JPH0225425A - Antihypertensive agent - Google Patents

Abstract

PURPOSE:To obtain an antihypertensive agent showing excellent hypertensive action without exhibiting side effects containing swine bile, chenodeoxycholic acid, etc., as an active ingredient. CONSTITUTION:An antihypertensive agent containing any of swine bile, chenodeoxycholic acid and a component prepared by partially separating and removing steroid compounds and lower-molecular weight compounds than the steroid compounds from the bile by using dialysis method or ultrafiltration method as an active ingredient.

Description

[Detailed description of the invention] [Industrial application field] This invention relates to antihypertensive agents.

[Conventional technology]

Currently, the prevalence of cardiovascular diseases is extremely high, especially in developed countries. Circulatory disorders include heart disease, cerebrovascular disorders,
It includes many diseases such as hypertension, but the most frequently occurring disease is hypertension.Factors related to blood pressure include vascular elasticity, vascular inner diameter, circulating blood volume, and cardiac output. , blood viscosity, vasoactive substances, and neurological factors related to vasomotion, and blood pressure values are determined by interrelation with each other.Research is being conducted on the causes of hypertension, including the above factors. It is broadly divided into essential hypertension and secondary hypertension.

Secondary hypertension is further subdivided into renal hypertension, endocrine hypertension, neurogenic hypertension, etc., depending on the cause of its occurrence.

■Essential hypertension: There is no obvious cause for essential hypertension, and it is thought that most of it is due to genetic and environmental factors. Essential hypertension gradually progresses from the age of 30 to 40, and as time progresses, vascular lesions appear in important organs such as the brain, heart, and kidneys. The frequency of essential hypertension is much higher than that of secondary hypertension.

■Secondary hypertension: The most common type of secondary hypertension is renal hypertension, which also includes renal vascular hypertension caused by renal artery lesions, nephritis, renal tuberculosis, I11 ulcer, etc. It is subdivided into sexual hypertension and urinary obstructive hypertension due to stones, etc. Typical examples of endocrine hypertension include primary hyperaldosteronism caused by adrenal tumors, Kunung syndrome, and pheochromocytoma. Neurogenic hypertension is thought to occur when there is a decrease in the responsiveness of the specular reflex system or abnormalities in the synthesis, storage, and release of catecholamines that have an effect on increasing blood pressure.

In general, secondary hypertension can be completely cured by treating the calcification that causes it, but there is no definitive treatment for essential hypertension because the cause has not been completely elucidated. Although extremely mild cases may be cured through dietary therapy and lifestyle changes, in most cases it is necessary to artificially control blood pressure by taking antihypertensive drugs for a long period of time. Currently, antihypertensive agents are classified into sympatholytic agents, vasodilators, diuretic antihypertensive agents, etc. according to their mechanism of action, including laheclol hydrochloride, guanedidine hydrochloride, reserpine, hilaralazine hydrochloride, diazukidite, thiazide, and furosemide. etc. are widely used. However, these antihypertensive drugs have many side effects (rash, dizziness, headache, nausea/vomiting, fatigue, etc.), and unless strict blood pressure control is required, dietary therapy, lifestyle guidance, etc. are recommended as much as possible. It is considered desirable to use it in combination with other treatments.

[Problem to be solved by the invention]

As described above, in the conventional technology, it is necessary to control blood pressure in the treatment of essential hypertension, and therefore, despite the many side effects, the above-mentioned antihypertensive drugs should not be taken continuously for a long period of time. There is a problem that it is not possible to
The challenge was to solve this problem.

[Means for Solving the Problems] In order to solve the above problems, the present invention uses as an active ingredient at least one of pig bile, chenodeoxycholic acid, or a component obtained by separating and removing a part of lower molecular weight compounds from pig bile. This method adopts the method of making it an antihypertensive agent. The details will be described below.

Since pigs, which are the resource source in this invention, are mainly used for human consumption, they are advantageous from the two viewpoints of safety and hygiene. After the pig is slaughtered, the meat and some of the internal organs are edible.
In addition, although the bones are used as fertilizer, many of the bones are disposed of without being used. However, it is known that blood, internal organs, secretory glands, etc. contain many physiologically active substances, and have been used as raw materials for pharmaceuticals and the like since ancient times. In particular, the liver and gallbladder (bile) are said to have high utility value.

As is well known, the bile used in this invention is a brown and bitter liquid secreted by liver cells, and has functions such as emulsifying fat in the body. The components of bile and its content are:
There are differences depending on the species and breed of animal, but in the case of pig bile, monohydroxy acids such as hyodeoxycholic acid, chenodeoxycholic acid, desoxycholic acid, 6-kedohyodeoxycholic acid, and lithocholic acid, dihydroxycholic acid, and I・Consists of bile acids, which consist of steroidal compounds such as lihydroxylic acid and higher bile acids, proteins, sugars, lipids (cholesterin, lecithin, etc.), inorganic salts, bile pigments (bilirubin, biliverdin, etc.), and other trace elements. has been done. When collecting bile, it may be appropriately collected using a syringe or the like from the gallbladder, cystic duct, and common bile duct that have been removed after the carcass is dissected.

In order to separate low molecular weight compounds such as steroid compounds from higher molecular weight compounds from bile, dialysis, ultrafiltration, etc. may be used. The fractionated substance on the high molecular weight side may be used as a liquid, or it may be made into a powder by vacuum freeze-drying or the like and used as an appropriate preparation. Regarding chenodeoxycholic acid, its presence in pig bile may be confirmed by liquid chromatography and then extracted as a low molecular weight compound, or a commercially available powder may be used.

(Action) Although many substances contained in bile have been clarified, many polymeric compounds have not yet been identified.

The above-mentioned bile exhibits a hypotensive effect even when administered as it is, but high-molecular-weight fractionated substances, in which steroid compounds and lower molecular compounds have been removed to some extent by dialysis or ultrafiltration, also have a hypotensive effect. Admitted. Furthermore, chenodeoxycholic acid, a bile acid, also had a hypotensive effect. Therefore, it can be said that the antihypertensive substance in bile is chenodeoxyfuric acid, but there is a possibility that it binds with other substances in bile and exhibits a hypotensive effect, or that other antihypertensive substances are contained in bile. It is also possible that

[Example] I Example 1 as a quick 1-in-1 experiment: Bile was aseptically injected using a syringe from fresh gallbladders removed from meat pigs that were three-way crossbred with Runtrace, Greater Yorkshire, Decorock, and Hampshire strains. It was taken on. The obtained bile was stored as a powder by vacuum lyophilization and dissolved in distilled water before administration.

(1) Experimental Animals Thirty mongrel dogs weighing 7 to 13 kg were anesthetized with Pen I-Harbital and experiments were conducted under artificial respiration.

(2) Measurement items: aortic blood pressure, mean aortic pressure, cardiac output, total peripheral vascular resistance, and electrocardiogram.

(3) Measurement force method Aortic blood pressure was measured via a pressure transducer and preamplifier using a large diameter catheter inserted from the left midscapular artery to the aortic arch. The average human arterial pressure was determined by integrating the aortic blood pressure within one heartbeat cycle using a filter with a time constant of 2 seconds. Cardiac output was measured via a probe attached to the aortic root and an electromagnetic blood flow meter. Total peripheral vascular resistance was calculated by dividing mean aortic pressure by cardiac output. The electrocardiogram was recorded using lead ■, and the waveform was drawn with a pen recorder.

(4) Administration method: Intravenous 1'J I>-' (The dose is expressed in mg per 1 kg of dog's body weight.) (5) Administration time: If administered once, approximately 2 hours after anesthesia, twice or more. 1 if
There was an interval of two hours.

(6) Judgment method The antihypertensive effect of the test agent was judged by the difference between the average human arterial pressure for 3 minutes immediately before administration and the minimum value after administration. Similarly to the mean aortic pressure, the cardiac output and total peripheral vascular resistance Ift values were determined by the difference between the average value for 3 minutes before administration and the maximum or minimum value after Uj injection. A t-test was used to test the difference.

The results of the tests conducted under the following conditions are shown in Table 1. 5.10.20.50 and 100mg of the test agent
/kg, mean aortic pressure and total peripheral vascular resistance decreased in a dose-dependent manner, and cardiac output increased in a dose-dependent manner. As a result of the significance test, it was at the 5% level for doses of 10 mg/kg or more, and 1% for doses of 20 mg/kg or more.
Significant differences were observed in the levels. No abnormal findings were seen in the electrocardiogram.

Table 1: Hydralazine hydrochloride (085 mg /
kg) and comparative test of antihypertensive effect with i=tl, tagoro,
Since the test agent exhibited the same effects as hydralazine hydrochloride (Table 2), it was determined that it was capable of fully exhibiting its function as an antihypertensive agent.

Table 2 Example 2 In order to investigate the role of the autonomic nervous system in the antihypertensive effect of the test drug (Cholene), α- and β-receptor blockers (phentolamine and propranolol) and atropine sulfate were administered to dogs in advance. The control of the sympathetic and parasympathetic nerves was blocked. Next, 20 and 50 mg/kg of the test agent were administered in the same manner as in Example 1, and aortic blood pressure, mean aortic pressure, cardiac output, and total peripheral vascular resistance were measured. Changes in the above measurement items in this case are summarized in Table 3. The mean aortic pressure, cardiac output, and total peripheral vascular resistance all showed the same trends as in Example 1, but each of the changes showed smaller values than in Example 1. Therefore, it was considered that the test agent acts on areas other than the autonomic nervous system, such as vascular smooth muscle, and causes a decrease in blood pressure.

Table 3 n, Example 3 as a chronic experiment: The bile collected in Example 1 was filled into a cellulose tube for dialysis with a pore size of 24 angstroms, and dialyzed for about 72 hours. The dialysis fluid was vacuum freeze-dried in the same manner as the bile to obtain a powder. For administration, this powder was dissolved in distilled water. A commercially available powder of chenodeoxycholic acid was used. 0 of this powder before administration.
．． It was dissolved in 1N sodium hydroxide and further neutralized with 0.1N hydrochloric acid.

(]) Experimental Animals Twenty-two Japanese white rabbits weighing 3.3 to 4.1 kg were used in which a catheter for measuring blood pressure was chronically placed in the aortic arch.

(2) Measurement items Mean aortic pressure.

(3) Force measurement method The average aorta of a freely moving rabbit in a rearing cage was continuously sampled using a computer for about 8 hours via a catheter, a pressure transducer and a preamplifier, and at the same time a pen recorder was used. It was recorded in

(4) Administration method: Oral administration (dosage is indicated by ■ per 1 kg of body weight.) (5) Administration period: Each test drug was administered once a day at around 6:00 pm for one week.

(6) Judgment method Among the 8-hour average aortic pressure sampled by computer, the 8-hour average value was determined, and a significant difference test was performed on the values before and after administration on each test side. The results are shown over time in Table 4 for bile, Table 5 for dialysis fluid, and Table 6 for chenodeoxycholic acid. When bile or its dialysate solution was orally administered, the mean aortic pressure decreased over time and in a dose-dependent manner after administration, and both were significant at the 5% level one week later.

In addition, a significant hypotensive effect was also observed when chenodeoxycholic acid was administered. Therefore, it can be determined that bile, its dialysate fluid, and chenodeoxycholic acid are effective as stimulants even when administered orally. Acute toxicity tests were conducted on rats and subacute toxicity tests on young rats. In acute toxicity tests, pig bile powder was added to 1 kg of body weight.
A maximum of 5,000 mg per kg of body weight was administered orally, and in a subacute toxicity test, a maximum of 500 mg per kg of body weight was administered at a dose of 28 mg per kg of body weight.
The drug was administered continuously for several days and the progress was observed. As a result, in all tests, no abnormal findings were observed in behavior, body weight, blood, and various organs compared to the control group and the water-administered group. Kiyoshi Aoki and three others have already reported that as a result of acute and chronic toxicity tests on porcine bile powder containing bile acids, no toxicity was observed when administered orally (Applied Pharmacology, 19 (6), 901- 918, (1
980) ). On the other hand, chenodeoxycholic acid has already been approved as a gallstone dissolving agent, and acute, subacute, and chronic toxicity tests have shown no toxicity.

〔effect〕

The antihypertensive agent of this invention exhibited an excellent blood pressure lowering effect comparable to that of hydralazine hydrochloride, a conventionally used antihypertensive agent, without exhibiting any side effects.
It can be said that this is extremely significant.

Patent applicant: Nippon Ham Co., Ltd. Same agent sickle Field Sentence

Claims (1)

[Claims] (1) An antihypertensive agent characterized in that the active ingredient is at least one of porcine bile, chenodeoxycholic acid, or a component obtained by separating and removing a portion of low-molecular-weight compounds from porcine bile.