptoms or diseases caused by a decrease in vascular endothelial function such as arteriosclerosis and a decrease in vascular elasticity
  • the worst causes of death in Japan 3 are cancer, heart disease, and cerebrovascular disease (Ministry of Health, Labor and Welfare demographic statistics).
  • heart disease and cerebrovascular disease are deeply related to a decrease in vascular endothelial function, and how normal vascular endothelial function is maintained is one of the prognostic factors of vascular disease.
  • Vascular endothelial cells further cover the luminal surface of the blood vessel and are the only cells that directly contact the blood, but they produce not only a barrier between the vascular lumen and the vascular wall, but also a wide variety of substances such as endothelium-derived relaxation factors.
  • ⁇ Plays an important role in maintaining blood vessel homeostasis.
  • causes of decreased endothelial function of blood vessels include hypertension, hyperlipidemia, obesity, diabetes, and smoking, but the inflammatory changes in the intima, including the vascular endothelium, are deeply involved. It has been confirmed.
  • Non-patent Document 1 Secondary preventive treatment with drugs, ACE inhibitors, anticoagulants, etc. is generally performed (Non-patent Document 1).
  • these drugs have not a few side effects, and there are few side effects when considering long-term prevention or treatment.
  • alpha-linolenic acid (GLA) one of polyunsaturated fatty acids (PUFA) is reported to be effective against serum cholesterol lowering activity (Non-patent Document 2) and arteriosclerosis.
  • Patent Document 1 Non-Patent Document 3
  • DGLA dihomo-gamma-linolenic acid
  • Patent Document 1 Japanese Patent Laid-Open No. 11-56315
  • Patent Document 2 W02006 / 085687
  • Non-Patent Document 1 Pharmacy 54, 2287-2303, (2003)
  • Non-Patent Document 2 Eliseo Guallar et al., N Engl J Med 2002; 347: 1747-54
  • Non-Patent Document 3 Yang-Yi Fan et al., J of Nutrition. 2001; 131: 1675-1681 Disclosure of the Invention
  • An object of the present invention is to provide a safe and more effective vascular disease, in particular, a preventive or therapeutic agent for a symptom or disease caused by a decrease in vascular endothelial function such as arteriosclerosis or a decrease in vascular elasticity, and these functions. Is to provide food and drink.
  • DGLA is useful for the prevention or treatment of vascular diseases, particularly symptoms or diseases caused by vascular endothelial functions such as arteriosclerosis and vascular elasticity. And found that the present invention is effective.
  • the present invention relates to vascular diseases, particularly arteriosclerosis and vascular elasticity
  • the present invention provides a preventive or therapeutic agent or a preventive or therapeutic method for a symptom or disease caused by a decrease in vascular endothelial function such as, and has the following characteristics.
  • a preventive or therapeutic agent or a preventive or therapeutic method for vascular diseases comprising dihomo-linolenic acid (DGLA) as an active ingredient.
  • DGLA dihomo-linolenic acid
  • the vascular disease is a symptom or disease caused by a decrease in vascular endothelial function.
  • the symptom or disease resulting from the decrease in vascular endothelial function is a decrease in vascular elasticity or arteriosclerosis.
  • It can be used as a pharmaceutical composition or food or drink for preventing or treating vascular diseases.
  • —It can be provided as a pharmaceutical composition or food / beverage product containing 1 to 1000 mg / kg body weight of dihomo-linolenic acid (DGLA) per daily intake.
  • DGLA dihomo-linolenic acid
  • DGLA dihomo-linolenic acid
  • the dihomo-alpha-linolenic acid exists in the form of glyceride, phospholipid, glycolipid, alkyl ester, or free fatty acid.
  • vascular endothelial function such as arteriosclerosis or reduced vascular elasticity. It provides a method.
  • the preventive or therapeutic agent for vascular disease of the present invention specifically, a symptom or disease caused by a decrease in vascular endothelial function such as arteriosclerosis or a decrease in vascular elasticity.
  • the preventive or therapeutic agent is characterized by containing dihomo-linolenic acid (DGLA) as an active ingredient, and has excellent vascular endothelial function improving action and anti-arteriosclerotic action.
  • DGLA dihomo-linolenic acid
  • FIG. 1 is a diagram showing vascular endothelial function at 34 weeks of age in each group. (The relaxation rate of acetylcholine was calculated with the relaxation response of papaverine as 100%.)
  • FIG. 2 shows the atherosclerotic lesion area at 34 weeks of age in each group. (Calculated as an Oil Red 0 positive region with respect to the blood vessel wall region of the entire cross section.) BEST MODE FOR CARRYING OUT THE INVENTION
  • polyunsaturated fatty acid is defined as having 18 or more carbon atoms and having 2 or more unsaturated moieties (double bonds).
  • the DGLA used in the present invention can be derived from any suitable source. Although there are few natural fats and oils known to have high DGLA content, for example, those extracted from cow liver, pig kidney, egg yolk, etc. can be used. In recent years, microbial fermentation technology has advanced and may be derived from microorganisms such as fungi, bacteria or yeast.
  • DGLA-containing fats and oils can prepare triglycerides in which about 40% of the constituent fatty acids consist of DGLA by microbial fermentation using Mortierella.
  • one or more additional PUFAs may be supplied.
  • this may be another n6 PUFA such as linoleic acid (LA), arylenoic acid (GLA), arachidonic acid (ARA), etc., or n3 PUFA such as EPA, Awakening is good.
  • LA linoleic acid
  • GLA arylenoic acid
  • ARA arachidonic acid
  • n3 PUFA such as EPA, Awakening is good.
  • the DGLA used in the present invention is, for example, a glyceride, jig U-series, or monodalise containing DGLA, or as a phospholipid or glycolipid, and also a free fatty acid, a fatty acid ester (for example, a methyl ester). Or ethyl ester) and sterol esters, and the like, which are supplied as physiologically acceptable derivatives.
  • PUFA is in the form of ⁇ U glyceride present in the oil.
  • It can be pure oil, processed oil (eg chemically and / or enzymatically treated oil) or concentrated oil, which can contain 10-100% PUFA, but the desired PUFA, eg
  • the content of DGLA may be 5% or more, preferably 10% or more, more preferably 25% or more of the oil if the oil is derived from microorganisms.
  • the oil may contain one or more PUFAs within these percentage concentration ranges.
  • the oil may be a single oil derived from a single cell or microorganism, or it may be a blended or mixed oil of two or more oils derived from other sources.
  • This oil may contain, for example, one or more additives, such as antioxidants (eg, tocopherol, vitamin E, tocotrienol, ascorbic acid derivatives, palmitates or esters, and astaxanthin). It may contain sesamin, CoQIO, etc.
  • additives such as antioxidants (eg, tocopherol, vitamin E, tocotrienol, ascorbic acid derivatives, palmitates or esters, and astaxanthin). It may contain sesamin, CoQIO, etc.
  • DGLA is taken in orally from normal foods, though in trace amounts, and is safe It is considered that the nature is high.
  • Oral administration of DGLA-containing fats and oils 2000mg / kg (approximately 900mg / kg as DGLA) in a rat was repeated for 13 weeks.
  • General condition observation, body weight, food intake, food intake efficiency, ophthalmic examination, urinalysis, No abnormality was confirmed in any of the hematological examination, blood biochemical examination, autopsy, organ weight and histopathological examination.
  • DGLA which is an active ingredient of a prophylactic or therapeutic agent for vascular diseases in the present invention
  • DGLA which is an active ingredient of a prophylactic or therapeutic agent for vascular diseases in the present invention
  • mice fed with a diet containing GLA 0.5 w / w% in the diet was GLA
  • a diet containing DGLA 0.5 w / w% strength DGLA in the diet
  • the DGLA intake at this time is equivalent to 500 mg / kg body weight per mouse day. Therefore, when orally administered to animals other than humans for the purpose of prevention or treatment of vascular diseases, the content of DGLA is 1 to 1000 mg / kg body weight per day of intake of the subject, preferably Can be 10 to 1000 mg / kg body weight, more preferably 50 to 500 mg / kg body weight.
  • DGLA is orally administered to humans (adults) for the purpose of preventing or treating vascular diseases, it is generally administered at 10 to lOOOOmg, preferably about 50 to 500mg per day. Good.
  • the prophylactic or therapeutic agent for vascular diseases according to the present invention can be used for pharmaceuticals, food and drinks, and the like.
  • dietary supplements, and (Pharmaceutical) Formulations and preparations such as tablets, pills and capsules.
  • solid or liquid food products such as dairy products (margarine, butter, milk, yogurt), bread, cakes; drinks such as beverages (tea, coffee, cocoa, chocolate drinks), fruit juices , Soft drinks (eg carbonated drinks); confectionery; oily foods (snack, salad dressing, mayonnaise), soups, sauces, carbohydrate-rich foods (rice, potatoes, sushi), fish foods, baby food ( Examples include infant formulas (as liquids or powders), pet foods, and cooked or microwaveable foods.
  • ingredients such as excipients, stabilizers, binders, emulsifiers, preservatives, and solvents that are acceptable as ordinary food additives are added as desired. Can be added.
  • the food can be provided in the form of health food, functional food, food for specified health use, or food for the sick. That is, for normal individuals (mammals), it is used for the purpose of disease prevention, health maintenance and maintenance, as well as a state in which vascular endothelial function is reduced, for example, a state in which arterial stiffness is increased. Long-term symptoms or diseases caused by decreased vascular endothelium function, such as arteriosclerosis or decreased vascular elasticity. It also provides use as a prevention or treatment, and can be used effectively, for example, in patients with hypertension, hyperlipidemia, diarrhea, alcoholics, smokers, and the like.
  • Example 1 Example 1
  • Reference example 1 Preparation of test oil Mortierella alpina SU strain was used as a DGLA-producing bacterium.
  • This culture medium (2w / w% glucose, 3. lw / w% soy flour, 0 ⁇ 02w / w% glycerol, 0.3w / w3 ⁇ 4 K 2 HP0 4 , 0. lw / w3 ⁇ 4 Na 2 SO had 0.06 w / w% MgS0 4 ⁇ 7 ⁇ 2 0, 0.06 w / w% CaS0 4 ⁇ 2H 2 0, 0.
  • DGLA-containing triglycerides were obtained through the edible oil refining process (degumming, deoxidation, deodorization, decolorization, etc.).
  • DGLA was about 40%, and other fatty acids such as palmitic acid, stearic acid, and oleic acid were the main fatty acids.
  • Table 1 shows the composition of the test meal.
  • the DGLA diet was adjusted so that about 0.5 w / w% of the diet weight was D GLA (calculated as the amount of free fatty acids).
  • the control diet was adjusted so that the fatty acid composition and other feed ingredients were the same except that DGLA was replaced with linoleic acid.
  • ApoE knockout mice arrived at the age of 8 weeks and CRF-1 meal (Oriental evening) 2 weeks purified at Le Yeast Industry Co., Ltd. At 10 weeks of age, each group was divided into a control diet group and a DGLA diet group so that there were 7 to 8 animals per group. In addition, as a non-onset control group, C 5 7 BL mice were similarly bred and fed with the control diet shown in Table 1 from 10 to 34 weeks of age.
  • the evaluation items were vascular endothelial function, arterial lipid deposition area, and plasma fatty acid composition at the 34th week after the end of the test meal intake. The evaluation method is as follows.
  • the aorta in the proximal part of the heart extracted from the mice after the intake of the test meal was cut into 3-5 mm round slices and fixed with 10% neutral buffered formalin solution.
  • a frozen block was prepared with the surface in the direction of the heart cut out, and then stained with Oil Red 0. Lipid deposits formed in atherosclerotic lesions appear as red areas.
  • the lesion area was calculated by taking this Oil Red 0-positive area as a ratio of the entire transverse cross section to the vascular wall area.
  • Ri O scraped directly silica gel layer, at 5 0 in hydrochloric acid methanol, and reacted for 3 hours, by extraction with hexane
  • a fatty acid methyl ester mixture was obtained. Penyu decanoic acid was used as the internal standard. The fatty acid methyl ester mixture was analyzed by capillary gas chromatography to determine DGLA (weight 3 ⁇ 4) in total fatty acids of serum phospholipids.
  • Fig. 1 shows the rate of vasorelaxation, which is the result of evaluating vascular endothelial function
  • Fig. 2 shows the area of atherosclerotic lesions in each group.
  • Table 2 shows the fatty acid composition of each group.
  • Table 3 shows the composition of the test meal.
  • the base of the test meal is 10w / fat component
  • the DGLA diet and GLA diet which are high-fat diets containing w%, were adjusted so that about 0.5 w / w% of the feed weight would be DGLA or GLA (calculated as the amount of free fatty acids).
  • SUNTGD prepared by the method shown in Reference Example 1 was used to adjust the DGLA diet.
  • Borage oil from Borago officinal is seeds Sigma-Aldrich, St. Louis, MO, USA
  • the control diet was adjusted so that the fatty acid composition and other feed ingredients were the same except that DGLA or GLA was replaced with linoleic acid.
  • ApoE knockout mice were received at the age of 8 weeks and acclimated on the CRF-1 diet (Oriental Yeast Industry Co., Ltd.) for 2 weeks. At 10 weeks of age, each group is divided into a control diet group, a DGLA diet, and a GLA diet group so that there are 4 to 5 animals per group.Each diet shown in Table 3 is allowed to eat freely until the end of the study at the 14th week of age. It was.
  • the evaluation items were vascular endothelial function and arteriosclerotic lesion area (arterial wall lipid deposition area) at the age of 14 weeks after the end of intake of the trial workers, and the evaluation method was the same as in Example 1.
  • Table 4 shows the endothelium-derived vasorelaxation reaction as an evaluation result of vascular endothelial function
  • Table 5 shows the area of atherosclerotic lesion.
  • the relaxation response by isolated blood vessels was significantly enhanced in the DGLA diet group compared to the control diet group of ApoE gene-deficient mice (control diet group: 62.6 ⁇ 11.5%, DGLA diet group: 87.1 ⁇ 2.7).
  • the GLA diet group also showed a tendency to increase, but there was no significant difference (GLA diet group: 77.4 soil 8.7%).
  • the ratio of lesion area to media area which is an index of arteriosclerosis, was lower in the DGLA and GLA diet groups than in the control diet group, and its effect was more pronounced in the DGLA diet group. (Control diet group: 62.4 soil 15.7%, DGLA diet group: 35.1 ⁇ 1 2.03 ⁇ 4, GLA diet group: 45.7 ⁇ 31.63 ⁇ 4).
  • DGLA has a stronger inhibitory effect on endothelial dysfunction and anti-arteriosclerosis than GLA. It is thought that it is possible to effectively prevent and improve the decrease in endothelial function of the blood vessels and arteriosclerosis.
  • the prophylactic or therapeutic agent for vascular diseases according to the present invention can be used for the prevention or treatment of symptoms or diseases caused by decreased vascular endothelial function, for example, arteriosclerosis and decreased vascular elasticity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

La présente invention concerne un agent prophylactique ou thérapeutique pour une maladie vasculaire, en particulier l'artériosclérose ou une affection ou une maladie provoquée par la réduction de la fonction de l'endothélium vasculaire telle que la réduction de l'élasticité des vaisseaux sanguins, qui est caractérisé en ce qu'il renferme de l'acide di-homo-Ϝ-linolénique (DGLA) en tant que principe actif ; un produit pharmaceutique, un aliment ou une boisson auxquels il a été communiqué les fonctions susmentionnées ; et d'autres.
PCT/JP2008/061289 2007-06-13 2008-06-13 Agent prophylactique ou thérapeutique pour une maladie vasculaire WO2008153220A1 (fr)

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JP2007156802 2007-06-13
JP2007-156802 2007-06-13

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06128154A (ja) * 1978-01-23 1994-05-10 Efamol Ltd 食品組成物
JPH07285915A (ja) * 1994-04-20 1995-10-31 Sando Yakuhin Kk グリセリン誘導体およびこれを含有する血小板凝集抑制剤
JP2003504333A (ja) * 1999-07-14 2003-02-04 ラクスディル リミテッド 必須脂肪酸およびホモシステイン低下剤を含有する製剤および栄養組成物
JP2006521368A (ja) * 2003-03-27 2006-09-21 サントリー株式会社 脂質改善剤及び脂質改善剤を含んでなる組成物
JP2007262014A (ja) * 2006-03-29 2007-10-11 Nisshin Oillio Group Ltd アディポネクチン分泌増加剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06128154A (ja) * 1978-01-23 1994-05-10 Efamol Ltd 食品組成物
JPH07285915A (ja) * 1994-04-20 1995-10-31 Sando Yakuhin Kk グリセリン誘導体およびこれを含有する血小板凝集抑制剤
JP2003504333A (ja) * 1999-07-14 2003-02-04 ラクスディル リミテッド 必須脂肪酸およびホモシステイン低下剤を含有する製剤および栄養組成物
JP2006521368A (ja) * 2003-03-27 2006-09-21 サントリー株式会社 脂質改善剤及び脂質改善剤を含んでなる組成物
JP2007262014A (ja) * 2006-03-29 2007-10-11 Nisshin Oillio Group Ltd アディポネクチン分泌増加剤

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FAN Y.Y. ET AL.: "Dietary gamma-linolenic acid suppresses aortic smooth muscle cell proliferation and modifies atherosclerotic lesions in apolipoprotein E knockout mice", J. NUTR., vol. 131, no. 6, 2001, pages 1675 - 1681 *
KERNOFF P.B. ET AL.: "Antithrombotic potential of dihomo-gamma-linolenic acid in man", BR. MED. J., vol. 2, no. 6100, 1977, pages 1441 - 1444, XP002743046 *
LAGARDE M. ET AL.: "Dihomogammalinolenic acid (20:3 omega 6) is more anti-aggregatory than eicosapentaenoic (20:5 omega 3) in a platelet-endothelial cell mixture", PROSTAGLANDINS MED., vol. 4, no. 3, 1980, pages 177 - 183, XP023092795 *
SIM A.K. ET AL.: "The activity of gamma-linolenate and dihomo-gamma-linolenate methyl esters in vitro and in vivo on blood platelet function in non-human primates and in man", THROMB. RES., vol. 10, no. 3, 1977, pages 385 - 397, XP022876521 *
SMITH D.L. ET AL.: "Eskimo plasma constituents, dihomo-gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid inhibit the release of atherogenic mitogens", LIPIDS, vol. 24, no. 1, 1989, pages 70 - 75, XP035175071, DOI: doi:10.1007/BF02535267 *

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