JP2000026300A - Pharmaceutical composition for protecting vascular endothelial cell - Google Patents

Abstract

PROBLEM TO BE SOLVED: To search for and obtain a compound having effects equal to those of an antithrombotic agent by protecting actions on a vascular endothelial cell. SOLUTION: This pharmaceutical composition such as a medicine or a food for the prophylaxis and/or therapy of diseases caused by injury to a vascular endothelial cell is obtained by including one or more kinds selected from a bile acid represented by the general formula (R denotes hydrogen or hydroxyl group), its taurine conjugate and a pharmacologically acceptable salt thereof. The bile acid such as ursodeoxycholic acid, cholic acid or taurodeoxycholic acid has protecting actions on the vascular endothelial cell and suppressing actions on the thrombogenesis. Thereby, the utilization of the composition containing the one or more kinds selected from the bile acid, the taurine conjugate and the pharmacologically acceptable salt thereof is considered as an agent for the prophylaxis of thrombi or even the prophylaxis of diseases such as thrombosis, hypoxia, infectious diseases, immune complex diseases diabetes or arteriosclerosis causing the injury to the vascular endothelial cell.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition having a protective effect on vascular endothelial cells, such as a medicine or food. More specifically, the present invention relates to a pharmaceutical composition having a vascular endothelial cell protective effect, comprising a bile acid represented by the following general formula, a taurine conjugate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

Embedded image (In the formula, R represents hydrogen or a hydroxyl group.)

[0003]

2. Description of the Related Art Blood system hypoxia caused by peripheral circulatory disorders and pulmonary dysfunction causes vascular endothelial cell damage due to lactic acidosis, which is directly induced by a decrease in oxygen supply to the vascular endothelium. At that time, the damage is further increased due to the toxicity of the generated radical and the generated peroxide, and a large endothelial cell damage is induced. When an endothelial cell is damaged, platelets adhere and aggregate at the site, and the blood coagulation system is activated by contact with tissue factor or a foreign substance (collagen) released from the damaged portion, thereby producing thrombin. Thrombin stimulates platelet activation and also converts fibrinogen to fibrin, forming a thrombus. By repeating this process, eventually
It is known to lead to morbid blood circulation disorders. In addition, various factors such as diabetes, hyperlipidemia, hypertension, and endotoxin cause blood circulation disorders.

[0004] In recent years, it has been noted that the formation or formation of arteriosclerosis involves injury or activation of endothelial cells. Atherosclerosis progresses quietly and suddenly manifests itself as a myocardial infarction or stroke. Antithrombotic agents are used because many of the causes are arterial thrombosis. However, such an antithrombotic agent not only has a problem in safety, but also has no known effect on endothelial cells, and thus has not solved a fundamental problem.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to search for and provide a compound having the same effect as an antithrombotic agent by protecting vascular endothelial cells.

[0006]

The present inventors have studied the pharmacological effects of bile acid alcohols and bile acids, and found that bile acids are effective in animal thrombosis models, and completed the present invention. Was.

[0007] Among the bile acids used in the present invention, ursodeoxycholic acid is an agent for improving the bile function in biliary tract diseases and liver diseases accompanied by bile stasis and as a liver function improving agent in chronic liver diseases. Chenodeoxycholic acid is cholesterol. Although used as gallstone dissolving agents, their antithrombotic and platelet aggregation inhibitory effects are not known.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The pharmacologically acceptable salts of the bile acids and taurine conjugates thereof of the present invention include, for example, inorganic salts such as sodium, potassium, magnesium and calcium.

The pharmacologically acceptable salts of these bile acids and their taurine conjugates can be mixed with solid pharmaceutical preparations such as tablets, capsules, powders, fine granules or granules by adding ordinary pharmaceutical carriers. Liquid preparations such as injections, inhalants, syrups, suspensions and emulsions can be prepared.

As the pharmaceutical carrier, various excipients, binders, lubricants, disintegrants, coating agents, solubilizers, emulsifiers, suspending agents, stabilizers, solvents and the like can be used.

Although the usage and dosage vary depending on the type of bile acid, age symptoms, etc., when bile acid is ursodeoxycholic acid, it is generally 10 to 30 orally per day for adults.
The dose is 00 mg, preferably 50 to 1500 mg, and 5 to 100 mg, preferably 10 to 60 mg by intravenous injection, and it is preferable to use them in 1 to 6 times, preferably 1 to 3 times.

In the case of chenodeoxycholic acid, it is generally used orally in an adult at a dose of 10 to 3000 mg, preferably 30 to 1000 mg per day, and it is preferable to use it in two or three divided doses.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The contents of the present invention will be described below in detail with reference to embodiments. However, it goes without saying that the present invention is not limited only to these examples.

1) Lactate-induced peripheral arterial occlusion model A model animal was prepared according to the method of Iwamoto et al. (Pharmacology and Therapy 14, 41-49 (1986)). That is, the rats reared in advance were fixed in a supine position under anesthesia, the right (or left) thigh was removed with a clipper, and then fixed with a cloth adhesive tape. The inside of the thigh was incised to a minimum and the femoral artery was dissected about 5 mm from the surrounding tissue. Next, the blood flow in the femoral artery was cut off with a clip for neurosurgery, and 5% was injected using a 1 ml syringe with an injection needle.
0.15 ml of lactate-monosaline (pH 1.67) was injected into the femoral artery at 0.05 ml per second. Thereafter, bleeding from the injection site was stopped by Aron Alpha, and the incision site of the femoral artery was closed with a suture clip. The sham surgery group was injected with saline instead of 5% lactate-saline.

The test drug was orally administered 2 hours before lactic acid injection after being suspended or dissolved in physiological saline.

The evaluation was based on the degree of foot pad edema and gangrene,
Platelet retention and lactate dehydrogenase (LDH) activity were used as indices.

A) The degree of edema is determined by Halliday
WJ) et al. (J. Nat. Cancer Inst., 43, 141-142 (196)
According to 9)), before and after the injection of lactic acid, the thickness of the footpad into which lactic acid was injected was measured using a caliper and determined.

B) The degree of gangrene of each finger is represented by a numerical value from 0 to 5 (no change: 0, black discoloration is limited to the toe portion: 1,
Black discoloration extends to the finger part: 2, finger necrosis (mummification): 3, finger fallout: 4, necrosis extends to the footpad part: 5), and sum the numerical values of five fingers The lesion index was used.

C) Measurement of platelet adhesion (retention rate) Method of Helem (Scand. J. Haemat., 7, 374-382)
(1970)).

D) Measurement of serum LDH activity; a clinical test kit was used.

<Results> Table 1 shows the results of the effects (single administration) of various bile acids on the progression of the disease state in a rat model of lactic acid-induced peripheral arterial occlusion.

[0022]

[Table 1] UDCA; ursodeoxycholic acid (20.5μmole / Kg, po) TUDCA; tauroursodeoxycholic acid sodium salt
(20.5μmole / Kg, po) *, ** and *** show significant differences (p <0.0
5, 0.01 and 0.001) from the control, respectively.

Table 2 shows the effects of bile acids on edema development and serum lactate decarboxylase activity in a rat model of lactic acid-induced peripheral arterial occlusion.

[0024]

[Table 2] UDCA; ursodeoxycholic acid (20.5 μmole / Kg, p.
o.) TUDCA; Tauroursodeoxycholic acid sodium salt
(20.5μmole / Kg, po) *, ** and *** show significant differences (p <0.0
5, 0.01 and 0.001) from the control, respectively.

All bile acids exhibited an effect of suppressing an increase in lesion index, development of foot pad edema and an increase in serum LDH activity.

Table 3 shows the effect of U on serum lactate decarboxylase activity.
4 shows the effects of DCA and argatropane.

[0027]

[Table 3] UDCA; ursodeoxycholic acid *, ** and *** show significant differences (p <0.0
5, 0.01 and 0.001) from the control, respectively.

When the isozyme pattern of LDH was examined with respect to the increased LDH activity, a clear difference was observed between the activity values of the drug-administered group and the control group.
The ratio between LDH ₄ and LDH ₅ was about 1: 4.5, and LDH ₄ and LDH ₅ obtained by analysis of LDH isozyme in vascular endothelial cells.
Ratio of 1: 3.3.

2) Influence on Streptozotocin-Induced Diabetes Diabetic rats were prepared by administering 35 mg / kg or 45 mg / kg of streptozotocin to male Wistar rats (10 weeks old) in the tail vein. A saline was administered to the control group. The evaluation was performed by measuring the blood glucose level, platelet retention rate, and serum LDH activity.

<Results> Table 4 shows the effect of ursodeoxycholic acid on the blood glucose level of streptozotocin-induced diabetic rats.

[0031]

[Table 4] UDCA; ursodeoxycholic acid *, ** and *** show significant differences (p <0.0
5, 0.01 and 0.001) from the control, respectively.

Table 5 shows the effect of ursodeoxycholic acid on the platelet retention rate and serum LDH activity of streptozotocin-induced diabetic rats.

[0033]

[Table 5] UDCA; ursodeoxycholic acid * shows significant differences (p <0.05) from the
control.

When the effect on the blood glucose level was examined by orally administering the test drug for two weeks, UDCA significantly reduced the blood glucose level and the platelet retention rate. In addition, it showed a tendency to suppress an increase in serum LDH activity.

3) Effect on Dietary Hyperlipidemia Male Wistar rats were allowed to freely ingest 1% cholesterol diet to prepare hyperlipidemic rats. A saline was administered to the control group. The evaluation was performed by measuring the blood sugar level, the whole blood coagulation time, and the serum LDH activity.

<Results> The effect on serum lipids by orally administering the test drug for 4 weeks was examined.
Sodium ursodeoxycholate significantly reduced serum lipid levels and platelet retention. In addition, sodium ursodeoxycholate significantly suppressed the increase in serum LDH activity.

[0037]

As described above, bile acids such as ursodeoxycholic acid, cholic acid and taurodeoxycholic acid are
It has the effect of protecting vascular endothelial cells and suppressing thrombus formation. Therefore, it can be used as an agent for preventing thrombosis, or for preventing diseases such as thrombosis, hypoxia, infection, immune complex disease, diabetes, and arteriosclerosis that cause damage to vascular endothelial cells.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Shin Fukushima 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture F-term in the Totsuka Research Laboratories, Totsuka Laboratory Co., Ltd. 4B018 LB10 MS03 4C086 AA01 AA02 DA11 MA01 MA02 MA04 NA14 ZA36 ZA45 ZA54 ZC02 ZC35 4C091 AA02 BB01 CC01 DD01 EE04 FF01 GG02 GG13 HH01 JJ03 KK01 LL02 MM03 NN01 PA02 PA05 PB03 QQ01

Claims (5)

[Claims] 1. The method according to claim 1, wherein the vascular endothelial cell contains one or more bile acids represented by the following general formula, a taurine conjugate thereof and a pharmacologically acceptable salt thereof. A composition for preventing and / or treating a resulting disease. Embedded image (In the formula, R represents hydrogen or a hydroxyl group.) 2. One or two or more kinds selected from bile acids represented by the above general formula, taurine conjugates thereof and pharmacologically acceptable salts thereof, are ursodeoxycholic acids and / or drugs thereof. The composition according to claim 1, which is a physically acceptable salt. 3. The composition according to claim 1, wherein the disease caused by damage to vascular endothelial cells is thrombosis. 4. The vascular endothelial cell injury is one or two selected from hypoxia, infectious disease, immune complex disease, diabetes, arteriosclerosis, vasculitis, shock and generalized intravascular coagulation syndrome. The composition according to claim 1, wherein: 5. A medicine or a food,
The composition according to claim 1.