JPH085789B2 - Antihyperlipidemic agent - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antihyperlipidemic agent which reduces total lipid and neutral fat in serum.

[0002]

BACKGROUND OF THE INVENTION In recent years, intake of high-fat foods and high-calorie foods has increased due to westernization of diet, and obesity and hyperlipidemia of young people have become a problem. Hyperlipidemia is closely related to arteriosclerosis, and regions and ethnic groups with high serum cholesterol levels,
Aortic and coronary arteriosclerosis are common in high-fat foods, especially those ingesting large amounts of animal fat, and myocardial infarction is also frequent. It is known that familial hyperlipidemia is often associated with coronary atherosclerosis and myocardial infarction even in young people, and it is considered that hyperlipidemia promotes arteriosclerosis. Although there is some controversy regarding the relationship between the increase in serum triglyceride and arteriosclerosis, it is known from epidemiological studies that the increase in triglyceride acts as an independent risk factor to promote arteriosclerosis.

As drugs for hyperlipidemia, β-sitosterol, which inhibits absorption of cholesterol and bile acids,
Anion exchange resin (Cholestyramine etc.), Nicomol
(Nicomol), clofibrate that inhibits cholesterol synthesis, etc. are known, but they do not have sufficient therapeutic / preventive effects, and at present, exercise therapy and diet therapy are used together.

On the other hand, smoking is an inhibitory effect on weight gain,
It is well known that smokers are more likely to become obese when they quit smoking. The mechanism of body weight suppression by smoking has not been fully elucidated, but some findings have been obtained.

[0005] For example, it has been reported that, by smoking, adenyl cyclase in adipose tissue is activated to stimulate catecholamine secretion, and finally fat is decomposed to increase blood free fatty acid level (Brischetto, CS
et al .: Am.J.Cardiol., 52 , 675, (1983)), by controlling the uptake and storage of neutral fat (Triglyceride) in adipocytes and clarifying lipemic blood. Known adipose tissue lipoprotein lipolytic enzyme (Adipose tissue)
The activity of lipoprotein lipase) was higher in smokers than in nonsmokers, and it was reported that smokers suppressed the uptake of neutral fat into adipocytes (Brunzell, JD et al .:
Intel.J.Obesity, 4 , 101, (1980)), for smokers,
A report that lipids are mobilized from the adipose tissue into the blood and its consumption is increasing (Asano Makishige: Clinician, 373 , 769, (1
986)), smoking and nicotine increase the heat-producing ability in brown adipose tissue of mice (Toshihide Yoshida: Kyoto Prefectural University of Medicine, Vol. 99, No. 2, pp. 233, 1990),
Report that nicotine increases energy expenditure in smokers (Perkins, KA et al .: New England J. Medi
cine, 320 , 898, (1989)).

[0006] However, of the 2,000 kinds of tobacco smoke components, which component decomposes fat and suppresses the uptake and storage of lipids (such as triglyceride) into adipocytes, and the lipids are adsorbed from the adipocytes into the blood. No clarification has been made about whether to mobilize and increase consumption. It was also unknown whether nicotine alone was effective in suppressing weight gain in smokers.

Under these circumstances, the inventors of the present invention have studied the changes in body weight and serum lipid components by synthesizing chemical substances present in cigarette smoke and administering them to animals. As a result, it was found that ride suppresses weight gain in obese rats, reduces total lipids and neutral fat in serum, and further increases HDL, which is said to be decreased during arteriosclerosis. The present invention has been made based on such findings, and provides a use as a new therapeutic agent or preventive agent for hyperlipidemia.

[0008]

OBJECT OF THE INVENTION It is an object of the present invention to provide an antihyperlipidemic agent which reduces total lipids and neutral fats in serum.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide an anti-high fat containing at least one of 2-methyl-2-butene-4-olide and 3-methyl-2-butene-4-olide as an active ingredient. Achieved by a sera drug.

2-Methyl-2-buten-4-olide, 3-methyl-2-buten-4-olide Each of the olides) can be produced by a known chemical synthesis method.
By oral administration, these reduce total lipids and neutral fats in serum without affecting blood insulin levels. It also has the effects of suppressing weight gain and decreasing food intake.

The administration method and administration form of the drug of the present invention are not particularly limited, and it can be administered orally or parenterally, but oral administration is particularly suitable. In addition, upon administration, a commonly used pharmaceutical carrier (binder, excipient, etc.)
Can be used to prepare an appropriate formulation. In addition, the drug of the present invention may be added to and mixed with food, or may be added to a material such as a cigarette or a tobacco filter to be ingested by smoking.

[0012]

Example 1 2-Methyl-2-butene-4-olide (hereinafter referred to as 2M2) dissolved in distilled water was used in 5 mice (ddY).
B4O) and 3-methyl-2-butene-4-olide (hereinafter abbreviated as 3M2B4O) were orally administered once, and changes in body weight were observed for 6 days after the administration. Distilled water was administered to the symmetrical group.

[0013]

[Table 1]

As shown in Table 1, 2M2B40 and 3M
2B40 was suppressed by the single-circuit oral administration of 1000 mg / kg compared to the control group for 6 days from the first day after administration. The reduction in food intake was slight. Further, there was almost no effect on the behavior by this administration, and all the cases survived. Therefore, the acute toxicity of 2M2B40 and 3M2B40 was judged to be extremely low.

[0015]

Example 2 Hereditary obese rat group (obese homozygous (Fa
/ fa) Female, 5 weeks old, CLEA Japan) and control rat group (lean heterozygous (Fa / fa) female, 5 weeks old, CLEA Japan) 300 mg / k of 2M2B40 or 3M2B40
After continuous oral administration for 28 days, the body weight and food consumption were examined. The administration volume was adjusted to 0.5 ml / 100 g in all cases.

As shown in FIG. 1, the body weights of the hereditary obese rats on the 28th day were the distilled water administration group (-●-), the 2M2B4O administration group (-Δ-) and the 3M2B4O administration group (-○-). , 359 ± 12g (5 animals), 317 ± 16g (4 animals)
, And 329 ± 26 g (5 animals), and significant inhibition of body weight increase was observed by administration of 2M2B40 or 3M2B40. On the other hand, as shown in FIG. 2, with respect to the control rat group, neither 2M2B40 nor 3M2B40 had an influence on the body weight.

The total food intake of individual rats in each group for 28 days is shown in Table 2. In hereditary obese rats, the amount of food intake by administration of 2M2B40 or 3M2B40 was about 19% and 13% lower than that in the distilled water administration group, respectively. On the other hand, the food intake of control rats was 2M2B40 or 3M2B40.
Was not affected. The number in parentheses after the numerical value indicates the number of rats in each group.

[0018]

[Table 2]

[0019]

Example 3 The effects of 2M2B40 and 3M2B40 on blood insulin, glucose, triglyceride, total cholesterol, HDL and total lipid concentrations were investigated. On the 28th day, the rats in each group of Example 2 were anesthetized with pentobarbital and blood was collected from the abdominal aorta to obtain samples. Insulin is produced by Fadec Insulin RIA Kit, and glucose is produced by Kanto Chemical Co., Ltd. Merck Auto Glucos
Triglyceride (neutral fat) was measured by E-kit using EH test TG555'Eiken 'manufactured by Eiken Chemical Co., Ltd., and total cholesterol was measured by enzyme colorimetric method (Medical Technology, 9
(7) , 557-562, (1981)). The HDL concentration was 500 μl of serum, mixed with 20 μl of 5000 U / ml heparin solution, and mixed with 20 μl of 2.5M manganese chloride solution. After standing for 30 minutes, the precipitate formed was collected by centrifugation (1,500 g, 30 minutes), and collected. It was determined by adding 3 ml of a determiner TC-5 containing 2.24 mM EDTA-2Na, mixing and incubating (37 ° C., 15 minutes), and performing colorimetry with a Hitachi 701 spectrometer at two wavelengths (505 nm, 570 nm). The total lipid value was calculated by the following formula. Total lipid concentration = total cholesterol concentration x 1.5 + triglyceride concentration + phospholipid concentration The phospholipid concentration is the Merck Auto P manufactured by Kanto Chemical Co., Inc.
Determined by L kit. The results for the hereditary obese rat are shown in Table 3, and the results for the control rat are shown in Table 4. In hereditary obese rats (Table 3), administration of 2M2B4O or 3M2B4O decreased the concentration of triglycerides and total lipids. On the other hand, the concentrations of HDL and total cholesterol were rather elevated. Although there were changes in the concentrations of insulin and glucose, no significant difference was found. In control rats (Table 4), there was no difference in total lipid, but the triglyceride concentration was significantly decreased, and total cholesterol and HDL tended to increase.

[0019]

[Table 3]

[0020]

[Table 4]

As described above, 2M2B4O and 3M2B4
O reduced blood triglyceride and total lipid without affecting blood insulin concentration. Therefore,
2M2B4O and 3M2B4O may reduce triglyceride biosynthesis in adipocytes.

2M2B4O and 3M2B4O increased total cholesterol. Regarding total cholesterol, in the case of obesity, the blood triglyceride level is high, and HD
It is known that L-cholesterol shows a low value. From this, it is considered that the total cholesterol disease caused by 2M2B4O and 3M2B4O raises HDL-cholesterol by the lipid change accompanying the decrease of triglyceride, and as a result, raises the total cholesterol level. Alternatively, LDL uptake into cells is 2M
It may be suppressed by 2B4O and 3M2B4O, and elevated total cholesterol levels may be seen. 2M2B4
It is unclear whether O and 3M2B4O suppress the weight gain in genetically obese rats due to central action or peripheral action, but suppress feeding and weight gain without affecting blood insulin concentration. It is suggested that what was done was not due to the action of the central nervous system-autonomic nervous system related hormones.

[0023]

INDUSTRIAL APPLICABILITY As described above, the antihyperlipidemic agent of the present invention contains 2-methyl-2-butene-4-olide or 3-methyl-2-butene-4-olide as an active ingredient. Yes, it reduces total lipids and triglycerides in serum and increases HDL. Especially for obesity, it also has the effects of suppressing weight gain and decreasing food intake. It is also useful as a drug because it has no acute toxicity and can be administered orally.

[Brief description of drawings]

FIG. 1 2M2B4O and 3 on hereditary obese rats
It is a figure which shows the body weight change by administration of M2B4O. In the figure,-●-shows the case of the distilled water administration group, -Δ- shows the case of the 2M2B4O administration group, and-○-shows the case of the 3M2B4O administration group, respectively.

FIG. 2 is a diagram showing changes in body weight due to administration of 2M2B4O and 3M2B4O to control rats. In the figure,-●-represents a distilled water administration group, -Δ- represents a 2M2B4O administration group, and-○-represents a 3M2B4O administration group.

Claims (1)

[Claims] 1. An antihyperlipidemic agent containing at least one of 2-methyl-2-butene-4-olide and 3-methyl-2-butene-4-olide as an active ingredient.