JPH1087480A - Therapeutic agent for arteriosclerosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent having direct treating and improving effect on various kinds of arteriosclerosis and exhibiting excellent safety by using natural geranylgeraniol as an active component. SOLUTION: This agent contains geranylgeraniol of the formula as an active component. The compound of the formula is a natural substance available in the market and having high safety. The daily clinical administration rate of the compound of the formula for adult is usually 10-2,000mg, preferably 30-1,500mg. The present agent enables the direct and safe treatment and amelioration of arteriosclerosis in contrast with conventional indirect treating method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the treatment of arteriosclerosis such as coronary atherosclerosis, abdominal aortic sclerosis, obstructive atherosclerosis, renal atherosclerosis, carotid atherosclerosis, fundus atherosclerosis, cerebral atherosclerosis and the like. -It relates to an improving agent.

[0002]

BACKGROUND OF THE INVENTION Cardiovascular disease progresses through the interaction of thrombosis and sclerotic changes in the arterial wall. The speed is generally slow, and the arterial wall thickens gradually and locally produces arteriosclerosis. The resulting arteriosclerosis further progresses to calcification. Thus, calcification of the arterial wall is the end picture of arteriosclerosis, and no effective treatment method has been found yet.

[0003] As described above, atherosclerosis gradually progresses, so that no subjective symptoms appear at first, and no objective findings are observed. However, as the condition progresses, symptoms such as palpitations / shortness of breath, cold sensation / pain in the limbs, transient seizures, swelling, etc. develop, and eventually heart attack, cerebral hemorrhage, necrosis of the limbs, renal failure, gait disturbance, perception・ Severe medical condition such as movement disorder,
It is a serious illness that eventually leads to death. In Japan,
Although the leading cause of death statistics is cancer, arteriosclerosis is the most common cause of death, considering that most heart and brain diseases are caused by arteriosclerosis.

[0004] As described above, arteriosclerosis is a serious or poor prognosis disease involving multiple sites in the body, and there is a need for a therapeutically ameliorating drug with high clinical utility.

[0005]

2. Description of the Related Art Conventionally, there is no drug directly effective against arteriosclerosis, and a serum cholesterol-lowering agent (lipid-lowering agent) or a platelet aggregation inhibitor (antithrombotic agent) is administered to indirectly cause the risk of arteriosclerosis. Only therapies that removed the factors (risk factors).

[0006]

[Problems to be solved by the present invention] However, the risk factors of arteriosclerosis are not limited to serum cholesterol and thrombus, but also triglyceride, obesity, diabetes, hyperuricemia, immune disease, aging, hypertension, stress, It is extremely diverse, including stimulant intake, genetics, gender differences, ethnic differences, and it is practically impossible to eliminate all risk factors by administering lipid-lowering agents or antithrombotic agents.

Therefore, in reality, there is no drug that has a direct therapeutic / improving effect on various arteriosclerosis and is also excellent in safety. Was desired.

[0008]

SUMMARY OF THE INVENTION The present inventor has long been engaged in the study of arteriosclerosis that causes human death, and has also searched for clinically useful drugs for treating and improving arteriosclerosis. As a result, they have unexpectedly found that geranylgeraniol, which is a natural product and represented by the following chemical formula, can achieve its intended purpose as an anti-atherosclerotic therapeutic agent, and completed the present invention.

[0009]

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[0010] Accordingly, an object of the present invention is to provide coronary sclerosis, abdominal aortic sclerosis, obstructive arteriosclerosis, renal arteriosclerosis, carotid arteriosclerosis, fundus arteriosclerosis, cerebral artery, for which there has been no clinically effective drug. New treatments with high clinical utility and excellent safety for various arteriosclerosis such as sclerosis
It is to provide an improving agent. More specifically, the present invention relates to an anti-atherosclerosis therapeutic agent containing geranylgeraniol as an active ingredient.

Here, geranylgeraniol according to the present invention is a natural substance, known as a pharmaceutical intermediate or the like, and sold as a reagent or an industrial raw material.

Further, the geranylgeraniol according to the present invention has a double bond in the molecule and has geometric isomers, but is not limited in the present invention, and any single geometric isomer may be used. Or a mixture of two or more. Among them, more preferably, for example, (2E, 6E, 10E)
-3,7,11,15-Tetramethyl-2,6,10,14-hexadecatetraen-1-ol [CAS registration No. 24034-73-9], which can be used in the present invention. It is not limited to.

[0013] Note that geranyl geraniol is in vivo polyisoprenoids, cholesterol, steroids, ubiquinones, precursor during the biosynthesis of many physiologically active substances such as dolichol (substrate), LD ₅₀ values are determined experimentally It is extremely expensive and extremely safe.

Next, the dosage forms of the compound of the present invention include, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and injections Preparations and the like. At the time of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.

That is, in order to produce an oral preparation, geranylgeraniol and an excipient and, if necessary, an antioxidant, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added. Powders, fine granules, granules, tablets,
Coated tablets, capsules, etc.

The excipients include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., coloring agents As a flavoring agent, cocoa powder, peppermint brain, aromasan, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. Of course, these tablets and granules can be sugar-coated and optionally coated as needed.

In preparing an injectable preparation, geranylgeraniol is added to a pH adjuster, a solubilizer, an isotonic agent, and the like.
If necessary, a solubilizing agent, a stabilizing agent, an antioxidant and the like are added, and the preparation is made by a conventional method.

The method for producing the external preparation is not limited.
It can be manufactured by an ordinary method. In other words, base materials used in the formulation include pharmaceuticals, quasi-drugs,
Various raw materials usually used for cosmetics and the like can be used.

Specific examples of the base materials used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and polyhydric acids. Raw materials such as alcohols, water-soluble polymers, clay minerals, purified water, etc. are added, and if necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. are added. However, the base material of the external preparation according to the present invention is not limited to these. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratolytic agent, and the like can be added. The amount of the base material to be added is an amount that usually results in a concentration set in the production of an external preparation.

The clinical dose of geranylgeraniol in the present invention is not limited and varies depending on symptoms, severity, age, complications and the like, and also varies depending on the kind of salt and administration route. 2000 mg, preferably 30 mg to 1500 mg, more preferably
50 mg to 1000 mg, administered orally, intravenously, intramuscularly, rectally or transdermally.

[0021]

Next, in order to show the usefulness of the compound of the present invention as a therapeutic or ameliorating agent for arteriosclerosis, pharmacological experimental examples will be given below as effect examples, but it is to be understood that the compounds of the present invention or uses are not limited thereto. Needless to say.

Experimental Method (1) Basis for Setting Dose of Normal Dose and High Dose Vitamin K Diet and Preparation of Test Diet In this test, phytonadione (Ph
ytonadione) and menatetrenone (Menatetrenone)
In addition, phytol (Phytol) and geranylgeraniol (Geranylgeraniol), which are the respective side chain components, were used as test compounds. First, the minimum dose required for prothrombin biosynthesis is determined by adding a certain amount of phytonadione to vitamin
K-deficient diet (from Hope Farm, Walden, The Netherlands)
And determined based on the results of experiments in which rats were bred for 3 weeks. As a result, the phytonadione concentration in the diet was 0.6 (μg /
g diet), the plasma prothrombin concentration decreased in a dose-dependent manner. On the other hand, when a higher concentration was fed, it was not different from that at the start of the experiment. Therefore, in order to prevent the plasma prothrombin concentration from changing minutely due to the fluctuation of the vitamin K amount in the daily diet,
In this experiment, the minimum required amount of phytonadione was
Three times, 1.8 μg / g was added. The diet containing phytonadione in this experiment was the minimum required amount of 5,000.
Phytonadione was added and mixed with a vitamin K-deficient diet at a dose of 3 mg (6.7 μmol) / g. Similarly, menatetrenone, phytol, and geranylgeraniol were similarly consumed in a vitamin K-deficient diet [(6.7 μmo
l) / g diet] to prepare each test meal.

(2) Animals and feeding Sixty 12-week-old male Wistar rats were divided into five groups and housed in individual flat-bed cages with a 12-hour light / dark cycle, air conditioning (20 ± 2 ° C., humidity 50 ± 10%), Feeding was controlled according to the table below. That is, 5 groups consisting of 12 rats each, vitamin K deficient diet (Group A, control),
A diet containing phytonadione (Group B), a diet containing menatetrenone (Group C), a diet containing phytol (Group D), and a diet containing geranylgeraniol (Group E) were given for 10 days each. Was.

[0024]

(3) Blood coagulation and platelet aggregation Before and after feeding control, 0.5 ml of blood was collected from the tail vein of each rat, and 0.1 M trisodium citrate was added.
0.05 ml was added. Plasma prothrombin agglutination
-van Dooren et al. (Biochem. Pharmacol., 50 , 797-80
1, 1995.). Plasma thrombin activity is C.
After activation by the method of Nieuwenhuys et al., The resulting blood soul is removed by hand and the method of Hemker et al. (Thromb. Haemostas., 70 , 617-
624, 1993.). After activation of the blood agglutination system by Innovin, the total amount of thrombin was added, and shortly, two-stage extractions were performed every 30 minutes to determine the actual thrombin concentration using the chromogenic substrate S-2238 ( sub-sampling) and recorded. To examine blood platelet aggregation, 6 ml of blood was collected from each rat,
0.6 M trisodium citrate was added to 0.6 ml. The aggregation tendency of the washed platelets was measured by the method of Heemskerk et al.

(4) Arterial Thrombus Propensity Rats were bred for 10 days under feed control, and then cultivated by the method of Hornstra and Russenberg (Atherosclerosi).
s, 22 , 499-516, 1975.), an extracorporeal circulation loop made of polyethylene cannula was inserted into the abdominal aorta. With this technique, blood flow observation was made possible by the environment that came out of the abdomen. At the site where the extracorporeal loop is placed on the wall of the arterial blood vessel, the endothelial cells are damaged and the blood flow is disturbed, so that a thrombus is formed and grows, and the blood vessel reaches an occluded state after 5 days. The occlusion can be confirmed by visual observation by changing the color tone of the blood in the translucent loop. In addition,
The time from insertion of the extracorporeal loop to complete occlusion
Call the closing time.

Results (1) Blood coagulation and platelet aggregation Prothrombin concentration and thrombin activity were measured for citrated plasma collected before and after feeding control. Washed platelets were used to measure the platelet aggregation rate stimulated by collagen, thrombin or ADP. However, since a large amount of blood was required for platelet isolation, platelet aggregation was not measured at the start of the experiment. As shown in Table 2, blood coagulation properties did not change before and after the experiment.
No difference was observed before or after the experiment among the three groups, Group A, Group B and Group C. Therefore, compared to before the experiment, vitamin K (phytonadione or menatetrenone) did not show a procoagulant effect.

[0028]

(2) Inhibitory effect of vitamin K on arterial thrombus formation After breeding for 10 days, a total of 60 rats in all 5 groups
An operation to insert an extracorporeal circulation loop into the abdominal aorta was performed, and the occlusion time was measured. The results are shown in FIGS. From FIG.
Menatetrenone substantially and significantly (p = 0.03) prolonged occlusion time (+22.5 hours), while phytonadione was significantly less
It is clear that the occlusion time was shortened (-28.7 hours) to (p <0.001).

(3) Inhibitory effect of phytol and geranylgeraniol on thrombus formation As is clear from FIG. 2, similar to menatetrenone, geranylgeraniol, its side chain, showed an increase in occlusion time, whereas (167 ± The phytol occlusion time (135 ± 10 hours) was slightly shorter than the control (140 ± 14 hours). The differences between the phytol-feeding group and the control group were very slight and were within normal variability. The difference Δ (32 hours) between the phytol and geranylgeraniol groups was 95% confidence-
0.023 <Δ <+0.217 was substantial.

From the results of the above pharmacological experiments, it is clear that menatetrenone and its side chain, geranylgeraniol, have extremely excellent anti-atherogenic effects, unlike phytonadione, a vitamin K homolog, and phytol, its side chain. It is. Menatetrenone is very unstable to light, while geranylgeraniol is stable and has a low production cost. Therefore, it is advantageous in terms of formulation or industry. Furthermore, considering the high safety of geranylgeraniol, the present invention can be expected to be extremely useful clinically.

[Brief description of the drawings]

FIG. 1 is a diagram showing the occlusion time in a vitamin K-deficient diet group (group A, control), a phytonadione-added diet group (group B), and a menatetrenone-added diet group (group C). (Indicated by mean ± standard error)

FIG. 2 is a diagram showing occlusion times in a vitamin K-deficient diet group (group A, control), a diet group supplemented with phytol (group D), and a dietary group supplemented with geranylgeraniol (group E). (Indicated by mean ± standard error)

Claims (2)

[Claims] 1. An anti-atherosclerotic therapeutic agent comprising geranylgeraniol represented by the following chemical formula as an active ingredient. Embedded image 2. The arteriosclerosis is at least one selected from coronary arteriosclerosis, abdominal aortic sclerosis, obstructive arteriosclerosis, renal arteriosclerosis, carotid arteriosclerosis, fundus arteriosclerosis, and cerebral arteriosclerosis. The anti-atherosclerotic therapeutic agent according to claim 1.