Atrial natriuretic peptide depressor therapeutic agent and prophylactic agent and method for producing the same

Abstract

SOLUTION: Heart diseases such as mitral valve myxomatous transformation are more effectively suppressed without impairing the health of a small animal by using a naturally derived substance.EFFECT: The present invention comprises, as main components: 5-9 wt.% of a pine bark dry extract which originates from bark of pines grown while being exposed to strong ultraviolet rays on a southwestern coast of France and which contains proanthocyanidin, and 5-9 wt.% of a fermented sesame dry extract which is obtained from sesame as a main raw material and which contains sesamin, an antioxidant lignan. The present invention further comprises 79-87 wt.% of an excipient such as starch or lactose, the excipient being obtained from starch, lactose, or the like as a raw material, making the powder homogeneous, being compressed into a tablet, and preventing quality deterioration due to moisture adsorption.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to atrial natriuretic peptide (ANP)-lowering therapeutic and prophylactic agents for small animals, particularly dogs, suffering from mitral valve regurgitation, and a method for producing the same. [Background technology]

[0002] Recently, small pet animals such as dogs and cats have become obese due to the increased nutritional value of pet food and overfeeding. When small animals become obese, they are at higher risk of developing heart disease, just like humans. One type of heart disease is mitral valve insufficiency.

[0003] <Overview of Mitral Regurgitation> The heart is an important organ that functions as a pump to circulate blood throughout the body and lungs. Blood collected from the entire body in the vena cava passes from the right atrium to the right ventricle, picks up fresh oxygen in the lungs, and then passes from the left atrium to the left ventricle and then the aorta to be sent back to the body. When small animals are healthy, blood always follows this route.

[0004] The mitral valve in the heart separates the left atrium from the left ventricle, and if there is an abnormality in this valve, the valve will not close properly, allowing blood to flow backward from the left ventricle to the left atrium. "Mitral valve myxomatous degeneration" is the most common heart disease in dogs, and as it progresses, the mitral valve becomes thicker, shorter, and more irregular, causing blood to flow backward. This heart disease is also known as "mitral valve insufficiency" or simply "mitral valve regurgitation."

[0005] As the amount of blood reflux increases, the blood stagnating within the heart pushes the heart into a larger space, causing cardiac enlargement. To a certain extent, cardiac function improves in a compensatory manner, allowing the increased blood volume to be adequately pumped throughout the body. However, as the condition progresses to severe cardiac enlargement, the heart is unable to compensate and fails. This means that the blood stagnating in the left atrium leaks into the lungs, impairing breathing and causing "pulmonary edema." Once pulmonary edema develops, respiratory failure progresses rapidly, and delayed treatment can lead to death.

[0006] <Symptoms of mitral valve regurgitation> Mitral valve insufficiency has few early symptoms, and in most cases, symptoms include slight fatigue and reduced play time. As the condition gradually progresses, the child may tire easily when exercising or excited, and the tongue may turn purple (a phenomenon known as cyanosis). Other symptoms include increased sleeping time. Increased coughing is also a bad sign. As the condition progresses further, the child may become less willing to move, tire easily, and even slight stimulation may cause persistent coughing, leading to cyanosis and fainting.

[0007] When mitral regurgitation becomes severe and pulmonary edema develops, symptoms include restlessness due to difficulty breathing, being unable to lie down and breathing with one's shoulders while sitting, heavy breathing and persistent cyanosis, stretching the neck and gasping for breath, etc. Eventually, symptoms include coughing up a pink liquid mixed with blood, lying down listlessly and unresponsive due to hypoxia of the brain, and death from respiratory failure.

[0008] <Diagnosis of mitral valve regurgitation> When regurgitation occurs in the mitral valve, a heart murmur can be heard. However, because auscultation alone cannot diagnose or assess the severity of heart disease, tests are often performed to objectively examine the shape, size, and function of the heart. These tests include X-rays, ultrasound, blood pressure measurements, and electrocardiograms. In addition, it is important to perform blood and urine tests to determine whether heart disease is related to problems in other organs.

[0009] <Stages of mitral regurgitation> Mitral valve insufficiency is generally described in five stages, as classified by the American College of Veterinary Internal Medicine (ACVIM): (1) Stage A Stage A is a stage where there is currently no abnormality in the heart. Dog breeds at high risk of developing heart failure in the future include Cavalier King Charles Spaniels and Chihuahuas. (2) Stage B1 Stage B1 is when heart murmurs, valve degeneration, and mitral regurgitation begin to appear, but there is no cardiac enlargement. (3) Stage B2 Stage B2 is the stage where heart murmurs, valve degeneration, mitral regurgitation, and cardiac enlargement are observed. (4) Stage C Stage C is when symptoms such as coughing and shortness of breath are present and the patient has previously been treated for pulmonary edema. (5) Stage D Stage D is the stage where there is a poor response to medical treatment despite all medical treatments.

[0010] This stage classification is very well-known and is used as a reference by many veterinarians who provide cardiology care. While it is simple and easy to understand, the same stage can include patients with different levels of severity, and the rate of progression can vary greatly from patient to patient, so it is essential to regularly check up on the condition.

[0011] <Treatment of mitral valve regurgitation> The recommended treatment for mitral regurgitation varies depending on the severity of the condition. However, as mentioned above, the condition of each patient varies even within the same stage, so the actual treatment is a little more complicated. (1) Stage A No drug or dietary treatments are recommended. (2) Stage B1 No drug or dietary therapy is recommended. Cardiac ultrasound and X-ray examinations are recommended every 6-12 months. (3) Stage B2 The use of a type of cardiac stimulant called pimobendan is strongly recommended. Dietary therapy is also recommended. Depending on the condition, the use of antihypertensive drugs, beta-blockers, aldactone (a weak diuretic), etc. may be considered. (4) Stage C In the acute phase, i.e., in the case of pulmonary edema, hospitalization and intensive care, including the administration of powerful diuretics (furosemide), pimobendan, sedatives, antihypertensives, and oxygen therapy, are strongly recommended. If respiratory distress does not improve and progresses, respiratory support with a ventilator under anesthesia may be considered to save the patient's life. In the chronic phase, i.e., after the pulmonary edema has subsided, continued administration of diuretics, pimobendan, and antihypertensive drugs, as well as frequent reevaluation of renal and cardiac parameters, is strongly recommended. Keeping a record of health status, such as diet and weight, at home is also recommended. (5) Stage D The patient's condition remains unstable and does not improve despite treatment with high-dose diuretics, pimobendan, and antihypertensive drugs, and treatment tailored to the situation is required. Cardiac surgery by a specialized cardiac surgery team may be the solution.

[0012] Techniques have been proposed for assessing the risk of developing this disease in dogs suspected of having mitral regurgitation. For example, Patent Document 1, entitled "Method for assessing the risk of developing disease in dogs," proposes a method for assessing the risk of developing disease in dogs, which includes the steps of measuring the body fat percentage of a dog and classifying the dog into cases where the body fat percentage is 35% or more and cases where the body fat percentage is less than 35%, and the steps of classifying the age of the dog measured into cases where the dog is 5 years old or older and cases where the dog is under 5 years old, and which determines that a dog that is 5 years old or older and has a body fat percentage of 35% or more has a high risk of developing mitral regurgitation and / or trichotomous regurgitation. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-97868 Summary of the Invention [Problem to be solved by the invention]

[0014] However, this patent document 1 only aims to prevent the onset of diseases in dogs by simply measuring the body fat percentage and maintaining the body fat percentage below a specific value through dietary management. It only contributes greatly to the health management of dogs, but does not improve the health of diseased small animals.

[0015] With conventional treatment methods, it is difficult to detect early stages such as Stage A and Stage B1, as cardiac abnormalities are unlikely to appear. In addition, when treating mitral valve regurgitation, drug therapy or dietary therapy is not recommended in these early stages, so by the time symptoms change significantly, it is often too late.

[0016] In light of these circumstances, the inventors of the present invention conducted extensive research. They found that bark extract possesses powerful antioxidant and anti-inflammatory properties. The proanthocyanidins contained in pine bark extract inhibit the oxidation of bad (LDL) cholesterol and are effective in preventing lifestyle-related diseases. They also promote blood flow. The inventors of the present invention therefore considered that heart diseases such as mitral valve myxomatous degeneration often progress relatively slowly, with no noticeable symptoms, and by the time they are noticed, the disease is terminal, or the patient may suddenly die. They believed that naturally derived substances could be taken regularly like supplements without posing a risk to health and preventing the rapid worsening of symptoms.

[0017] Furthermore, we have focused on the effectiveness of sesame as a functional food ingredient. Sesame has long been consumed as a highly nutritious food, and sesamin in particular has attracted attention as an antioxidant food ingredient derived from sesame. Furthermore, we have focused on the fact that fermented sesame significantly enhances the antioxidant and immunostimulating effects that sesame naturally possesses, and we believe that it may also contribute to improving blood pressure.

[0018] When a dog suffers from mitral valve insufficiency, the amount of blood pumped from the heart decreases. To prevent a drop in blood pressure, the body attempts to maintain systemic blood pressure by constricting peripheral blood vessels through homeostasis. This maintains the amount of blood returning to the heart. However, at the same time, this causes poor circulation in peripheral tissues and volume overload on the heart. Cardiac volume overload stretches the right and left atrial muscles. When excessive left atrial volume overload causes excessive left atrial pressure, it can lead to "pulmonary edema." When the atrial muscles are stretched in this way, excessive secretion of atrial natriuretic peptide (ANP) occurs. The inventors of the present invention have noticed that the above-mentioned pine bark extract and sesame fermented product has the effect of relaxing peripheral blood vessels. This effect of relaxing peripheral blood vessels reduces the amount of blood returning to the heart, thereby reducing the volume load on the atrium. This effect reduces the amount of ANP secreted. They believe that the pine bark extract and sesame fermented product ultimately reduces the left atrial volume load, thereby having the effect of suppressing the occurrence of pulmonary edema, etc.

[0019] The inventors of the present invention have noticed that pine bark extract and sesame fermentation product are effective in improving mitral valve insufficiency in dogs, but the blending ratio was unknown. They believed that there was an optimal blending ratio that could reduce left atrial volume overload without increasing the burden on the heart of each dog.

[0020] The present invention has been devised to solve these problems. That is, an object of the present invention is to provide a therapeutic and preventive agent for atrial natriuretic peptide lowering that can more effectively suppress heart diseases such as mitral valve myxomatous degeneration without harming the health of small animals by using naturally occurring substances, and a method for producing the same. [Means for solving the problem]

[0021] The atrial natriuretic peptide lowering therapeutic and prophylactic agent of the present invention comprises: An atrial natriuretic peptide lowering therapeutic or preventive agent for use in an animal suffering from mitral valve regurgitation, comprising: in the southwest of France The bark of pine trees that grow on the coast exposed to strong ultraviolet rays is A step of extracting the pine bark extract using an extract solution of 30% by weight or more at 10 to 50°C to produce a pine bark extract, and a step of concentrating the pine bark extract to a water content of 5 to 20%. a step of adding 30% by weight or more of amino acids to sesame seeds, inoculating one or more bacteria selected from lactic acid bacteria, and fermenting the mixture at 10 to 50°C to produce a fermented sesame dry extract; and a step of blending the concentrated pine bark dry extract with the fermented sesame dry extract so that the weight mixing ratio of the pine bark dry extract to the fermented sesame dry extract is 1:0.5 to 2.0. The atrial natriuretic peptide lowering treatment and prophylactic agent further comprises 0.5 to 0.9% by weight of glutathione yeast, which is composed of glutamic acid, cysteine, and glycine.

[0022] The fermented sesame dry extract is an extract containing organic selenium at a weight ratio of 75 ppm or more. Atrial natriuretic peptide lowering therapeutic and prophylactic agents can be formulated with potassium, magnesium, zinc, manganese, or copper as essential mineral supplements. Antioxidant lignans, including sesamin and sesamolin, can be compounded in atrial natriuretic peptide lowering therapeutic and preventive drugs.

[0023] Atrial natriuretic peptide lowering therapeutic and preventive drugs are preferably prepared by coating a tablet formed by pressure to a certain hardness with a polysaccharide such as starch, glycogen, or cellulose, and then coating the outer surface of that with a water-soluble monosaccharide or disaccharide such as starch or dextrin.

[0024] Atrial natriuretic peptide lowering therapeutic and prophylactic drugs can be filled into double-walled capsules in which the inner shell (12) is made of starch and the outer shell (11) is made of gelatin that is more soluble in water than the inner shell (12).

[0025] The method for producing an atrial natriuretic peptide lowering therapeutic agent and a preventive agent of the present invention includes extracting bark of pine trees grown on the coast exposed to strong ultraviolet rays at 10 to 50°C using an extract solution of 30% by weight or more to produce a pine bark extract; The pine bark extract is concentrated to a water content of 5 to 20%. Adding 30% by weight or more of amino acids to sesame seeds, inoculating one or more bacteria selected from lactic acid bacteria, and fermenting the mixture at 10 to 50°C to produce a fermented sesame dry extract; The concentrated pine bark dry extract is blended with the fermented sesame dry extract in a weight mixing ratio of 1:0.5 to 2.0. [Effects of the Invention]

[0026] The atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention contain naturally derived substances, pine bark dry extract and fermented sesame dry extract, which is made primarily from sesame seeds, in an optimal blend ratio without diminishing the functions of the pine bark dry extract, fermented sesame dry extract, and glutathione yeast, and therefore can reduce left atrial volume overload without increasing the burden on the dog's heart, thereby preventing the rapid worsening of symptoms without harming the health of small animals. Glutathione yeast has the antioxidant effect of glutathione and can contribute to improving blood pressure. Proanthocyanidins contained in dried pine bark extract inhibit the oxidation of bad (LDL) cholesterol and can prevent lifestyle-related diseases. The antioxidant and immunostimulating properties inherent in sesame can contribute to improving blood pressure.

[0027] By molding atrial natriuretic peptide lowering therapeutic and prophylactic drugs into sugar-coated tablets or double-layered capsules, it is possible to prevent the drugs from adhering to the palate or the lining of the throat or esophagus, and to administer the drugs to small animals without having to worry about odors or bitter tastes. [Brief explanation of the drawings]

[0028] [Figure 1] 1 is a table showing the mixing ratio of atrial natriuretic peptide lowering therapeutic agents and prophylactic agents of the present invention. [Figure 2] FIG. 1 is an enlarged cross-sectional view showing a therapeutic and prophylactic atrial natriuretic peptide lowering drug in the form of a sugar-coated tablet with a double sugar coating. [Figure 3] FIG. 1 is an enlarged cross-sectional view showing atrial natriuretic peptide lowering therapeutic and prophylactic agents filled in a double capsule. [Figure 4] FIG. 1 is a flow chart showing a method for producing a therapeutic and prophylactic atrial natriuretic peptide lowering agent of the present invention in Example 2. [Figure 5] FIG. 1 is a flow chart showing in detail the manufacturing process of pine bark dry extract. [Figure 6] FIG. 1 is a flow chart showing in detail the manufacturing process of the fermented sesame dry extract. [Figure 7] 1 is a graph showing the change in ANP values ​​before and after administration of an atrial natriuretic peptide-lowering therapeutic agent and a prophylactic agent of the present invention to an animal (dog) suffering from mitral regurgitation (MR). [Figure 8] 1 is a graph showing changes in symptoms at each stage. [Figure 9] 1 is a graph showing the distribution of severity. [Figure 10] 1 is a graph showing the improvement in clinical symptoms after administration of an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent to nine dogs in Group A. [Figure 11] 1 is a graph showing the improvement of clinical symptoms in 9 cases in Group A by administration of an atrial natriuretic peptide-lowering therapeutic agent and a prophylactic agent of the present invention. [Figure 12] 1 is a graph showing the improvement of clinical symptoms in 12 cases in Group B by administration of an atrial natriuretic peptide-lowering therapeutic agent and a prophylactic agent of the present invention. [Figure 13] This is an image showing a comparison of chest x-ray images of a dog. [Figure 14] 10 is an image showing a comparison of x-ray images taken from different angles of a dog's chest. [Figure 15] This is an image showing a comparison of ultrasound examinations (echo examinations) on the right parasternal four-chamber view. [Figure 16] This is an image showing a comparison of ultrasound examination (echo examination) on the right parasternal short axis four-chamber view. [Figure 17] This is a comparison of color blood flow jet areas, and is an image showing a comparison of ultrasound examination (echo examination) of left ventricular inflow blood flow velocity waveforms. [Figure 18] This study examined the cardiac activity of dogs with symptoms of bradycardia-tachycardia syndrome. [Figure 19] FIG. 1 is an explanatory diagram showing the improvement in clinical symptoms when a therapeutic and prophylactic atrial natriuretic peptide-lowering agent of the present invention is administered to a dog with symptoms of bradycardia-tachycardia syndrome. [Figure 20] 1 is an image showing a comparison of X-ray images when a therapeutic atrial natriuretic peptide lowering agent and a preventive agent of the present invention are administered to a dog with sick sinus syndrome symptoms. [Figure 21] 1 is an image showing a comparison of X-ray images when a therapeutic atrial natriuretic peptide lowering agent and a preventive agent of the present invention are administered to a dog with sick sinus syndrome symptoms. BEST MODE FOR CARRYING OUT THE INVENTION

[0029] The raw materials for the therapeutic and prophylactic atrial natriuretic peptide lowering drugs of the present invention are mainly composed of two ingredients: pine bark extract and fermented sesame extract. The pine bark extract contains a flavonoid called proanthocyanidin. The fermented sesame extract contains sesamin, an antioxidant lignan. Example 1

[0030] <Dry pine bark extract> FIG. 1 is a table showing the types, raw materials, and mixing ratios of the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention. The atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention in Example 1 are drugs containing, as their main ingredients, a pine bark dry extract containing proanthocyanidins and a fermented sesame dry extract containing sesamin, an antioxidant lignan derived primarily from sesame. The mixing ratio of the pine bark dry extract to the fermented sesame dry extract is 1:0.5 to 2.0 by weight of the fermented sesame dry extract. This proanthocyanidin is a polyphenol having a structure in which catechin molecules are linked together. It is a component that functions as an antioxidant.

[0031] The main ingredient of the first of the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention, "dried pine bark extract," is a natural plant extract taken from the bark of maritime pine trees growing on the coast of southwestern France. This French maritime pine bark extract is an ingredient extracted from the bark of pine trees growing on the coast of southwestern France, which are exposed to strong ultraviolet rays. This coastal area of ​​France has sunny weather for more than 320 days a year and is exposed to very strong ultraviolet rays, so the pine trees growing in this area have developed a large accumulation of antioxidants to protect themselves.

[0032] Proanthocyanidins contained in pine bark dried extract, the main ingredient of this invention, possess excellent antioxidant properties that strengthen the body's antioxidant capacity. They increase nitric oxide and improve blood flow, strengthening the circulatory system. They bind to collagen and elastin, repairing and strengthening blood vessel walls. They inhibit NF-kB (nuclear factor-kappa B), providing potent anti-inflammatory effects. NF-kB is a regulator of the acute phase of inflammatory responses and is required for effective immune defense and the elimination of transformed cells. They stabilize blood sugar levels by suppressing postprandial increases in blood glucose levels through α-glucosidase inhibition. α-glucosidase assists in the hydrolysis of sugar bonds, where water reacts with the bonds between sugars.

[0033] The proanthocyanidins contained in dried pine bark extract have the effect of improving blood flow, which reduces the risk of heart disease. First, they have the effect of suppressing platelet aggregation. In humans, they are effective against platelet aggregation caused by smoking and against economy class syndrome. They also have the function of dilating blood vessels. They reduce the production of the vasoconstrictor endothelin-1 and promote the production of the vasodilator prostacyclin.

[0034] Proanthocyanidins contained in dried pine bark extract have the effect of reducing the risk of heart disease. Vascular regulatory factors derived from vascular endothelial cells include the following: Endothelin is a powerful vasoconstrictor peptide derived from vascular endothelial cells, and its production increases during heart failure. Prostacyclin (PGI2) has vasorelaxant and platelet aggregation inhibitory effects. Nitric oxide (NO) is a representative vasorelaxant factor derived from vascular endothelial cells.

[0035] <Fermented sesame dry extract> "Fermented sesame dry extract" contains sesamin, an antioxidant lignan unique to sesame. Sesame has long been consumed as a highly nutritious food. In recent years, its functionality has been studied, and sesame lignan, a type of phenylpropanoid, has been used in many supplements as a functional food ingredient. Sesamin, in particular, has attracted attention as an antioxidant food ingredient derived from sesame. Antioxidation and immunity are important elements of modern functional foods, and these can improve the so-called pre-disease state that is the root cause of all diseases. In this invention, the functionality of conventional sesame fermentation products is enhanced, and in addition to the blood pressure suppressing effect that sesame naturally has, lactic acid fermentation is used to efficiently produce gamma-aminobutyric acid, thereby enhancing the blood pressure suppressing effect.

[0036] Fermented sesame dry extract is a plant-derived physiologically active ingredient containing high concentrations of the essential trace mineral organic selenium, as well as other essential minerals such as potassium, magnesium, zinc, manganese, and copper, as well as antioxidant lignans (sesamin and sesamolin) unique to sesame.

[0037] Glutathione yeast is composed of glutamic acid, cysteine, and glycine. Glutathione yeast has the antioxidant effect of glutathione, and is effective in contributing to improving blood pressure. Glutathione yeast is preferably contained in an amount of 0.5 to 0.9% by weight.

[0038] The pine bark dry extract, fermented sesame dry extract, and glutathione yeast are molded using excipients made from starch, lactose, and other raw materials. This ensures uniformity of the powder and prevents tablets from hardening and deterioration due to moisture absorption. The formulations are tablets, capsules, and powders. As this is a therapeutic and preventative medicine for small animals, tablet form is preferred. Powders are difficult to administer to small animals, but they can be mixed into feed.

[0039] <Mixing ratio> The optimal combination of the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention was as shown in the table in Figure 1. The pine bark dry extract was 5-9% by weight, the fermented sesame dry extract was 5-9% by weight, and the excipient was 79-87% by weight. For small dogs weighing around 10 kg, and small to medium-sized dogs, if the amount of atrial natriuretic peptide lowering therapeutic and preventive medication to be administered is 140 mg, then the appropriate amounts are 7 to 13 mg of fermented sesame dry extract, 7 to 13 mg of fermented sesame dry extract, 0.7 to 1.3 mg of glutathione yeast, and 110 to 122 mg of excipients.

[0040] <Adjuvants> Potassium, magnesium, zinc, manganese or copper can be incorporated as an essential mineral supplement into the atrial natriuretic peptide lowering therapeutic and prophylactic agents of the present invention. Furthermore, antioxidant lignans including sesamin and sesamolin can be incorporated as adjuvants into the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention.

[0041] <Sugar-coated tablets with double sugar coating> FIG. 2 is an enlarged cross-sectional view showing a therapeutic and prophylactic atrial natriuretic peptide lowering drug in the form of a sugar-coated tablet having a double sugar coating. When administering the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention to small animals, the sugar-coated tablets may adhere to the palate of the small animal or to the inner wall of the throat or esophagus. If the sugar in the sugar-coated tablets dissolves before reaching the stomach and the drug inside is exposed to the mouth or throat, the odor and taste of the drug may become bothersome, causing the animal to dislike administration of the drug. Therefore, the sugar in the sugar-coated tablets is designed to form a double coating around the drug, with the outer sugar coating being more water-soluble than the inner sugar coating, making it less likely to adhere to the inner wall of the throat or esophagus.

[0042] For example, the inner sugar coating 2 that coats tablet 1 is made of polysaccharides such as starch, glycogen, and cellulose. This is to protect the drug from dissolving until it reaches the stomach. After being exposed to saliva and gastric juices, it dissolves in about 5 minutes, exposing the drug 1 inside. The outer sugar coating 3 is made of monosaccharides such as glucose and fructose, or disaccharides such as sucrose and lactose, which are more soluble in water than the inner sugar coating 2. This takes advantage of the tablet's ability to be easily dissolved by the digestive enzymes in saliva. By molding the outer sugar coating 3 of this tablet from a material that dissolves easily, it is possible to prevent the tablet 1 from sticking to the roof of the mouth or the inner walls of the throat and esophagus.

[0043] <Double capsule> FIG. 3 is an enlarged cross-sectional view showing a therapeutic atrial natriuretic peptide lowering agent and a prophylactic agent filled in a double capsule. This double capsule also prevents the capsule from adhering to the roof of the mouth or the inner wall of the throat or esophagus of small animals. If the gelatin and sugar in the capsule dissolve before reaching the stomach and the medicine inside is exposed to the mouth and throat, the smell and taste of the medicine can bother the animal, leading to a reluctance to take the medicine. Therefore, the medicine 13 is filled into a double-layered capsule, with the outer coating 11 made of gelatin, which dissolves more easily in water than the inner coating 12 (starch).

[0044] For example, the inner coating 12 of the capsule is made by thoroughly drying vegetable fiber or starch to form a hard coating that protects the filled drug 13. It dissolves in saliva and gastric juices in about 5 minutes, exposing the drug 13 inside. The outer coating 11 of the capsule is made of a material that dissolves more easily in water than the inner coating 12. For example, gelatin dissolves more easily in the digestive enzymes of saliva and the stomach than vegetable fibers or starch. By making the outside of the capsule out of a material that dissolves easily, it is possible to prevent the capsule from adhering to the roof of the mouth or the inner walls of the throat or esophagus. Example 2

[0045] <Method of manufacturing therapeutic and preventive atrial natriuretic peptide lowering drugs> Figure 4 is a flow chart showing the method for producing the therapeutic and prophylactic atrial natriuretic peptide lowering agent of the present invention in Example 2. Figure 5 is a flow chart showing in detail the process for producing the pine bark dry extract. Figure 6 is a flow chart showing in detail the process for producing the fermented sesame dry extract. The method for producing the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention involves collecting bark from pine trees exposed to strong ultraviolet light on the coast, shredding it, and pulverizing it. The pulverized bark is then extracted with a butylene glycol extract. For example, the extraction is performed using a butylene glycol extract containing 30% by weight or more at 10 to 50°C. The solvent is not limited to butylene glycol, and solvents (oils) such as ethanol can also be used. This pine bark extract is filtered and concentrated under reduced pressure until the water content reaches, for example, 10 to 30%. It is then spray dried and pulverized to produce a dry pine bark extract.

[0046] Fermented sesame dry extract is produced by adding amino acids to sesame seeds, inoculating one or more lactic acid bacteria and fermenting them to produce a fermented sesame dry extract. To efficiently ferment sesame, it is necessary to sterilize the bacteria on the surface of the sesame seeds. Sterilization methods include heat sterilization and pH treatment sterilization, and degreasing may also be performed if necessary. Sesame seeds can be fermented in their granular form, but for better fermentation, they are used after being finely ground. Sesame fermentation is carried out in the presence of water. Fermentation methods include tank culture, in which a large amount of water is added, solid culture, in which a small amount of water is added, and a method in between, in which the sesame is fermented in a paste form. Tank culture, which can process large amounts relatively quickly, is preferred.

[0047] The types of lactic acid bacteria to be inoculated include Lactobacillus, Bifidobacterium, Lactococcus, Pediococcus, and Leuconostoc, among others, and non-toxic strains can be used. Lactobacillus casei is particularly preferred because it efficiently ferments the substrate in sesame seeds and converts sesaminol to sesamol, and Lactobacillus reuteri is even more preferred because it efficiently produces γ-aminobutyric acid. The amount of lactic acid bacteria to be inoculated is 0.5 to 10% by weight of a liquid cultured bacterial solution to the liquid or solid containing sesame, and it is particularly preferable to inoculate 1.0% by weight aseptically.

[0048] The fermented sesame dry extract produced in this way is made by fermenting sesame flakes to reduce their molecular weight, removing unnecessary fiber components, and then using a separation and purification method to highly concentrate selenium and other essential minerals.This is a pure plant-derived physiologically active material (phytochemicals) powder that contains a high concentration of organic selenium (selenium), an essential trace mineral derived from sesame.

[0049] The fermented sesame dry extract is a light brown powder containing 75 ppm or more of selenium (average 100 ppm), less than 20% oil, less than 8% moisture, less than 1 ppm arsenic (as As2O3), less than 10 ppm heavy metals (as Pb), and a general viable bacteria count of 3 x 10 3 Less than 100 count / g, E. coli negative.

[0050] The concentrated pine bark dry extract is mixed with fermented sesame dry extract in a ratio of 1:0.5 to 2.0 by weight, thereby completing the production of atrial natriuretic peptide lowering therapeutic and preventive medicines. The compound is then formulated into tablets, capsules, etc. to produce therapeutic and preventive atrial natriuretic peptide lowering drugs.

[0051] <Administration of atrial natriuretic peptide lowering drugs and preventive medications> The recommended dose of the therapeutic and prophylactic atrial natriuretic peptide lowering agent of the present invention to be administered to small animals such as dogs is preferably about 560 mg for dogs weighing 10 kg or less.

[0052] <Case description> The effects of the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention on animals (dogs) suffering from mitral regurgitation (MR) will be described below. Table 1 shows the changes in ANP (atrial natriuretic peptide) values ​​after one month of administration of the atrial natriuretic peptide lowering therapeutic and preventive agents of the present invention to 26 dogs with mitral regurgitation (MR). ANP values ​​are hormones secreted primarily from the atria and are a value that indicates an important role in regulating body fluid volume and blood pressure. After administration, the values ​​decreased in many cases. Three dogs (three dogs) received the agent alone, and 23 dogs (23 dogs) received it in combination with other drugs.

[0053] [Table 1]

[0054] <Changes in ANP values ​​in 26 dogs> FIG. 7 is a graph showing the change in ANP levels before and after administration of the atrial natriuretic peptide lowering therapeutic and prophylactic agents of the present invention to animals (dogs) suffering from mitral regurgitation (MR). Figure 7 also shows the changes in ANP levels. The left bar of each line shows the value before administration, and the right bar shows the value one month after administration. This shows that ANP levels decreased in 10 of the 26 dogs after administration. In addition, ANP levels increased in 6 dogs, and remained unchanged in 10 dogs.

[0055] Table 2 shows the changes in QOL (quality of life) scores. This QOL score is a numerical value that quantifies the impact that the disease and treatment have on the patient's (dog's) subjective sense of well-being (mental health, vitality, pain, etc.) and daily activities. As shown in Table 2, most of the scores improved after administration.

[0056] [Table 2]

[0057] Figure 8 is a graph showing the change in symptoms at each stage, and Figure 9 is a graph showing the distribution of severity. Figure 8 explains the "symptoms," "heart murmur," "cardiac enlargement," "need for treatment," and the need for administration of "ACEI," "furosemide," and "pimobendan" in stages A to D. Figure 9 is a graph showing the distribution of severity of 20 cases from stage B1 to stage D.

[0058] Figure 10 is a graph showing the improvement in clinical symptoms after administration of an atrial natriuretic peptide lowering agent and a preventative agent to the nine dogs in Group A. Dogs diagnosed with mitral valve regurgitation were observed for one month. They were divided into two groups based on the veterinarian's examination. Group A included 9 dogs in which ANP levels were measured. Group B mainly underwent clinical observation, including 12 dogs. During this observation, each dog's owner monitored their respiratory rate while the dog was sleeping. Similarly, they were observed for coughing and behavior during walks. There were no changes to the medication regimen for the atrial natriuretic peptide-lowering therapeutic and preventative drugs of the present invention during the one-month administration period. Furthermore, no other supplements were used concomitantly.

[0059] The improvement in clinical symptoms resulting from the administration of the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention will be described. The nine dogs in Group A showed improvements after administration as classified as "markedly effective," "alleviated," "no change," or "worsened." Table 3 shows the improvement in clinical symptoms after the administration of the atrial natriuretic peptide lowering therapeutic and preventive drugs to the nine dogs in Group A. The rates of "markedly effective" and "alleviated" were 77.8%.

[0060] [Table 3]

[0061] FIG. 11 is a graph showing the improvement in clinical symptoms of 9 cases in Group A as a result of administration of the therapeutic and prophylactic atrial natriuretic peptide lowering drugs of the present invention. Each pair of bars shows the ANP values ​​for each dog. The dark gray bar on the left is the ANP value before administration of the atrial natriuretic peptide-lowering drug and preventive drug of the present invention, and the light gray bar on the right is the ANP value one month after administration. After administration, the values ​​decreased in many cases.

[0062] FIG. 12 is a graph showing the improvement in clinical symptoms of 12 cases in Group B as a result of administration of the therapeutic and prophylactic atrial natriuretic peptide lowering drugs of the present invention. Next, the 12 dogs in Group B were shown to show whether they were "improved," "no change," or "discontinued due to worsening" after administration. Table 4 shows the improvement in clinical symptoms after administration of atrial natriuretic peptide lowering therapeutic and preventive medications. The improvement rate was 66.7%.

[0063] [Table 4]

[0064] Next, we will explain the changes in resting respiratory rate for both Group A and Group B. Table 5 shows the improvement in clinical symptoms for 11 cases after administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. Many of the values ​​decreased after administration compared to before administration, indicating an improvement in resting respiratory rate.

[0065] [Table 5]

[0066] <Comparison of X-ray images of cases> Figures 13 and 14 are images showing a comparison of X-ray images for each case. Figure 13 shows chest X-ray images of a dog. The image on the left is before administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. The image on the right is 25 days after administration. This image shows that administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention has resulted in a clearer outline of the heart and improved lung opacity.

[0067] Figure 14 shows X-ray images of the dog's chest taken from a different angle. The image on the left is before administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. The image on the right is 25 days after administration. This image shows that administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention has made the outline of the heart clearer and improved lung opacity.

[0068] <Comparison of ultrasound examination (echo examination) images of cases> Figures 15 and 16 are images comparing the color blood flow jet area and showing a comparison of ultrasound examinations (echo examinations) on the right parasternal four-cavity section. Figure 15 shows images of a dog's right parasternal long axis ultrasound examination (echocardiography). The image on the left is before administration of the atrial natriuretic peptide-lowering drug and preventive drug of the present invention. The image on the right is 25 days after administration. These images demonstrate that administration of the atrial natriuretic peptide-lowering drug and preventive drug of the present invention significantly reduced the area of ​​the left atrium reflux color blood jet, predicting a reduction in the amount of reflux blood. The ARJ / LAA ratio decreased from 50% to 30%.

[0069] Figure 16 shows images of a right parasternal short-axis ultrasound examination (echocardiography) of a dog. The image on the left is before administration of the atrial natriuretic peptide-lowering agent therapeutic and prophylactic agents of the present invention. The image on the right is 25 days after administration. The left ventricular end-diastolic internal diameter (LVIDd) changed from 4.36 cm to 3.56 cm. Left ventricular end-systolic internal diameters (LVIDs) changed from 1.57 cm to 1.51 cm.

[0070] FIG. 17 is a comparison of color blood flow jet regions, and is an image showing a comparison of ultrasound examination (echo examination) of left ventricular inflow blood flow velocity waveforms. Figure 17 shows ultrasound (echo) images of the left ventricular inflow velocity waveform in a dog. The image on the left is before administration of the atrial natriuretic peptide lowering therapeutic and prophylactic drugs of the present invention. The image on the right is 25 days after administration. E wave velocity (early diastolic wave) changed from 1.24 m / s to 0.89 m / s. E / A ratio changed from 1.56 to 1.17. A wave velocity is the atrial systolic wave.

[0071] <Sick sinus syndrome> We describe the case of a 7.1 kg, neutered female miniature schnauzer with a medical history of diabetes and Cushing's syndrome. She also had mitral valve insufficiency (III / VI). Clinical symptoms included syncope at rest due to sinus bradycardia (ISACHC classification Ib, ACVIM classification B2). Concomitant medications included Vetmedin, cilostarol, and a Chinese herbal medicine (water leech plant extract).

[0072] Sick sinus syndrome is a disease that causes bradycardia due to abnormalities in the cells of the sinoatrial node, which sends commands to the heart to contract. Sinus bradycardia (awareness of a slow heart rate, causing subjective symptoms such as dizziness, lightheadedness, and a floating sensation), sinus arrest (frequent dizziness and lightheadedness, and prolonged sinus arrest can lead to fainting (Adams-Stokes attack)), sinoatrial block (a condition in which the cells of the atrioventricular node, which transmit the command to contract the heart, are impaired, preventing the command from being properly transmitted from the atria to the ventricles), supraventricular tachycardia (a condition in which the pulse suddenly becomes (paroxysmal) fast and continues (tachycardia), and when the fast pulse comes from the atria or nearby areas (supraventricular), it is called paroxysmal supraventricular tachycardia). Sick sinus syndrome is a combination of these, not a single disease. Sick sinus syndrome is characterized by (A) severe sinus bradycardia, (B) severe sinus arrest, and (B) bradycardia-tachycardia syndrome.

[0073] Figure 19 shows the results of examining the cardiac activity of a dog with symptoms of bradycardia-tachycardia syndrome. Figure 19 is an explanatory diagram showing the improvement in clinical symptoms when a dog with symptoms of bradycardia-tachycardia syndrome is administered with an atrial natriuretic peptide-lowering therapeutic drug and a preventive drug of the present invention. Dogs with bradycardia-tachycardia syndrome alternate between severe bradycardia and severe tachycardia. Bradycardia is often accompanied by syncope. In Figure 18, the oval area indicates a severe bradycardia lasting 30 seconds or longer. When this dog was administered the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention, the heart rate increased from 40 to 48 beats / min, the respiratory rate decreased from 43 to 35 breaths / min, and the blood pressure increased from 120 / 82 to 125 / 90 mmHg. Furthermore, syncope disappeared approximately two weeks after the start of administration.

[0074] Figures 20 and 21 are images showing a comparison of X-ray images of dogs with sick sinus syndrome symptoms when the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention were administered. The left image is an image taken before administration of the atrial natriuretic peptide lowering therapeutic and prophylactic drugs of the present invention, and the right image is an image taken one month after administration.

[0075] The atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention can promote NO synthesis, promote prostacyclin production, and inhibit endothelin production, thereby contributing to the improvement of pulmonary edema and the elimination of bradycardic syncope.

[0076] Furthermore, the present invention is not limited to the above-described embodiments of the invention, and can of course be modified in various ways within the scope of the gist of the present invention, as long as it uses naturally derived substances that can be taken regularly like a supplement without harming the health of small animals and can more effectively suppress heart diseases such as mitral valve myxomatous degeneration. [Industrial Applicability]

[0077] The therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention can be used as dietary supplements that are effective when given to small animals, particularly dogs, suffering from mitral valve regurgitation. [Explanation of symbols]

[0078] 1 tablet (medicine) 2. Inner sugar coating 3. Outer sugar coating 11 Outer membrane 12 Inner membrane 13 Drugs

Claims

1. An ANP-lowering therapeutic or preventive drug to be given to an animal suffering from mitral regurgitation, comprising: 5 to 9% by weight of a dried pine bark extract derived from the bark of pine trees grown on the southwest coast of France exposed to strong ultraviolet rays and containing proanthocyanidins; The main ingredient is sesame, and the main ingredient is 5 to 9% by weight of fermented sesame dry extract, which contains sesamin, an antioxidant lignan. The ANP lowering therapeutic and preventive drug is characterized by comprising 79 to 87% by weight of excipients such as starch and lactose, which are made from raw materials such as starch and lactose, and which make the powder uniform, prevent the tablets from solidifying, and prevent quality deterioration due to moisture absorption.

2. 2. The ANP lowering therapeutic or preventive agent according to claim 1, further comprising 0.5 to 0.9% by weight of glutathione yeast, which is composed of glutamic acid, cysteine, and glycine.

3. 2. The ANP lowering therapeutic or preventive drug according to claim 1, wherein the fermented sesame dry extract is a plant-derived extract containing organic selenium at a weight ratio of 75 ppm or more.

4. 10. A therapeutic or prophylactic ANP lowering agent, comprising the therapeutic or prophylactic ANP lowering agent according to claim 1, further containing potassium, magnesium, zinc, manganese or copper as an essential mineral supplement.

5. 2. A therapeutic or prophylactic ANP lowering agent, comprising the therapeutic or prophylactic ANP lowering agent according to claim 1, and antioxidant lignans including sesamin and sesamolin.

6. The ANP lowering therapeutic drug and prophylactic drug according to claim 1, characterized in that the tablet is compressed to a certain hardness by pressure, and the outer surface of the tablet is coated with polysaccharides such as starch, glycogen, and cellulose, and the outer surface of the polysaccharides is coated with water-soluble monosaccharides and disaccharides such as starch and dextrin.

7. 2. The ANP lowering therapeutic or prophylactic drug according to claim 1, characterized in that the ANP lowering therapeutic or prophylactic drug is filled in a double-layered capsule in which the inner coating (12) is made of starch and the outer coating (11) is made of gelatin that is more soluble in water than the inner coating (12).

8. The bark of pine trees grown on the coast and exposed to strong ultraviolet rays is extracted at 10 to 50°C with an extractant having a concentration of 30% by weight or more to produce a pine bark extract; The pine bark extract is concentrated to a water content of 5 to 20%. sesame seeds are added with 30% by weight or more of amino acids, and inoculated with one or more bacteria selected from lactic acid bacteria, and fermented at 10 to 50°C to produce a fermented sesame dry extract; The concentrated pine bark dry extract is blended with the fermented sesame dry extract in a weight mixing ratio of 1:0.5 to 2.

0. A method for producing an ANP lowering therapeutic drug and a preventive drug.

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