WO2015005393A1 - Prophylactic or therapeutic agent for aortic aneurysm and packaged food or drink - Google Patents

Prophylactic or therapeutic agent for aortic aneurysm and packaged food or drink Download PDF

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WO2015005393A1
WO2015005393A1 PCT/JP2014/068333 JP2014068333W WO2015005393A1 WO 2015005393 A1 WO2015005393 A1 WO 2015005393A1 JP 2014068333 W JP2014068333 W JP 2014068333W WO 2015005393 A1 WO2015005393 A1 WO 2015005393A1
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aortic aneurysm
epa
therapeutic agent
prophylactic
present invention
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PCT/JP2014/068333
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French (fr)
Japanese (ja)
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信宏 財満
陽平 毛利
賢一 柳本
韓 力
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日本水産株式会社
学校法人近畿大学
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic 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
    • A61K31/202Carboxylic 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
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A23B - A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12Fatty acids or derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56Materials from animals other than mammals
    • A61K35/60Fish, e.g. seahorses; Fish eggs
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The purpose of the present invention is to provide a novel prophylactic or therapeutic agent for aortic aneurysm whereby aortic aneurysm can be prevented and/or treated, and a packaged food or drink comprising the same. As the results of evaluation of the effects of n-3 type highly unsaturated fatty acids on aortic aneurysm with the use of aortic aneurysm model animals, the present inventors found that eicosapentaenoic acid (EPA) has preventive and therapeutic effects on aortic aneurysm. Thus, provided is a prophylactic or therapeutic agent for aortic aneurysm that comprises eicosapentaenoic acid as an active ingredient. Also provided is a packaged food or drink that comprises the prophylactic or therapeutic agent for aortic aneurysm.

Description

Aortic aneurysm prophylactic or therapeutic agent and packaged food or beverage

The present invention relates to pharmaceutical and food or drink for preventing or treating aortic aneurysms.

Aortic aneurysm is a disease that a progressive expansion of the aorta and the main lesion. Progressive expansion of the aorta eventually cause rupture of the aorta, the survival rate at the time of rupture is low rate and about 30%. Aortic aneurysm is a disease which has about 10 percent of the 65 years of age or older Japanese men, is a major disease is located in the 10th before and after the annual cause of death.

Treatment of aortic aneurysms, focus rupture prevention of aneurysm has been placed, the aneurysm diameter exceeds a predetermined size, the stent graft insertion surgery or vascular prosthesis replacement surgery is used. These therapies, although the mortality rate is relatively low effective as 1-2%, a large burden on the elderly. Also, since the aneurysm diameter is not smaller initial drug therapy and treatments that target the patient is still present, these patients have no choice in addition to observation progress until just before the growing risk of rupture of the aneurysm. Therefore, development of a drug therapy and diet that can be the prevention and treatment of aortic aneurysms has been desired.

However at present, drug and food ingredients or the like capable of preventing and treating aortic aneurysms there is a problem that has not been found.

The following Patent Document 1, aneurysm progression prevention and / or therapeutic agent comprising as an active ingredient, a compound having a PPARγ inhibitory activity have been described. Fibroblasts constituting the abdominal aortic aneurysm wall outer membrane, express PPARγ by circulatory disorder in the vascular wall and differentiate into adipose-like cells, triglycerides and the abnormal accumulation in the vessel wall, weakening the vessel wall. Therefore, to inhibit PPARy, development of an aneurysm, and preventing the development or rupture, but to improve the prognosis of aneurysm patients.

Further, Non-patent Document 1, docosahexaenoic acid (DHA) have been reported to inhibit the expression of matrix metalloproteases (MMP). However, this paper EPA does not describe any possibility of inhibiting aortic aneurysm.

International Publication No. WO 2011/007565

Biochemical and Biophysical Research Communications 368 (2008 ) 343-349

An object of the present invention is to provide a prophylactic or therapeutic agent of a new aortic aneurysm that can be prevented and / or treatment of aortic aneurysms, and food or drink containing the same.

The present inventors have conducted extensive studies in order to solve the above problems. Histopathology of an abdominal aortic aneurysm, rupture of elastic fibers and collagen fibers in the middle and outer membrane, infiltration of inflammatory cells around the such as lymphocytes and macrophages, and is characterized such angiogenic. In order to improve these conditions, it is important to clarify the abdominal aortic aneurysm development mechanism, still there are many unclear points with respect to the abdominal aortic aneurysm development mechanism.

To clarify the abdominal aortic aneurysm onset mechanism, the present inventors have carried out an analysis of abdominal aortic aneurysm patients vessel wall by imaging mass spectrometry (IMS), it found that the patients blood vessel wall has become ischemic It was. By further artificially induced ischemia in rats abdominal aorta, and it succeeded in the production of model animals to develop abdominal aortic aneurysm. Vascular wall of the model animal, rupture of elastic fibers and collagen fibers in the middle and outer membrane, infiltration of inflammatory cells such as macrophages, and vascularization, such as was consistent with the pathological image in humans.

We used the model animals produced in the manner described above, n-3 highly unsaturated fatty acids having anti-inflammatory action, evaluated the effect on the abdominal aortic aneurysm development of animal models. As a result, the known eicosapentaenoic acid have various functions (EPA), it found that the effect of preventing and / or treating aortic aneurysms, and conceived the present invention.

Namely, the present invention provides eicosapentaenoic acid as an active ingredient, a preventive or therapeutic agent for aortic aneurysm.

The present invention, the eicosapentaenoic acid is contained as a seafood extract, provides a preventive or therapeutic agent of the aortic aneurysm.

The present invention further comprises a docosahexaenoic acid, provides a preventive or therapeutic agent of the aortic aneurysm.

The present invention also provides a packaged food product containing a prophylactic or therapeutic agent of the aortic aneurysm.

Prophylactic or therapeutic agent and packaged food aortic aneurysm according to the present invention, as described above, since eicosapentaenoic acid as an active ingredient, it is possible to prevent the development of aortic aneurysm, and reducing the aortic aneurysm .

It shows an abdominal aortic aneurysm which is formed in the control group and the EPA high dose group. Graph comparing aneurysm diameter of the abdominal aorta extension portion formed in the control group and the EPA high dose group. Graph comparing expansion ratio of the abdominal aorta extension portion formed in the control group and the EPA high dose group. It shows the results of HE staining of tissue specimens in the control group and EPA high dose group. It shows the results of PSR staining of tissue specimens in the control group and EPA high dose group. Graph comparing collagenous fiber area in the control group and EPA high dose group. Diagram illustrating an exemplary elastic plate belonging to the elastic plate grade. Graph showing the percentage of individuals corresponding to each of the elastic plate grading criteria in each treatment group. Graph comparing abdominal aortic extension portion formed in the control group and the EPA low dose group. It shows the results of PSR staining of tissue specimens in the control group and EPA low dose group. Graph comparing collagenous fiber area in the control group and EPA low dose group. It shows the results of EVG staining tissue sections in the control group and EPA low dose group. Shows the mortality ruptured abdominal aortic aneurysm in the control group and EPA high dose groups when administered EPA aortic aneurysm formation early.

Prophylactic or therapeutic agent for aortic aneurysm according to the present invention, eicosapentaenoic acid (hereinafter, also referred to as "EPA".) Containing as an active ingredient. EPA is one of the polyunsaturated fatty acids of the n-3 fatty acids, 20-carboxylic acid having a carbon with five cis double bond.

EPA used in the present invention can be used those obtained in natural or artificial. EPA is primarily fats and oils derived from fish and microorganisms deacidification, decolorization, deodorization, it can be extracted and treated by a conventional method such as degumming, and dewaxing. In the present invention, EPA, for example may be contained as an extract of fish or microorganisms. Seafood extracts, for example, fish oil and cod liver oil and the like. Seafood refers to generic generally recognized as aquatic animals in the art, for example herring, mackerel, salmon, etc. sardines and krill and the like. As the microorganisms include, for example, microalgae such labyrinthulean.

Prophylactic or therapeutic agent for aortic aneurysm of the present invention may contain an EPA any amount, for example, is preferably daily dose 3 mg / kg body weight or more, so that particularly preferably at 30 mg / kg body weight or more it can be contained in the. With such a dosage, as shown in the examples below, it is possible to obtain a preventive or therapeutic effect sufficient aortic aneurysm. The upper limit of the daily dose of EPA is not particularly limited, and may be for example 1000 mg / kg body weight or less. EPA is because there is already a long experience in other applications, can be used without considering safety issues.

The prevention or treatment of aortic aneurysms, to suppress the expansion of the aorta, to suppress the progress of aortic aneurysm, inhibiting the degradation of collagen fibers and elastic fibers, to shrink the aortic aneurysm, or the like to prevent the rupture of aortic aneurysm by the action, preventing the development of aortic aneurysm, inhibiting the progression, or refers to improving.

EPA, as shown in the examples below, with aortic expansion suppressing action, aortic aneurysm progression inhibition, rupture inhibition of aortic aneurysm, thickening inhibitory effect of the vascular wall, the collagen fibers decomposition inhibiting effect and elastic fiber degradation inhibiting action . Accordingly, the present invention can be utilized as a preventive or therapeutic agent for aortic aneurysm.

Prophylactic or therapeutic agent for aortic aneurysm of the present invention further docosahexaenoic acid (hereinafter, also referred to as "DHA".) It may contain. DHA has six double 22 amino acids having a carbon chain containing binding (22: 6), and having a double bond in all cis for example 4,7,10,13,16 and 19 of , including compounds classified into n-3 fatty acids. DHA may be contained as seafood extracts, as described above.

Prophylactic or therapeutic agent for aortic aneurysm of the present invention may further contain components other than EPA. For example, suitable carriers for use in this invention, excipients, binders, disintegrating agents may further contain such lubricants and coloring agents.

Examples of carriers and excipients include lactose, dextrose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, and calcium sulfate, and microcrystalline cellulose.

Further, examples of binding agents include starch, gelatin, syrup, tragacanth, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, methyl cellulose, and the like ethyl cellulose and carboxymethyl cellulose.

Further, examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, carboxymethylcellulose sodium and carboxymethylcellulose calcium and the like.

Further, examples of lubricants include magnesium stearate, hydrogenated vegetable oil, talc and macrogol.

The colorants can be used any coloring agent to be added to medicines are allowed.

Furthermore, prophylactic or therapeutic agent for aortic aneurysm of the present invention may optionally, sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, or be coated with more than one layer, such as methyl methacrylate and methacrylic acid polymers. If necessary, pH adjusters, buffering agents, and the like may be added stabilizing agents and solubilizing agents.

Furthermore, prophylactic or therapeutic agent for aortic aneurysm of the present invention can be provided as a formulation of any form. For example, the present invention is, as an oral administration preparation, dragees, buccal tablets, coated tablets and tablets chewable tablets, etc., troches, pills, capsules containing powders and soft capsules, granules, suspensions, emulsions, and dry syrup syrups containing, as well as a liquid such as elixirs. Further, the present invention may contain, for parenteral administration, intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, rectal administration, intraoral administration and transmucosal administration it can be formulated for administration such. For example, injection, transdermal absorption tapes, can be located in such aerosols and suppositories.

Furthermore, prophylactic or therapeutic agent for aortic aneurysm of the present invention can be prepared using any method. For example, prophylactic or therapeutic agent for aortic aneurysm of the present invention, using known manufacturing methods, the EPA, were mixed with various materials as described above such that the desired content, then the desired form it can be produced by molding as a formulation.

Prophylactic or therapeutic agent for aortic aneurysm of the present invention can be utilized pharmaceuticals, quasi-drugs and food products such as. If preventive or therapeutic agent for aortic aneurysm of the present invention is a food product, for example general foods, specific health foods, nutritional functional foods, dietary supplements, functional foods, with sick food and geriatric foods it can be there. The present invention may be in the like display the food products and food products displaying the aortic aneurysm prophylactic effect or improvement to be, for example, food for specified health use. Furthermore, prophylactic or therapeutic agent for aortic aneurysm of the present invention is added to other foods, it can be used as food materials mixed or coated.

The present invention also provides a packaged food product containing a prophylactic or therapeutic agent for aortic aneurysm as described above. The packaged food product of the present invention is a food or beverage that is provided in a state where a prophylactic or therapeutic agent for aortic aneurysm as described above is filled in a container sealed. That is, the packaged food or beverage of the present invention contains EPA, which is packaged food or beverage for the prevention or amelioration of aortic aneurysms. Food and drink, can be filled into the container after the sterilization process.

The packaged food product of the present invention may be one that is enriched engineered to ingest diluted, or may be directly ingested without dilution. Container, generally it can be used container used in food products, for example retort pouch, paper cartons, PET bottles, can be located in a metal can and a glass bottle. Further, the packaged food or beverage of the present invention can be prepared using any method. For example, EPA for the desired content is made as mixed with various materials as described above, can be filled in a container as described above according to the procedure for any food preparation.

The packaged food product of the present invention is not particularly limited, for example, is preferably ingested per day of EPA 3 mg / kg body weight or more, particularly preferably in an amount such that 30 mg / kg body weight or higher. With such a dosage, as shown in the examples below, it is possible to obtain a preventive or therapeutic effect sufficient aortic aneurysm. Further, the packaged food or beverage of the present invention is not particularly limited, for example, the upper limit of the daily allowance of EPA may also be 1000 mg / kg body weight or less.

With the above structure, the packaged food product of the present invention can be suitably used for the prevention and / or amelioration of aortic aneurysms. For example, it can be used in diet therapy for treatment and patient, such as a hard elderly be performed, such as graft insertion surgery and prosthetic vascular replacement, such as small initial patient aneurysm diameter.

The present invention also includes mammalian, to preferably a human, comprising administering an effective amount of eicosapentaenoic acid in the prevention and / or treatment of aortic aneurysms, a method for preventing or treating aortic aneurysms .

The present invention also provides a mammalian, to preferably a human, eicosapentaenoic acid as an active ingredient, comprising administering a prophylactic or therapeutic agent for aortic aneurysms, a method for preventing or treating aortic aneurysms to.

The present invention also eicosapentaenoic acid is contained in the prophylactic or therapeutic agent as a seafood extract, it provides the above method.

The present invention also provides the above method, the prophylactic or therapeutic agent further comprises a docosahexaenoic acid, provides the above method.

The present invention also includes mammalian, to preferably a human, comprising administering a packaged food product containing the prophylactic or therapeutic agent, provides a method for preventing or treating aortic aneurysms.

The subject to mammalian methods of the invention include, for example, human, mouse, rat, cat, dog, cow, pig, sheep, goats and horses.

"Effective amount" refers to prophylactic or therapeutically effective amount, as compared such quantities to a corresponding subject who have not received, to suppress the expansion of the aorta, the development of aortic aneurysms suppressing, inhibiting the degradation of collagen fibers and elastic fibers, to shrink the aortic aneurysm, or refers to any amount that produces the effects and preventing rupture of aortic aneurysm.

Eicosapentaenoic acid can be administered by any route of administration including oral and parenteral administration. Moreover, eicosapentaenoic acid, for example, can be administered in the form of such packaged food products of prophylactic or therapeutic agents, and the invention of the present invention. Eicosapentaenoic acid can be administered at various time intervals in a predetermined period, or according to the appropriate dosing regimen once.

The following examples will be described in more detail an embodiment of the present invention, the present invention is not limited to the following examples.

(EPA-rich preparation of purified fish oil)
EPA-rich purified fish oil used was Nippon Suisan Co. of refined fish oil EPA28 (containing EPA28% or higher).

(Method creation of animal models)
Unless otherwise stated, it was created a model animal in the following ways.
Using male SD rats of 6-week-old (160 ~ 180g). Were preliminarily bred for 1 week, 1145mg / kg body weight / day triolein (manufactured by Wako Pure Chemical Industries, Ltd.) (control group) and 1145mg / kg of body weight / day 300 mg / kg body weight of EPA-rich purified fish oil (EPA amount of ) and (EPA high dose group) was forcibly orally administered respectively a week rats. Then, a catheter was inserted into the rat abdominal aorta, by ligating the abdominal aorta with the catheter inserted, were generated aortic aneurysm model animal. Then it was further euthanized after continued for 4 weeks.

Further, to produce a EPA low dose group using a similar method. The EPA low dose group, and EPA-rich refined fish oil and triolein 1: The mixed sample (30 mg / kg body weight of EPA weight) 1145mg / kg body weight / day 9 was orally administered.

Using these models animals were subjected to the following tests.

Test Example 1: changes in body weight]
In changes in body weight of the control group and EPA high dose group, significant differences were observed.

Test Example 2: Effect on the development of aortic aneurysm]
It was assessed an extension of the aorta formed in the abdomen of the control group and EPA high dose group. Where the ratio of vessel diameter of maximum expansion unit to the vessel diameter of the non-expansion portion is 2.0 or higher (extension ratio) is defined as abdominal aortic aneurysm formation, it was evaluated.

As a result, (one animal is out aneurysm) developed five abdominal aortic aneurysm in five in the control group, develop abdominal aortic aneurysm Eight of 9 animals in EPA high dose group (of aneurysm rupture is 0 mice) did. Figure 1 is a diagram showing an abdominal aortic aneurysm which is formed in the control group and the EPA high dose group, 1 (a) shows an abdominal aortic aneurysm in one animal in the control group, FIG. 1 (b) EPA High It shows an abdominal aortic aneurysm in one animal treated group. Figure 1 shows that the abdominal aortic aneurysm formed in EPA high dose group was in a small tendency as compared to the control group.

2 and 3 are graphs comparing the aneurysm diameter and expansion ratio of the abdominal aorta extension portion formed in the control group and the EPA high dose group, 2 aneurysm diameter extension (mm), and 3 shows an extension / unexpanded portion Kobu径 (expansion ratio). The average expansion ratio of the control group whereas the 5.0, the average expansion ratio of EPA high dose group was 2.5 (Fig. 3). There were no significant differences in mass diameter of the non-expanded portion in both groups. These results, EPA has been shown to inhibit the development of abdominal aortic aneurysm in an animal model.

Test Example 3: blood vessel wall thickening]
For control group and EPA high dose group performs hematoxylin-eosin (HE) staining of tissue specimens were observed thickening of vascular Chugai film. Specifically, after the abdominal aorta excised, after immersion overnight in 4% paraformaldehyde-phosphate buffer (Nacalai Tesque, Inc.) was immersed in the 1 hour in the order of 10, 15, 20% sucrose. Then, the tissues were embedded in OCT Compound (manufactured by Sakura Fine Tech Japan Co., Ltd.), after frozen by liquid nitrogen, the cryostat; created the sections of 10μm using (CM1850 Leica Microsystems Co., Ltd.).

After washing dipped 1 minute in distilled water tissue sections, and nuclear staining put 10 minutes to hematoxylin. After washing with distilled water, after applying 10 seconds in a 1% hydrochloric acid 70% ethanol, and washed with running water. Then, distilled water was immersed for 10 minutes, immersed 5 minutes in eosin. Each immersed for one minute in 80 and 90% ethanol was repeated twice to work soaking 100% ethanol for 1 minute. Then dipped 5 minutes in xylene clearing. Sealed with Entellan new, biological microscope; was observed using (CX21LED manufactured by Olympus Corporation).

Figure 4 is a diagram showing a result of the tissue pieces were HE staining in the control group and EPA high dose group, A is the control group of FIG. 4, FIG. 4 B is EPA high dose group, C in FIG. 4 the control group , D of FIG. 4 shows the EPA high dose group. Scale bars A and B in FIG. 4 shows a 500 [mu] m, scale bar for C and D in FIG. 4 shows a 200 [mu] m. 4, compared to the control group, indicating that there was a tendency for thickening of the vessel wall is suppressed in EPA high dose group.

Test Example 4: Effect on collagen fibers of the abdominal aortic aneurysm]
For control group and EPA high dose group were pathologic evaluation of collagen fibers. After the collagen fibers were Picrosirius Red (PSR) staining, it was to evaluate the effect on the collagen fibers by image analysis with ImageJ.

(Reagent preparation)
Weigert iron hematoxylin solution, Weigert's iron hematoxylin solution I (manufactured by 1% hematoxylin (SIGMA Co.) and 96% ethanol) and Weigert iron hematoxylin solution II (2% ferric chloride (manufactured by Nacalai Tesque, Inc.) and 0.25% hydrochloric acid) the door 1: was prepared by mixing 1.

Van Gieson solution, Van Gieson solution P (manufactured by Wako Pure Chemical Industries, Ltd.) and 1% Sirius Red (WALDECK Co., Ltd.) and a 20: was prepared by mixing in a ratio of 1.

(Methods and evaluation results)
Tissue sections were washed with distilled water for 1 minute. After wearing 10 minutes in Weigert's iron hematoxylin solution, and washed with distilled water. It dipped 10 seconds in hydrochloric acid alcohol, washed with distilled water. Thereafter, Wan - immersed 15 minutes in Son solution, washed with distilled water, soaked 30 seconds in 100% ethanol (manufactured by Nacalai Tesque, Inc.). Sealed with Entellan new (MERCK Co.), the ratio of the area of ​​the collagen fibers in the vessel being observed with a polarizing microscope after drying was determined by Image J.

Figure 5 is a graph showing the results of PSR staining of tissue specimens in the control group and EPA high dose group, 6 is a graph comparing the collagenous fiber area in the control group and EPA high dose group. As shown in FIGS. 5 and 6, the collagen fibers of EPA high dose group compared with the control group was significantly greater. These results, the degradation of collagen fibers was suggested that was suppressed by the administration of EPA-rich purified fish oil.

Test Example 5: Effect on elastic fibers of the abdominal aortic aneurysm]
For control group and EPA high dose group were pathologic evaluation of elastic fibers. After staining of elastic fibers by Elastica-van Gieson (EVG) staining, to evaluate the elastic plate grade for each treated group.

(Reagent preparation)
Weigert iron hematoxylin solution (Nacalai Tesque Co., Ltd.), the Weigert iron hematoxylin solution I (1% hematoxylin (SIGMA Co.) and 96% ethanol) and Weigert iron hematoxylin solution II (2% ferric chloride (Nacalai Tesque, Inc. Ltd.) and 0.25% hydrochloric acid) and 1: it was prepared by mixing 1.

Van Gieson solution, Van Gieson solution P Gieson solution F and (Wako Pure Chemical Industries, Ltd.) (manufactured by acidic fuchsin (Waldeck Inc.) 5 g and distilled water 500ml) and 100: were prepared by mixing at 15.

(Methods and evaluation results)
Washed with water for 1 minute Tissue sections with distilled water, soaked 60 minutes in Wye Gert resol fuchsin solution (manufactured by Nacalai Tesque, Inc.). After wearing 3 minutes 3 times in 100% ethanol (manufactured by Nacalai Tesque, Inc.), washed with water for 2 minutes. Thereafter, it is 10 minutes in Weigert's iron hematoxylin solution, and then washed with water for 10 minutes. Thereafter, Wan - dipped for 3 minutes in Son solution, 3 times for 1 minute in 70% ethanol, gave one minute each twice 90,100% ethanol. After clearing by xylene, it was sealed with enteritidis run New (MERCK Co., Ltd.). After drying, the elastic plate grade sections are observed under a microscope, the elastic plate grading criteria (1: intact, 2: dilution of wavy defect structure, or the elastic plate, 3: partial disappearance of the elastic plate, and 4: were evaluated according to the disappearance of the elastic plate). Figure 7 is a diagram illustrating an exemplary elastic plate belonging to the elastic plate grade. Further, FIG. 8 represents the percentage of individuals corresponding to each of the elastic plate grading criteria in each treatment group.

As Figure 8, the percentage of individuals corresponding to each of the elastic plate grading criteria in each dose group, grade 4 is 50% in the control group, grade 2 and grade 3 whereas a 25%, EPA high dose grade 4 is 12.5% ​​in the group, grade 3 is 37.5%, grade 2 was 50%. These results showed that the EPA high dose group tends to degradation of the elastic fibers is suppressed.

Test Example 6: EPA effects on the development of aortic aneurysms in the low dose group]
Next, the EPA low dose group, were evaluated expansion of the aorta formed in the abdomen in the same manner as in Test Example 2. Figure 9 is a graph comparing (average of 3 individuals) abdominal aortic extension portion formed in the control group and the EPA low dose group. From this result, when administered to EPA in 30 mg / kg body weight / day was also shown that in the suppressing trend the development of abdominal aortic aneurysms.

Test Example 7: Effect on collagen fibers of abdominal aortic aneurysms in EPA low dose group]
For EPA low dose group were pathologic evaluation of the collagen fibers in the same manner as in Test Example 4. Figure 10 is a graph showing the results of PSR staining of tissue specimens in the control group and EPA low dose group, (a) shows the control group of FIG. 10, (b) of FIG. 10 shows the EPA low dose group. Figure 11 is a graph comparing the collagenous fiber area in the control group and EPA low dose group. As shown in FIGS. 10 and 11, the collagen fibers of EPA low dose group compared with the control group was significantly greater. From this result, even when administered at the 30 mg / kg body weight / day EPA, the degradation of collagen fibers is suppressed was suggested.

Test Example 8: Effect on elastic fibers of abdominal aortic aneurysms in EPA low dose group]
For EPA low dose group were pathological evaluation similarly elastic fibers as in Test Example 5. Figure 12 is a graph showing the results of EVG staining tissue sections in the control group and EPA low dose group, (a) shows the control group of FIG. 12, (b) of FIG. 12 shows the EPA low dose group. Evaluation of the elastic plate grade, in the control group to 4 was a (disappearance of the elastic plate), the EPA low dose group were 3 (partial loss of elastic plate). These results, also when administered at the 30 mg / kg body weight / day EPA, suggesting that there is a tendency that degradation of the elastic fibers is suppressed.

[Test Example 9]
To evaluate the effect of the administration of EPA to aortic aneurysm formation early, the following test was conducted.
The model animal, was used a 6-week-old male SD rats. After preliminary breeding of 12 days, a catheter was inserted into the rat abdominal aorta for creation of aortic aneurysm model animals were treated ligating abdominal aorta with inserted catheter. Treatment one day after striking the aortic aneurysm formation initial stage, the control group 1145Mg / kg body weight / triolein day, the EPA treated group 1145Mg / kg body weight / EPA rich refined fish day (EPA amount as 300 mg / kg forcibly orally body weight) and continued up to 4 weeks. Laparotomy individuals who died during the administration period, to evaluate the presence or absence of the rupture with the onset of abdominal aortic aneurysm.

As a result, 10 out of 5 mice in the control group died by ruptured abdominal aortic aneurysm, one out of 8 animals in the EPA dose group died by rupture of abdominal aortic aneurysm. Figure 13 is a diagram showing the mortality ruptured abdominal aortic aneurysm in the control group and EPA treated group. As shown in FIG. 13, the mortality rate due to abdominal aortic aneurysm in the control group and the EPA-administered group was 50% and 12.5%. This result, EPA, when administered in the abdominal aortic aneurysm formation initial stage, suppressing rupture of aneurysm, it became clear that to reduce the mortality rate due to abdominal aortic aneurysm.

The present invention is, preventing the aortic aneurysm, it can be suitably used for such as medicines and food or drink for improving or treating.

Claims (4)

  1. Eicosapentaenoic acid as an active ingredient, aortic aneurysm prophylactic or therapeutic agent.
  2. The eicosapentaenoic acid is contained as a seafood extract, prophylactic or therapeutic agent for aortic aneurysm according to claim 1.
  3. Further comprising docosahexaenoic acid, prophylactic or therapeutic agent for aortic aneurysm according to claim 1 or 2.
  4. Packaged food or drink containing the agent for preventing or treating aortic aneurysm according to any one of claims 1-3.

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Citations (2)

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WO2006053184A2 (en) * 2004-11-10 2006-05-18 The Trustees Of Columbia University In The City Of New York Methods for treating or preventing a vascular disease
WO2010127099A2 (en) * 2009-04-29 2010-11-04 Amarin Corporation Plc Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
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