JP2005314435A - Cardiovascular disease medicine and health food - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine useful for treating and preventing cardiovascular diseases such as hypertension, apoplexy and diabetes, and to provide a health food. <P>SOLUTION: The cardiovascular disease medicine is characterized by containing at least one of ferulic acid and/or a physiologically acceptable salt of the ferulic acid. The health food is characterized by containing at least one of ferulic acid and/or the physiologically acceptable salt of the ferulic acid in a food or drink. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention is based on a novel pharmacological action of ferrulic acid and / or physiologically acceptable ferulate, which is a blood pressure lowering action, a stroke onset inhibiting action, a microvascular protective action, and a weight gain inhibiting action. The present invention relates to a drug useful for the treatment and prevention of hypertension, hypertensive cerebrovascular disease, diabetes and the like, and a health food.

  Traditionally, ferulic acid is present in the cell walls of rice, barley, wheat and other grains, asparagus, tomatoes, olive fruits, strawberries, citrus fruits, brown sugar and many other plants. For example, in γ-oryzanol as a pharmaceutical material obtained from rice bran, various sterols and esters are formed therein. Rice bran is produced as a by-product of milled rice in Japan about 1 million tons per year and is used as a raw material for rice oil. However, there is a need for the development of methods for using this valuable natural resource. Ferulic acid has two isomers, a cis form and a trans form. Ferulic acid contained in γ-oryzanol is a trans form. The trans form is obtained by a method of subjecting rice bran-derived raw material containing γ-oryzanol to an alkaline hydrolysis. The action of ferulic acid is, for example, an antioxidant action (Patent Document 1, Non-Patent Document 1), an ultraviolet absorption action (Patent Document 2, Non-Patent Document 2), an anti-HBV agent (Patent Document 3), a cell differentiation promoting agent ( Patent Document 4), active oxygen scavenger (Patent Document 5), phospholipase A2 inhibitor (Patent Document 6), peroxynitrite scavenging action (Non-patent Document 3) and collagen synthesis inhibition The action (Patent Document 7) and the like are known, but the antihypertensive action and the therapeutic effect on cerebrovascular disorders such as stroke according to the present invention, the protective effect on the brain and peripheral microvascular vessels, and the weight gain inhibiting effect are known. Absent.

Hypertension is a basic disease of vascular complications in the main organs brain, heart and kidney. Except in the case of hypertension emergency, pharmacotherapy for hypertension is a method in which the blood pressure is gradually decreased over time to the target blood pressure value in order to avoid adverse effects on cerebral ischemia or cardiac function. In general, in the prevention of mild hypertension or complications of hypertension and the suppression of progress, it is recommended to improve lifestyles by improving dietary habits such as restricting salt intake, regular exercise, and weight restrictions. However, there is a limit to the effects of improving lifestyle habits, and health foods during the onset of hypertension are required as drug therapy or as an adjunct therapy, and this is also true for pet animals.
JP 7-300412 A Graf E., Free Radical Biology & Medicine Vol.13 435-484 (1992) JP-A-1-13016 Taro Murakami et al. FOOD Style Vol.21 61-65 (1999) JP-A-4-234319 JP-A-5-310526 Japanese Patent Laid-Open No. 7-330412 JP 7-330611 A Pannala A. et al., Free Radical Biology & Medicine Vol. 24 594-606 (1998) Japanese Patent Laid-Open No. 9-40553

  In Japan, due to the westernization of lifestyle habits, diabetes, hypertension and its complications have increased due to an increase in lifestyle-related diseases caused by obesity due to the intake of high-calorie diets such as high-fat and high-protein diets, and the aging society of the population. There is concern about the increase of cardiovascular diseases such as stroke, cardiac hypertrophy, myocardial infarction, congestive heart failure, coronary artery stenosis. Therefore, the development of preventive and therapeutic methods for these diseases is an important social issue to be solved at an early stage. Stroke is one of the three leading causes of death after cancer and heart disease in Japan, but death due to cerebral hemorrhage has decreased due to the development of antihypertensive therapy, but conversely mild stroke that does not lead to death such as cerebral infarction has increased. There is a tendency. The development of an economical, safe and effective method for preventing the onset and progression of such pathological conditions and improving the prognosis while dementia, reduced motivation, and a decrease in QOL due to stroke increase. It has been demanded.

  In order to answer the above problems, the present inventors have conducted intensive research on the components contained in rice as a staple food, and as a result, ferulic acid and / or physiologically acceptable salts of ferulic acid are found to have hypertension and stroke as well as cerebrovascular. It has excellent inhibitory effects on vascular lesions such as endothelial disorders, diabetes, arteriosclerosis, dementia, etc., which is a disease based on abnormalities of microvessels, and also has microvascular protective action and weight gain inhibitory action, and has few side effects. The headline and the present invention have been completed.

  That is, the therapeutic agent for cardiovascular disease of the present invention contains ferulic acid and / or a physiologically acceptable salt of ferulic acid (hereinafter also referred to as ferulic acid compound, FA) as an active ingredient. It is characterized by that.

  The therapeutic agent for cardiovascular disease is a therapeutic agent for cerebrovascular disease.

  The therapeutic agent for cardiovascular disease is a therapeutic agent for hypertension.

  The therapeutic agent for cardiovascular disease has a microvascular protective effect. The therapeutic agent for cardiovascular disease has an effect of suppressing weight gain. The health food of the present invention is characterized by containing at least one or more ferulic acid and / or physiologically acceptable salts of the ferulic acid as an active ingredient in food and drink.

  Said food-drinks are for animals.

  The health food is characterized by having a weight gain inhibitory action.

  The present invention relates to a novel use of ferulic acid and its salts. More specifically, prevention of hypertension and hypertensive or ischemic organ lesions, especially stroke and cerebral infarction with degeneration of cerebrovascular, and diseases based on microvascular abnormalities such as diabetes, arteriosclerosis, dementia, etc. Regarding treatment. More specifically, as an active ingredient of natural product-derived pharmaceuticals, foods for specified health use, health foods, slow treatment of hypertension and / or its adjunct therapy and / or transient ischemic attack, oxidative stress state Useful for improvement, treatment of cerebrovascular neuropathy in cerebral thrombosis, cerebral infarction, subarachnoid hemorrhage and stroke, adjuvant therapy, improvement of disease prognosis, and hypertension or as an active ingredient of animal food and drink It is useful for suppressing ischemic vascular lesions and weight gain.

  Ferulic acid can be used in either of two isomers, a cis isomer and a trans isomer. In addition, as a physiologically acceptable salt of ferulic acid, the following general formula

  Wherein B is a basic component that forms a salt together with ferulic acid, for example, metal ions such as sodium, potassium, lithium, calcium, magnesium, zinc, arginine, arginine ethyl ester, Examples include amino acid compounds such as lysine and lysine ethyl ester.

  Usually, an amino acid salt compound of ferulic acid can be produced from an amino acid compound having a ratio of 1 or 2 equivalents to 1 equivalent ratio of ferulic acid. The amino acid compound can be used in an excess amount of 3 to 10 equivalent ratio with respect to 1 equivalent ratio of ferulic acid, if necessary.

  In the present invention, ferulic acid compounds are prepared by known pharmaceutical techniques using tablets, granules, powders, lipid microspheres, hard capsules, soft capsules, liposomes, ointments, poultices, eye drops, infusion solutions, hemodialysis solutions, peritoneum Arbitrary pharmaceutical forms such as dialysate and liquid can be used, and an appropriate administration method can be selected and used depending on the purpose of use. Examples of components constituting the preparation of the present invention include excipients, binders, disintegrants, lubricants, coating agents, wetting agents, stabilizers, solubilizers, purified water, pH adjusters, preservatives. , Charged liposome carriers, collagen, polyvinylpyrrolidone, water-soluble polymer compounds, and the like, which can be selected according to the dosage form and prepared by a known and commonly used production method.

  Furthermore, the compounds of the present invention include various types of noodles including cooked rice, miso, soy sauce, cup noodles, kala lou, stew, various soups, sausages, bamboo rings, rice cakes, hampen and other kneaded products, dressings, breads, powdered milk, yogurd, milk It can be added to beverages, lactic acid beverages, tomato beverages, soft drinks, sports beverages, chocolate, cookies, chewing gum, candy, etc. and used for foods for specified health use, health foods and the like. In foods containing the compound of the present invention, retinol such as dietary fiber, whey protein, whey protein hydrolyzate, saccharide, vitamin A, vitamin B1, riboflavin, riboflavin phosphate, ascorbic acid, vitamin D, etc. , Tocopherols such as vitamin E, cyanocobalamin, biotin, nicotinamide, folic acid, calcium pantothenate, taurine, casein, lecithin, monoglyceride, polyglyceride, chlorophyll, etc. Can do. In addition, the compound of the present invention is added to animal feed and is useful as an animal health food for improving various pathologies caused by vascular diseases such as obesity, diabetes and hypertension.

The dose of the compound of the present invention varies depending on the administration route, the type and degree of the pathological condition to be treated, the age and sex of the patient, the body weight, the sensitivity to the administered drug, the timing of administration and the administration interval, etc. 1 to 1000 mg, preferably 1 to 300 mg can be increased or decreased depending on the symptoms and administration route. For animals, 0.01 to 5%, preferably 0.1 to 5% of food is mixed and used, and the amount may be increased or decreased according to symptoms.
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these.

  The preparation method of ferulic acid-L-arginine salt used in the following examples is as follows.

  Under stirring, an aqueous solution (50 ml) of 19.43 g of ferulic acid was added dropwise to an aqueous solution (100 ml) of 17.4 g (0.1 mol) of L-arginine to form a salt, and then concentrated under reduced pressure to obtain crude crystals. . This was recrystallized from water to obtain colorless crystals (yield 87%) of mp 160 ° C. (decomposition).

Example 1
(Evaluation of antihypertensive effect on spontaneously hypertensive rats)
Spontaneously hypertensive rats (purchased from SHR: SHR and other disease model joint study groups) and WKY rats (Wistar-Kyoto rats) showing normal blood pressure as comparative control animals, as drinking water at the same time as the start of the test (5 weeks of age) A test substance-mixed feed in which 1% saline and ferulic acid (FA) as a test substance were mixed with feed (powder feed SP: purchased from Funabashi Farm) by the double dilution method was freely ingested during the test period.

  For blood pressure measurement, systolic blood pressure was measured once a week using a non-invasive automatic blood pressure monitor (developed by Riken Corporation). After measuring blood pressure and body weight at the 6th week, the FA-mixed feed was replaced with a normal feed excluding FA, and thereafter the blood pressure and body weight were similarly measured until the 12th week. The results are shown in Tables 1 and 2.

  In the table, the test substance non-administration control group was ingested with only 1% saline, the FA 1.8% administration group was ingested with 1% saline and 1.8% FA, and the FA 2.7% administration group was 1% saline and 2.7% FA were taken together.

  In addition, the significant difference test in the following Tables 1 to 7 is a statistical process based on a Student's t-test having no correspondence after calculating an average value ± standard error. P represents a significant difference test (t-test method) from the test substance non-administered control group, and a risk rate of less than 5% (p <0.05) was considered significant. Moreover, when * is not attached, it is a case where there is no significant difference compared with the test substance non-administration control group.

(Table 1)
Antihypertensive effect of ferulic acid (FA) on SHR ────────────────────────────────────
Previous value (week 0) Week 6 Week 9 Week 12 Test substance untreated control blood pressure (mmHg) 134.4 ± 4.3 221.4 ± 4.6 237.3 ± 7.2 236.3 ± 7.6
Weight (g) 135.8 ± 2.3 301.0 ± 4.8 308.6 ± 5.8 333.8 ± 4.1
Number of animals (n) 7 7 6 ¹⁾ 6 ¹⁾
FA 1.8% group blood pressure (mmHg) 128.5 ± 2.2 201.1 ± 6.2 * 225.6 ± 6.1 233.6 ± 6.0
Weight (g) 135.5 ± 1.8 264.8 ± 4.1 ** 293.8 ± 5.0 307.0 ± 6.7
Number of animals (n) 6 6 6 5 ²⁾
FA 2.7% group blood pressure (mmHg) 135.4 ± 2.7 192.0 ± 2.5 *** 211.8 ± 3.1 ** 217.7 ± 4.7
Weight (g) 136.8 ± 1.5 239.5 ± 3.4 ** 292.1 ± 3.0 309.4 ± 3.1
Number of animals (n) 7 7 7 7
───────────────────────────────────
* P <0.05, ** P <0.01, *** P <0.001
¹⁾ : 1 case died at 7-8 weeks, ²⁾ : 1 case died at 9-10 weeks (after 6 weeks, FA mixed feed was replaced with normal feed).

(Table 2)
Antihypertensive effect of ferulic acid on WKY rats────────────────────────────────────
Previous value (week 0) Week 6 Week 9 Week 12 No test substance administered WKY Control group blood pressure (mmHg) 99.7 ± 3.0 124.0 ± 3.9 124.0 ± 3.7 124.2 ± 6.4
Weight (g) 123.1 ± 1.8 302.2 ± 4.1 337.2 ± 2.9 349.2 ± 12.0
Number of animals (n) 7 7 7 7
FAKY 2.7% WKY
Blood pressure (mmHg) 99.5 ± 3.1 128.4 ± 4.7 124.0 ± 3.7 135.5 ± 2.8
Weight (g) 122.2 ± 2.8 263.2 ± 4.3 ** 310.1 ± 7.3 ** 349.2 ± 12.0
Number of animals (n) 7 7 7 7
───────────────────────────────────
** P <0.01.

  Evaluation of drug efficacy: FA showed a significant antihypertensive effect in a dose-dependent manner during the 6-week administration period against SHR. On the other hand, FA does not show an antihypertensive effect on WKY rats exhibiting normal blood pressure, but has an antihypertensive effect on the blood pressure increase of spontaneously hypertensive rats, so it is clear that FA has a selective action on hypertensive animals. is there.

  Moreover, from Table 1 and Table 2, significant suppression of the body weight was seen in the FA administration group with respect to SHR and WKY. Subsequent anatomical findings showed that the test substance-administered group showed a significant decrease in fat weight in the lower abdomen, suggesting that it has an effect of suppressing the accumulation of body fat. It was.

(Example 2)
(Evaluation of hypotensive effect on spontaneous stroke rats)
Spontaneous stroke rats (SHR-SP: purchased from the SHR and other disease model collaborative study group) 1% saline as drinking water, ferulic acid (FA) and ferula as test substances simultaneously with the start of the study (5 weeks old) A test substance-mixed feed in which acid arginine salt (FA-Arg) was mixed with feed (powder feed SP: purchased from Funabashi Farm) by the double dilution method was freely ingested during the test period.

  For blood pressure measurement, systolic blood pressure and heart rate were measured once a week using a non-invasive automatic blood pressure monitor (developed by Riken Corporation). The period of blood pressure measurement was set to the 5th week because there is a possibility that a side effect such as an increase in the development of hypertension or an accelerated death period may be caused by stress generated during blood pressure measurement on animals. From the 6th week onward, the onset of symptom and the degree of onset, the presence or absence of death, body weight, etc. were observed until the 7th week.

  In the table, the test substance non-administered control group was ingested alone with 1% saline, the FA 1.8% administered group was ingested with 1% saline and 1.8% FA, and the FA-Arg 1.8% administered group Is a combination intake of 1% saline and 1.8% FA-Arg.

(Table 3)
Antihypertensive effects of ferulic acid (FA) and ferulic acid arginine salt (FA-Arg) on spontaneous stroke rats (SHR-SP) ────────────────────── ─────────────
Previous value (week 0) Week 2 Week 4 Week 7 Test substance non-administration control group blood pressure (mmHg) 124.5 ± 9.0 172.7 ± 4.8 218.4 ± 5.0 NT
Weight (g) 102.0 ± 4.8 169.4 ± 6.2 213.0 ± 6.5 173.0 ± 14.5
Number of animals (n) 7 7 7 4 ¹⁾
FA 1.8% group blood pressure (mmHg) 124.5 ± 5.5 150.2 ± 6.1 * 203.4 ± 4.6 * NT
Body weight (g) 94.0 ± 2.3 148.8 ± 3.3 * 198.2 ± 3.1 233.0 ± 3.8 *** Number of animals (n) 7 7 7 7
FA-Arg 1.8% group blood pressure (mmHg) 122.8 ± 4.6 155.2 ± 4.6 * 196.1 ± 5.8 * NT
Weight (g) 103.2 ± 3.2 156.7 ± 3.8 204.4 ± 4.5 226.4 ± 10.9 *
Number of animals (n) 7 7 7 7
───────────────────────────────────
* P <0.05, *** P <0.001
¹⁾ : 3 cases died
NT: Blood pressure is not measured (not measured after the fifth week, as described in the method section of Example 2).

  From Table 3, in the SHR-SP control group not administered with the test substance, significant weight loss was observed with the onset of neurological symptoms from the 4th week to the 7th week, and 3 out of 7 cases died. On the other hand, in the test substance-administered group, the body weight increased until the seventh week, and no death occurred.

(Table 4)
Delayed onset of neurological symptoms and life-prolonging effect of test substance on SHR-SP────────────────────────────────────
Test substance Number of cases Until onset of neurological symptoms From onset to death Average days of death
(n) Average days Average test days Non-test substance control group
7 41.6 ± 2.1 5.1 ± 1.8 46.7 ± 5.1
FA 1.8% administration group
7 59.6 ± 1.4 *** 10.4 ± 0.6 * 70.0 ± 1.8 ***
FA-Arg salt 1.8% administration group
7 65.4 ± 4.8 *** 8.2 ± 2.2 73.9 ± 4.7 ***
───────────────────────────────────
* P <0.05, *** P <0.001.

Judgment of test results:
Compared with the test substance non-administered SHR-SP control group, a significant antihypertensive effect was observed in the FA administration group and the FA-Arg salt administration group after 2 weeks (Table 3).

  The test results in Table 4 show clear neurological symptom onset delaying effects and life-prolonging effects in the FA administration group and the FA-Arg salt administration group as compared with the test substance non-administration SHR-SP control group.

(Example 3)
(Evaluation of microvascular protective effects in the brain for spontaneous stroke rats)
Spontaneous stroke rat (SHR-SP: purchased from SHR and other disease model joint study group) started 0.005% L-nitroarginine methyl ester (L-NAME: monoxide on vascular endothelium) at the same time as 5 weeks old Nitrogen synthesis inhibitor) mixed drinking water and ferulic acid (FA) and ferulic acid arginine salt (FA-Arg) as test substances were mixed with the feed, respectively, and the test period (8) in parallel with 0.003% L-NAME drinking water. During the week), they were allowed to ingest freely. During the test period, body weight was measured once a week.

  For blood pressure measurement, systolic blood pressure and heart rate were measured once a week using a non-invasive automatic blood pressure monitor (developed by Riken Corporation). During the period of blood pressure measurement, the stress that occurs during blood pressure measurement on animals may lead to secondary effects such as increased hypertension or accelerated death, so this experiment (Example) while observing animal symptoms In this case, the period was up to the 8th week. During the test period, the onset of symptom and the degree of onset, the presence or absence of death, body weight, etc. were observed up to 8 weeks.

  In the table, the test substance non-administration control group received only 0.003% L-NAME drinking water alone, the FA 2.7% administration group received 0.003% L-NAME drinking water and 2.7% FA, FA- The Arg 1.8% administration group received 0.003% L-NAME drinking water and 1.8% FA-Arg in combination.

(Table 5)
Antihypertensive effects of ferulic acid (FA) and ferulic acid arginine salt (FA-Arg) on spontaneous stroke rats (SHR-SP) ────────────────────── ─────────────
Previous value (week 0) Week 2 Week 4 Test substance untreated control group blood pressure (mmHg) 114.4 ± 3.2 154.3 ± 2.8 208.0 ± 7.5
Weight (g) 106.0 ± 1.4 186.0 ± 2.2 210.3 ± 15.8
Number of animals (n) 7 7 7
FA 2.7% group blood pressure (mmHg) 115.0 ± 4.7 141.4 ± 3.1 * 185.1 ± 1.9 *
Body weight (g) 107.7 ± 1.9 137.6 ± 3.0 *** 175.9 ± 3.2
Number of animals (n) 7 7 7
FA-Arg 1.8% group blood pressure (mmHg) 116.0 ± 4.3 146.4 ± 5.0 * 183.6 ± 5.7 *
Weight (g) 102.7 ± 2.9 179.9 ± 4.0 225.7 ± 3.0
Number of animals (n) 7 7 7
───────────────────────────────────
* P <0.05, *** P <0.001.

(Table 6)
Antihypertensive effect of ferulic acid (FA) and ferulic acid arginine salt (FA-Arg) on spontaneous stroke rats (SHR-SP) (continued)
───────────────────────────────────
Week 6 Week 8 Test substance untreated control blood pressure (mmHg) 222.7 ± 19.2 228.0 ± 28.0
Weight (g) 222.5 ± 27.2 233.0 ± 40.0
Number of animals (n) 4 ¹⁾ 2 ²⁾
FA 2.7% group blood pressure (mmHg) 203.1 ± 7.5 207.8 ± 6.0
Body weight (g) 195.1 ± 5.0 213.5 ± 7.4
Number of animals (n) 7 6 ³⁾
FA-Arg 1.8% administration blood pressure (mmHg) 205.7 ± 7.7 221.8 ± 7.1
Body weight (g) 244.3 ± 4.2 * 263.6 ± 6.9
Number of animals (n) 7 5 ⁴⁾
───────────────────────────────────
* P <0.05, *** P <0.001
¹⁾ : ² deaths at 5th week, 1 death at 6th week, ²⁾ : 1 death at 7th week, 1 death at 8th week, ³⁾ : Accidental death after 6th week after blood pressure and weight measurement ⁴⁾ : 1 case died at 7th week and 1 case at 8th week.

(Table 7)
Delayed onset of neurological symptoms and life-prolonging effect of test substance on SHR-SP────────────────────────────────────
Test substance Number of cases Until the onset of neurological symptoms Average days of death
(n) Average number of days
7 38.9 ± 5.3 (6/7) 44.7 ± 4.0 (5/7)
FA 2.7% administration group
6 ¹⁾ 56.0 ± 0.0 ** (0/6) 56.0 ± 0.0 * (0/6)
FA-Arg salt 1.8% administration group
7 54.9 ± 1.1 * (2/7) 55.0 ± 1.0 * (2/7)
───────────────────────────────────
* P <0.05, ** P <0.01
(): (Number of animals that developed or died / number of animals used), ¹⁾ : Accidental death immediately after blood pressure measurement at 6 weeks.

(Determination of test results)
From the test results in Table 7, in the test substance non-administered control group, blood pressure rapidly increased by L-NAME, and the brain microvessels became fragile, and 5 of 7 cases died during the 8-week observation period. However, a clear preventive effect was seen in the FA administration group and the FA-Arg salt administration group. Further, since the average number of days from the start of administration to the onset of neurological symptoms or death from the start of administration was significantly extended as compared with the test substance non-administered SHR-SP control group from Table 7, the FA administration group, FA-Arg salt It was suggested that the microvessels in the brain were protected in the order of the administration group.

Claims (8)

A therapeutic agent for cardiovascular disease, comprising at least one ferulic acid and / or a physiologically acceptable salt of ferulic acid. The therapeutic agent for cardiovascular disease according to claim 1, which is a therapeutic agent for cerebrovascular disease. The therapeutic agent for cardiovascular disease according to claim 1, which is a therapeutic agent for hypertension. The therapeutic agent for cardiovascular disease according to claim 1, which has a microvascular protective effect. The therapeutic agent for cardiovascular disease according to claim 1, which has an action of suppressing weight gain. A health food comprising at least one ferulic acid and / or a physiologically acceptable salt of the ferulic acid in a food or drink. The health food according to claim 6, wherein the food or drink is for animals. The health food according to claim 6 or 7, wherein the health food has an action to suppress weight gain.