JPH11246398A - Prophylactic or therapeutic agent for disorder caused by increment of lipoperoxide in vivo - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent useful for treating diseases caused by the increase of a lipoperoxide in vivo such as nephropathia by including a specified curcumin derivative and/or a specified tetrahydro curcumin derivative. SOLUTION: This prophylactic or therapeutic agent is obtained by including a curcumin derivative of formula I (R<1> to R<4> are each H, hydroxy or a lower alkoxy) [e.g. diferuloylmethane or (E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dionel and/or a tetrahydro curcumin derivative of formula II as active ingredient(s) and preferably furthermore a support (e.g. a diluent, a vehicle). The daily dose of the curcumin and/or tetrahydro curcumin is preferably 1 mg to 2 g per kg-body weight. The compounding ratio (by weight) of the active ingredient(s) is preferably 1-99.0% based on 100% whole compositions of the preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for preventing or treating a disease caused by an increase in lipid peroxide in a living body. The present invention also relates to beverages or foods and animal feeds for suppressing an increase in lipid peroxide in vivo.

[0002]

2. Description of the Related Art Peroxidation of cell membrane lipids induced by active oxygen in a living body induces oxidative damage in the living body and is considered to be a cause of various diseases. Diseases caused by an increase in lipid peroxide in the living body include, for example, renal disorders. Renal damage is considered as one of the diseases caused by peroxidation of cell membrane lipids. Renal diseases such as nephrosis, glomerulonephritis, glomerulosclerosis, and diabetic nephropathy are lesions in which vascular endothelial cells and pericytes of the renal glomerulus are impaired, resulting in failure of renal function. As these treatments, drug treatments such as steroids, antiplatelet agents, and anticoagulants are performed. However, no safe and highly effective drug has been found. Also, in diabetic nephropathy, there is no active treatment other than blood sugar and blood pressure control, and even if strict blood sugar control is performed, the progress of renal damage cannot often be sufficiently suppressed. Since renal disease is a chronic progressing disease, the treatment is also performed for a long period of time. Therefore, development of an effective method for preventing and treating renal disorder is desired.

[0003]

An object of the present invention is to provide an agent for preventing or treating a disease caused by an increase in lipid peroxide in a living body. Another object of the present invention is to provide a beverage or food and an animal feed for suppressing an increase in lipid peroxide in a living body.

[0004]

Means for Solving the Problems The present inventors have studied the protective effect on renal function when various substances are given orally and intraperitoneally by using an animal model that reflects the onset and progress of renal damage. As a result of intensive studies, the curcumin derivative represented by the following formula (I) and the tetrahydrocurcumin derivative represented by the following formula (II) have been found to have an excellent inhibitory effect on the increase of lipid peroxide in vivo, thereby completing the present invention. Reached. Accordingly, the present invention provides a compound of formula (I)

[0005]

Embedded image

Wherein R ¹ , R ² , R ³ and R ⁴ are
Curcumin derivatives represented by the same or different hydrogen, hydroxy or lower alkoxy) (hereinafter simply referred to as curcumins);

[0007]

Embedded image

Wherein R ¹ , R ² , R ³ and R ⁴ are
Prevention of a disease caused by increased lipid peroxide in vivo, which contains, as an active ingredient, a tetrahydrocurcumin derivative represented by the same or different hydrogen, hydroxy or lower alkoxy) (hereinafter simply referred to as tetrahydrocurcumins) or both. Or provide a therapeutic agent. The present invention also provides a food additive for suppressing an increase in lipid peroxides in a living body, comprising a tetrahydrocurcumin derivative as defined above as an active ingredient.

[0009] The present invention further provides a beverage or food for suppressing an increase in lipid peroxide in a living body, comprising a tetrahydrocurcumin derivative as defined above as an active ingredient.
The present invention also provides an animal feed for suppressing an increase in lipid peroxides in a living body, comprising the above-defined tetrahydrocurcumin derivative as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In formulas (I) and (II), the alkyl portion of lower alkoxy of R ¹ , R ² , R ³ and R ⁴ is a straight-chain or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. As specific alkoxy, methoxy and ethoxy having 1 to 2 carbon atoms are preferable. In the formula (I), a compound in which R ² and R ⁴ are hydroxy is preferable.

The curcumins include, for example, U1 [diferuloylmethane, (E, E) -1,7-
Bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione, sometimes simply referred to as curcumin], U2 [demethoxycurcumi
n), bis (4-hydroxy-3-methoxycinnamoyl) methane], U3 [bisdemethoxycurcumin
curcumin), bis (4-hydroxycinnamoyl) methane], DMU1 [(E, E) -1,7-bis (3,4-dimethoxyphenyl) -1,6-heptadiene-3,5-dione], DHU1 [(E,
E) -1,7-bis (3,4-dihydroxyphenyl) -1,6-heptadiene-3,5-dione], U1, U2, U3
And DHU1 are preferably used, and U1 and DHU
1 is particularly preferably used.

Examples of the tetrahydrocurcumins include tetrahydrocurcumins obtained by reducing the above curcumins, and THU1 obtained by reducing U1.
(Hereinafter sometimes simply referred to as tetrahydrocurcumin) is preferred. These curcumins and tetrahydrocurcumins are known substances. Curcumins,
Tropical ginger turmeric ( Curcuma longa L.)
, A dry pigment of turmeric rhizome and curcumin purified therefrom are commercially available. Tetrahydrocurcumin is an extremely safe substance that is known to be produced in vivo when curcumin contained in a large amount in curry or the like is ingested.

There are no particular restrictions on the raw material or method for producing the tetrahydrocurcumins, which are the active ingredients in the present invention, but for example, biochemical pharmacology (Bioc).
Chemical Pharmacology) 52 , 519 (1996), and can be obtained by reducing curcumins by a hydrogenation method using a metal catalyst. Further, tetrahydrocurcumins can also be obtained by converting curcumins into tetrahydrocurcumins using microorganisms.

The agent for preventing or treating diseases caused by increased lipid peroxide in vivo according to the present invention may be in any dosage form as long as it contains a substantially effective amount of curcumins and / or tetrahydrocurcumins. . Such prophylactic or therapeutic agents include veterinary medicines, marine medicines, and the like. Diseases caused by increased lipid peroxide in vivo include, for example, renal disorder, and examples of the renal disorder include nephrosis, glomerulonephritis, glomerulosclerosis, diabetic nephropathy, and the like, but are not limited thereto.

When used as pharmaceuticals, curcumins and / or tetrahydrocurcumins are used alone or in the form of various preparations together with carriers such as diluents and excipients and other additives. Dosage forms include oral preparations,
For example, in addition to capsules, pills, granules, emulsions, powders, troches, syrups, and the like, parenteral dosage forms such as infusions or injectable preparations can be given, and further, if necessary, preservatives, binders, Substances used in normal pharmaceutical production, such as flavoring agents and stabilizers, can be added.

The prophylactic or therapeutic agent of the present invention is orally or parenterally administered to a human or animal in need thereof at a predetermined dose in a single dose or in a plurality of doses, or continuously. The daily dose of curcumins and / or tetrahydrocurcumins is appropriately adjusted depending on the age, sex, and symptoms of a human or animal, but is preferably 0.1 mg to 5 g per kg of human or animal body weight.
Preferably, the dose is 0.4 mg to 4 g, more preferably 1 mg to 2 g. In addition, the compounding amount when the total composition of the preparation is 100%
(Weight ratio) is 0.01% to 100%, preferably 0.1% to 99.9%,
It is more preferably 1% to 99.0%. In addition, curcumin and / or tetrahydrocurcumin may be added to an existing drug used for the prevention and / or treatment of a disease caused by an increase in lipid peroxide in a living body or a drug intended for a different disease, so that the in vivo disease may be reduced. It is also possible to enhance the effect of preventing and / or treating a disease caused by an increase in oxidized lipid, or to newly impart the effect.

When used as a food, beverage or feed, any form may be used as long as it contains a tetrahydrocurcumin and is intended to suppress an increase in lipid peroxide in a living body. Examples of the food include a solid food, a semi-liquid food, and a gel food.
Examples of the beverage include a soft drink and an alcoholic beverage. The feed may be in either powder or solid form. The drink or food is not particularly limited, but examples include chocolate, gum, yogurt, soft drink, coffee, tea, alcoholic drink, biscuit, jelly, and the like. In the case of blending, tetrahydrocurcumins are blended in a weight ratio of 0.001% to 10.0%, more preferably 0.1% to 5.0%.

The beverage, food or feed of the present invention can be orally administered to humans or animals in need thereof in a predetermined amount orally in single or multiple doses. In this case, the daily dose of the tetrahydrocurcumins is appropriately adjusted depending on the age, sex, and symptoms of the human or animal.
The dose is 0.1 mg to 5 g, preferably 0.4 mg to 4 g, more preferably 1 mg to 2 g per g.

In the production of beverages or foods, various substances can be added as required. For example, sugars such as sucrose, fructose and glucose, sugar alcohols such as xylitol, amino acids, organic acids such as citric acid, lactic acid, malic acid and ascorbic acid, tocopherols, flavonoids, antioxidants such as catechin, gelatin, vitamins Any substance used in the normal production of foods, such as foods, pigments, fragrances, calcium agents, glycerin fatty acid esters, pectin, etc., can be appropriately compounded.

As the beverage or food, a fermented beverage or a fermented product utilizing a microorganism having an activity of converting curcumin into tetrahydrocurcumin can also be used. Animal feed includes, for example, fish feed, livestock feed, and the like. In the production of animal feed, curcumins and / or tetrahydrocurcumins are added to a composition usually used for animal feed in a weight ratio of 0.001% to 10.0%, more preferably 0.1% to 5.0%. It can be manufactured by blending with. At this time, various substances can be added according to the form and purpose of the feed. For example, sugars such as sucrose, fructose and glucose, sugar alcohols such as xylitol, amino acids, organic acids such as citric acid, lactic acid, malic acid and ascorbic acid, tocopherols, flavonoids, antioxidants such as catechin, gelatin, vitamins Ingredients that can be added to foods and animal feeds, such as foods, animal feeds, and the like, can be used as appropriate. When tetrahydrocurcumin is added to the feed, a purified product can be used. For example, a microorganism containing tetrahydrocurcumin or a processed product thereof can be mixed with the feed.

The following are test examples showing the effect of curcumin or tetrahydrocurcumin on the prevention and / or treatment of diseases caused by an increase in lipid peroxides in vivo, and the prophylactic or therapeutic agent, food, beverage and animal feed of the present invention. The present invention will be described more specifically with reference to examples showing formulation examples, but the present invention is not limited by these specific examples.

[0022]

EXAMPLES Test Example 1: Curcumin or tetrahydroc
Therapeutic effect of lucumin on renal disorders 4-6 mice in each group were 7.5 m / kg body weight in 6 week old ddy male mice
g of iron nitrilotriacetic acid (hereinafter abbreviated as Fe-NTA) was intraperitoneally administered to induce renal damage. 30 minutes later, weight 1kg
1.5 g of curcumin (U1) or tetrahydrocurcumin (THU1) was administered intraperitoneally. After a further 2.5 hours, the mice were dissected and the collected kidneys were homogenized in 50 mM phosphate buffer, pH 7.4. Thiobarbituric acid-reactive substance (hereinafter referred to as T
BARS). As a control, TBARS in kidney tissues without administration of Fe-NTA was measured. That is, a 0.3 ml sample prepared from the kidney was taken in a test tube, 3 ml of a 20% aqueous solution of trichloroacetic acid and 1 ml of an aqueous solution of 0.67% 2-thiobarbituric acid were added, and then placed in boiling water for 10 minutes, and immediately cooled with ice. Thereafter, extraction was performed with 4 ml of n-butanol, and the absorbance of the butanol layer at 532 nm was measured. Also, 165 μl
Take 1,1,3,3-tetramethoxypropane and add 1N hydrochloric acid 8
35 μl was added and dissolved. After leaving this at room temperature for 1 hour, this stock solution was diluted 10-fold with 1N hydrochloric acid to obtain a 100 mM standard solution. To prepare a calibration curve, this standard solution was appropriately diluted and allowed to undergo the same reaction as a kidney sample.The relationship between the concentration and the absorbance (532 nm) was plotted. TBARS value was determined. Table 1 shows the results.
Shown in

[0023]

[Table 1]

As shown in Table 1, the increase in TBARS value, which indicates the degree of renal damage caused by Fe-NTA, was significantly suppressed by the administration of curcumin and tetrahydrocurcumin, and was used as a therapeutic agent for diseases caused by increased lipid peroxide in vivo. It can be said that Test Example 2: Curcumin or tetrahydrocurcumin
Preventive action on renal damage Curcumin (U1) was administered to 4 to 6 6-week-old ddy male mice in each group
Alternatively, after freely taking a diet containing 0.5% tetrahydrocurcumin (THU1) for one month, 7.5 mg / kg body weight
Fe-NTA was administered intraperitoneally to induce renal damage. One hour later, the mouse was dissected, and a sample obtained by homogenizing the collected kidney in 50 mM phosphate buffer (pH 7.4) was used for TBARS and 8-hydroxydeoxyguanosine (hereinafter referred to as 8-OH) produced as a result of tissue oxidative damage. -dG) was measured using an ELISA method. Specifically, the sample or standard 8-OH-dG was immobilized on a microplate on which 8-OH-dG was immobilized.
50 μl of the G solution was dispensed into three separate wells. Dispense 50 μl of anti-8-OH-dG monoclonal antibody into each well,
For 1 hour, and then washed with a phosphate buffer. 100 μl of a horseradish peroxidase-labeled anti-mouse immunoglobulin G antibody solution was dispensed, and incubated at 37 ° C. for 1 hour. Further, the wells were washed with a phosphate buffer, reacted with 100 μl of a color developing solution for detecting peroxidase for 30 minutes, and then stopped with 100 μl of 2N sulfuric acid. The absorbance of this reaction solution at 492 nm was measured, and the amount of 8-OH-dG in the sample was determined by comparison with a standard curve prepared using standard 8-OH-dG. The kit for quantifying 8-OH-dG by the above ELISA method is commercially available from the Japan Institute of Aging Control. The result
The results are shown in Tables 2 and 3.

[0025]

[Table 2]

[0026]

[Table 3]

As shown in Tables 2 and 3, increases in both TBARS value and 8-OH-dG value, which indicate the degree of renal damage caused by Fe-NTA, were significantly suppressed in mice receiving tetrahydrocurcumin. Therefore, it can be said that it can be a preventive agent for diseases caused by increased lipid peroxide in vivo. Next, production examples of various pharmaceuticals, beverages, foods, and animal feeds will be described, but these specific examples do not limit the present invention. Example 1: Tablet containing tetrahydrocurcumin After mixing the components according to the following composition, the mixture was tableted with a tableting machine to produce a tablet having a diameter of 8 mm and a weight of 200 mg.

[0028]

[Table 4]

Example 2 Including Tetrahydrocurcumin
Granules having the tablet prepared in Example 1 are crushed, sieved and
Granules of 顆粒 50 mesh were produced. Example 3: Capse containing tetrahydrocurcumin
After mixing the ingredients in accordance with Le agent of the following composition, encapsulated in a gelatin capsule to prepare a capsule.

[0030]

[Table 5]

Example 4 Including Tetrahydrocurcumin
Chocolate having Chocolate was produced according to the following composition. The blended tetrahydrocurcumin had no effect on the color, flavor or taste of the chocolate.

[0032]

[Table 6]

Example 5: Including tetrahydrocurcumin
Gum having A gum was produced according to the following composition. The blended tetrahydrocurcumin did not affect the gum color, flavor, or taste.

[0034]

[Table 7]

Example 6: Including tetrahydrocurcumin
Candy having candy was prepared according to the following composition. The blended tetrahydrocurcumin had no effect on the color, flavor or taste of the candy.

[0036]

[Table 8]

Example 7: Including tetrahydrocurcumin
Beverage having A beverage was produced according to the following composition. The blended tetrahydrocurcumin did not affect the color, flavor, or taste of the beverage.

[0038]

[Table 9]

Example 8: Including tetrahydrocurcumin
Animal feed having Dog food was produced according to the following composition. The blended tetrahydrocurcumin did not affect the color, flavor or taste of the dog food.

[0040]

[Table 10]

[0041]

According to the present invention, it has been found that curcumins or tetrahydrocurcumins have an effect of suppressing an increase in lipid peroxide in a living body, whereby curcumin or tetrahydrocurcumin has a renal effect caused by an increase in lipid peroxide in a living body. It has become possible to use it as an active ingredient in food additives, foods, beverages and animal feeds for preventing and / or treating diseases such as disorders and for suppressing an increase in lipid peroxide in vivo.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A23L 2/38 A23L 2/38 C (72) Inventor Chantimer Wampunt Lagoon 2-37 Ikatsucho, Showa-ku, Nagoya-shi, Aichi

Claims (8)

[Claims] 1. A compound of the formula (I) Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and represent hydrogen, hydroxy or lower alkoxy, a curcumin derivative represented by the formula (II): (Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above),
Or a preventive or therapeutic agent for a disease caused by an increase in lipid lipids in a living body, comprising an active ingredient or both. 2. The preventive or therapeutic agent according to claim 1, wherein the disease is a renal disorder. 3. The preventive or therapeutic agent according to claim 1, further comprising a carrier. 4. A food additive for suppressing an increase in lipid peroxides in a living body, comprising the tetrahydrocurcumin derivative defined in claim 1 as an active ingredient. 5. A beverage or food for suppressing an increase in lipid peroxide in a living body, comprising the tetrahydrocurcumin derivative defined in claim 1 as an active ingredient. 6. The food according to claim 5, wherein the food is chocolate, gum or candy. 7. An animal feed for suppressing an increase in lipid peroxide in a living body, comprising the tetrahydrocurcumin derivative defined in claim 1 as an active ingredient. 8. The feed according to claim 7, wherein the animal is a domestic animal or a farmed fish.