JPH08268885A - Suppressing agent for increase of peroxylipid - Google Patents

Abstract

PURPOSE: To obtain a new agent having an anti-oxidation effect and capable of suppressing the increase of peroxylipids in a living body. CONSTITUTION: This suppressing agent for the increase of peroxylipids contains at least one kind of material selected from 3,5-diprenyl-4-hydroxy cinnamic acid and its salts as active ingredients. Since 3,5-diprenyl-4-hydroxy cinnamic acid and its salts are active ingredients of the suppressing agent for the increase of peroxylipids and have an anti-oxidation effect, and have a potent suppressing effect on the increase of peroxylipids in a living body and also an extremely low toxicity, it is useful for the treatment and prevention of aging, and ischemic cardiopathy, arteriosclerosis, ischemic cerebropathy, hepatitis, cataract, etc., in which the peroxidation of lipids by various factors such as an activated oxygen, are considered to be one of the factors causing the diseases.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel lipid peroxide increase inhibitor having an antioxidant effect.

[0002]

2. Description of the Related Art It is well known that lipid peroxidation occurs in vivo due to various factors such as active oxygen. In addition, it has been reported in recent years that the increased amount of lipid peroxide in vivo is deeply involved in various diseases such as ischemic heart disease, arteriosclerosis, ischemic encephalopathy, hepatitis, cataract and aging. Therefore, in order to prevent or treat the above-mentioned diseases and prevent aging, studies on drugs that suppress the production and increase of lipid peroxide have been earnestly attempted, but any of the drugs that have been reported up to now has a manufacturing method. It was difficult, and the stability and action were not sufficient in an experimental system using a living body. Here, 3,5-diprenyl-4-hydroxycinnamic acid to which the present invention relates is a substance known per se,
The pharmacological action of this compound is to promote bile secretion ["Che
m. Pharm.Bull. ", Vol 36, No. 2, pages 769-775 (1
988) and JP-A-60-163841], antibacterial action [Biosc
i. Biotechnol. Biochem. ", Vol 58, No. 5, pages 945
-946 (1994)] and hair growth promoting / hair-growth action (Japanese Patent Laid-Open No. 6-3
No. 12918 gazette) is known, but it is not known that it has an antioxidant action and a lipid peroxide production or increase inhibitory action.

[0003]

Problems to be Solved by the Invention [Problems to be Solved by the Invention] A substance which has an antioxidant effect and which strongly suppresses the production and increase of lipid peroxide in vivo is a preventive and therapeutic treatment for the above-mentioned various diseases and a prophylactic treatment of aging. It is considered to be extremely effective against. Therefore, the object or object of the present invention is to suppress the increase in lipid peroxides, which uses as an active ingredient a substance that exerts an antioxidant effect in vivo and strongly suppresses the increase in lipid peroxides and has safety for living bodies. To provide the agent.

[0004]

[Means and Actions for Solving the Problem and Achieving the Object] The inventors of the present invention have conducted various searches for various compounds in order to solve the above-mentioned problems, and as a result, repeated investigations have revealed that
3,5-diprenyl-4-hydroxycinnamic acid and its salts have a new pharmacological action, that is, as described above, strongly suppress the increase of lipid peroxide in vivo. The present invention has been completed by finding out the above and confirming that these substances have low toxicity.

[0005]

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Therefore, the lipid peroxide increase inhibitor according to the present invention is characterized by containing at least one substance selected from 3,5-diprenyl-4-hydroxycinnamic acid and salts thereof as an active ingredient. I am trying.

3,5-diprenyl-4-hydroxycinnamic acid, which is an active ingredient of the lipid peroxide increase inhibitor according to the present invention, is
Also known as epillin C, it is the first compound isolated from a plant of the genus Astereae baccharis ["Phytochemistr
y ", Vol. 20, pages 281-286 (1981)], a reddish resin that is a material used to strengthen honeycombs and is a mixture of components collected from flower buds and bark and bee saliva. It is also found in propolis, which is a solid substance and is also called "bee wax" or "bee crocodile"["Biosc
i. Biotechnol. Biochem. ", Vol. 58, No. 5, pages 94
5-946 (1994)]. As a method of synthesizing this compound, a method of reacting 4-hydroxycinnamic acid and prenyl bromide in an alkaline aqueous solution has been reported.
(JP-A-60-163841).

Examples of the salt of the above-mentioned compound used in the agent for increasing the amount of lipid peroxide according to the present invention include salts with alkali metal compounds (sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal compounds (calcium hydroxide, Examples thereof include pharmaceutically acceptable salts such as salts with magnesium hydroxide), ammonium salts, salts with organic bases (triethylamine, triethanolamine, dibenzylamine, α-phenethylamine, etc.).

The formulation can be carried out by a conventional method, and the dosage form in this case is not particularly limited, and auxiliary agents such as bases, excipients and additives can be added. Depending on the type, it is made into injections, powders, granules, tablets, capsules, syrups, ointments and the like. The dose depends on various factors such as the purpose of administration (prevention or treatment), dosage form, administration route, type and degree of disease, age and weight of patient, etc., but the amount of the compound or salt as the active ingredient per day 0.1-20
About mg / kg is appropriate.

[0010]

EXAMPLES Next, the present invention will be described in more detail and specifically with reference to pharmacological test examples and formulation examples. Pharmacological test example 1 (Inhibition of lipid peroxidation of low-density lipoprotein) Low-density lipoprotein was isolated from serum of white rabbits with hypercholesterolemia caused by intake of high-cholesterol diet, and 0.15 M KCl and 1 μM ethylenediamine tetrachloride were isolated. Acetic acid (EDTA)
10 mM Tris-HCl buffer (pH 7.4) containing and
Low density lipoprotein solution prepared by adding
(Containing 1 mg / ml as protein) 0.95 ml contained 3,5-diprenyl-4-hydroxycinnamic acid (hereinafter referred to as "DPHC") as a test substance.
Abbreviated as `` A '') or a comparative substance known butylhydroxytoluene (hereinafter abbreviated as `` BHT '') was added to dimethylsulfoxide (DMSO) so as to have a concentration of 0.5-1.5 mM. ml and then added to these analyte solutions with an aqueous solution of cupric sulfate (CuSO ₄ ) (5
(00 mM) was added in an amount of 0.01 ml (5 nmol) and incubated at 30 ° C. for 2 hours, and the amount of lipid peroxide produced was measured by the thiobarbituric acid method. The same volume of DMSO as the sample solution was added and treated in the same manner as a control. The results are shown in Table 1 below, and it was found that DPHCA has a much higher inhibitory effect on lipid peroxide increase than BHT, which is a known antioxidant.

[0011]

[Table 1]

Pharmacological Test Example 2 (Inhibition of Lipid Peroxidation of Egg Yolk Lecithin Liposomes) Egg yolk lecithin (50 mg) was dissolved in 10 ml of chloroform and placed in a 100 ml pear-shaped flask, which was then concentrated to dryness under reduced pressure. Create a lipid thin film on the inner wall, add 20 ml of 0.1 M NaCl to this, stir for 1 minute with a vortex mixer, and further sonicate under an argon gas stream to form liposomes (lipid:
3 mg) was prepared. The liposome is a test substance
Liposome suspension obtained by adding sample solutions of various concentrations in which DPHCA or the comparative substance BHT was dissolved in 0.05 ml of dimethyl sulfoxide (DMSO) 2.
Place 95 ml (in 0.1M NaCl) in the cell of the oxygen electrode and incubate at 37 ℃.
After equilibration to 0.05 ml of 600 mM 2,2'-azobis
An oxygen consumption rate was measured by adding an aqueous solution of (2-amidinopropane) 2 hydrochloric acid. The results are shown in Table 2 below, and the 50% oxygen consumption inhibition rate (IC ₅₀ ) of DPHCA is
BHT is 1.0 μM compared to 0.7 μM, and the lipid peroxidation inhibitory effect on liposomes is higher than that of BHT by DPHC.
A turned out to be more powerful.

[0013]

[Table 2]

Pharmacological test example 3 (acute toxicity test) DPHCA was orally administered to ddy mice in an amount up to 1.0 g / kg, and general symptoms were observed. However, no change in behavior was observed and death cases were also observed. There wasn't. Therefore, it can be said that the toxicity of DPHCA is extremely low.

Formulation Example 1 (Injection for Skin) An injection for skin was prepared by a conventional method by mixing the following components.

Formulation Example 2 (Tablets) The following ingredients were blended to prepare tablets according to a conventional method.

Formulation Example 2 (Soft Capsule) The following ingredients were mixed to prepare a soft capsule by a conventional method. Ingredients Blend amount DPHCA 10 (mg) olive oil 105 Lecithin 5 120 mg / capsule

[0018]

[Effects of the Invention] 3,5-diprenyl-4-hydroxycinnamic acid and its salts, which are the active ingredients of the lipid peroxide increase inhibitor according to the present invention, have an antioxidative effect and potently increase the amount of lipid peroxide in vivo. It has an inhibitory effect on erythrocyte and has extremely low toxicity. Therefore, ischemic heart disease, arteriosclerosis, and ischemic brain are considered to be one of the causes of lipid peroxidation due to various factors such as active oxygen. It is effective in the prevention and treatment of disorders such as disorders, hepatitis, and cataracts, as well as the prevention of aging.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiko Oishi 1-17 Tenjin-cho, Inuyama-shi, Aichi Shirohigashi Mansion No. 305

Claims (1)

[Claims] 1. An agent for increasing lipid peroxides, which comprises at least one substance selected from 3,5-diprenyl-4-hydroxycinnamic acid and salts thereof as an active ingredient.