JP2835066B2 - Inhibitor of increase in lipid peroxide in vivo - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel lipid peroxide inhibitor in vivo.

(Prior art) Lipid peroxide ischemic heart disease, arteriosclerosis, retinopathy of prematurity, iron rust, cataract, hepatitis, pancreatic salt, diabetic vascular disorder,
It is known that it causes various diseases such as melanosis, melasma, and preeclampsia and aging.

The present inventors have already found that the female hormone estrone,
Estradiol and estriol have been shown to exhibit antioxidant potential in in vitro reactions [Yagi, K. and Komur
a, S. “Biochemistry International”, Vol.13, page 1051
-1055 (1986)].

(Problems to be Solved by the Invention) However, since the above-mentioned estrone, estradiol and estriol naturally have a female hormone action, it is difficult to apply them to the treatment and prevention of the above-mentioned diseases. Had a problem.

(Object of the Invention) Accordingly, an object of the present invention is to provide an inhibitor for increasing the amount of lipid peroxide in a living body which is highly effective and excellent in use safety.

(Means and Actions for Solving the Problems and Achieving the Object) The present inventors have focused on catechol estrogens, which are metabolites of estrogens, and as a result of intensive studies on their effects, have found that catechol estrogens are more effective than female hormones themselves. The inventors have found that the present invention exhibits a strong inhibitory action on the increase in lipid peroxide in vivo and that it does not show any side effect as a female hormone at an effective concentration relating to the inhibitory action on the increase in lipid peroxide, thereby completing the present invention.

Accordingly, the gist of the present invention is a lipid peroxidation inhibitor in a living body, which comprises catechol estrogen as an active ingredient.

Catechol estrogen, which is an active ingredient of the lipid peroxide inhibitor in vivo according to the present invention, is a compound known per se having the following structural formula.

Wherein R ₁ represents —OH, R ₂ represents —H or —C≡CH, or R ₂ together with R ₁ represents = 0, and R ₃ represents —H or As a catechol estrogen represented by the above general formula and usable as an active ingredient of the agent according to the present invention,
Specifically, 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 2
Examples thereof include -hydroxyethynyl estradiol and 2-hydroxyethynyl estriol, which can be used alone or as a mixture of two or more.

As these catechol estrogens, commercially available ones can be used, but if necessary, known methods [“Journal”
nal of Organic Chemistry ", Vol. 25, pages 585-588 (19
60) etc.].

Lipid peroxide bulking inhibitor according to the present invention, if necessary, the required other and already known lipid peroxide lowering agent such as vitamin B ₂ and its derivatives, tocopherols, ascorbic acid, and formulated with glutathione It can be formulated by mixing with bases, additives, excipients, stabilizers and the like.

The inhibitor for increasing the amount of lipid peroxide in vivo according to the present invention can be in any dosage form, and can be orally administered, for example, in the form of powders, granules, tablets, capsules, syrups and the like. It can also be administered as parenteral preparations such as injections and ointments.

The dosage of the agent according to the present invention varies depending on the type of catechol estrogen as an active ingredient, the administration route or dosage form, the type and degree of disease, etc.
/ kg range.

(Examples, etc.) Next, the present invention will be described further and specifically with reference to pharmacological test examples and preparation examples.

Pharmacological Test Example 1 (Inhibition of increase in lipid peroxide in vivo due to irradiation) 1% BALB / c male mouse (10 weeks old) as an experimental animal
Catechol estrogens suspended in carboxymethyl cellulose (hereinafter, "catechol estrogens"
0.5 to 1) (using 2-hydroxyestradiol)
After subcutaneous administration to the back at a dose of mg / kg, γ-ray [1000 rad (
⁶⁰ Co)] was applied to the whole body. Three hours after irradiation, the same dose of catechol estrogen was administered again in the same manner.

On the other hand, the mice of the control group were similarly administered with the same amount of a solvent containing no catechol estrogen.

Four days after irradiation, serum and liver lipid peroxide levels were determined by the thiobarbituric acid method [Yagi, K. “Biochemical M.
edicine ", Vol. 15, page 212-216 (1976)]. The results are shown in Table 1 below.

From the results shown in this table, the irradiation group (test group)
Lipid peroxide levels in both serum and liver of mice were clearly higher than those in the non-irradiated group, which was a control, but administration of catechol estrogen was found to significantly suppress the increase in lipid peroxide. .

Pharmacological Test Example 2 (Effect on the Survival Rate of Irradiated Mice) BALB / c male mice (10 weeks old) were used as experimental animals at 1%
Catechol estrogens suspended in carboxymethyl cellulose (hereinafter referred to as “catechol estrogens”
2 mg / kg of 80-hydroxyestradiol)
It was subcutaneously administered twice before and after irradiation with 0 rad of γ-ray. Control mice were similarly administered the same amount of solvent but without catechol estrogens. The survival rates of both groups of mice after irradiation were as shown in FIG.

As is clear from FIG. 1, the survival rate of the control group mice on day 30 after irradiation was only 20%, whereas the survival rate of the test group, the catechol estrogen administration group mice, was 80%. There was a significant difference between the two groups, demonstrating that catechol estrogens were effective in preventing radiation damage.

Pharmacological Pharmacological Test Example 3 (Suppressive Effect on Increase of Lipid Peroxide in Female Mice Caused by Ovariectomy) Bilateral ovaries of ddY female mice (12 weeks old) were excised, and the ovariectomized mice were divided into two groups, and a test group was obtained. Was administered subcutaneously at 0.2 mg / kg catechol estrogen (hereinafter referred to as "catechol estrogen" using 2-hydroxyestradiol) three times a week for 4 weeks from the 4th week after the extraction. On the other hand, the control group was similarly administered with the same amount of a solvent containing no catechol estrogen. Eight weeks after the ovaries were removed, that is, four weeks after the start of administration, the levels of lipid peroxide in the serum and liver of both groups of mice were measured. In addition, the lipid peroxide level was measured in the same manner for non-ovarian unexcited group mice of the same age (sham-operated). The results were as shown in Table 2 below.

From the results shown in this table, it is found that the serum and liver lipid peroxide levels of female mice 8 weeks after bilateral ovariectomy are significantly higher than those of non-excised group mice, and that the administration of catechol estrogens results in lipid peroxide. It has been found that the level can be kept low.

Pharmacological Pharmacology Test Example 4 (Effect on Serum Lipid Peroxide of Senescence Acceleration Model Mice) Senescence acceleration model mice (using SAM-P / 1 mice) have a short lifespan, loss of coat gloss, coarse hair, hair loss, It presents characteristic aging findings such as skin ulcers, inflammation around the eyelids, spinal curvature or decreased activity and learning ability. Furthermore, the onset of cataract and aging amyloidosis is also known.

Using this SAM-P / 1 male mouse (8 months old) as an experimental animal, catechol estrogen suspended in 1% carboxymethylcellulose (hereinafter, 2-hydroxyestradiol was used as "catechol estrogen")
Was administered subcutaneously to the back at a dose of 5 mg / kg daily for 3 days.
The day after the last administration, serum lipid peroxide levels were measured. Serum lipid peroxide levels of each mouse before and after administration of catechol estrogen were as shown in FIG.

The value before administration (mean ± standard error) is 6.78 ± 0.83 nm.
ol / ml, whereas the value after administration was 4.04 ± 0.29 nmo
l / ml, and the administration of catechol estrogens significantly (p <
0.05).

Formulation Example 1 (Injection for topical application) The following components were blended to prepare an injection for topical application according to a standard method.

Catechol estrogen (2-hydroxyestradiol) 3 mg Propylene glycol 0.4 ml Sodium chloride 5 mg 1 ml per vial of the remaining purified water Formulation Example 2 (tablets) The following components were blended to prepare tablets by a standard method.

Catechol estrogen (2-hydroxyestradiol) 10 mg Crystalline cellulose 60 mg Lactose 75 mg Corn starch 45 mg Magnesium stearate 10 mg 200 mg per tablet Formulation Example 3 (Ointment) The following components were blended to prepare an ointment according to a standard method.

Catechol estrogen (2-hydroxystradiol) 0.5 mg Stearic acid 80 mg Cetyl alcohol 25 mg Paraffin 25 mg Sperm wax 30 mg Liquid paraffin 50 mg Isopropyl myristate 50 mg Polyoxyethylene cetyl ether 20 mg Glycerin monostearate 10 mg Methyl paraben 1 mg Butylparaben 1 mg Propylene glycol 70 mg Purified water balance 1.0 g (Effect of the invention) Catechol estrogen suppresses abnormal increase in lipid peroxide in the body during pathological conditions, and increases the level of lipid peroxide during aging. And thus prevent tissue damage from lipid peroxides.

Therefore, the in vivo lipid peroxide increase inhibitor according to the present invention comprising catechol estrogen as an active ingredient can be used for the following purposes, for example.

(1) Prevention and treatment of radiation injury, (2) Prevention and treatment of arteriosclerosis and menopause (It is known that the incidence of arteriosclerosis is higher in postmenopausal women than in premenopausal women. In recent years, it has been clarified that lipid peroxide is involved in the onset and progression of arteriosclerosis), (3) Prevention of aging.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of examining the survival rate by irradiating γ-rays to a test group mouse to which catechol estrogen was administered and a control group mouse to which no catechol estrogen was administered. FIG. 2 is a graph showing catechol estrogen to aging promotion model mice. It is a graph which shows the result of having investigated the lipid peroxide level in serum before and after administration.

Claims (2)

(57) [Claims] 1. An agent for suppressing an increase in the amount of lipid peroxide in a living body, comprising catechol estrogen as an active ingredient. 2. The catechol estrogen is at least one substance selected from 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 2-hydroxyethynylestradiol and 2-hydroxyethynylestriol. The in vivo lipid peroxide increase inhibitor according to claim (1).