JP2009137844A - Agent for lowering blood uric acid value - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop a new system effective for preventing and/or improving hyperuricemia and gout, without having a fear of adverse reactions, and also having effectiveness and a high safety even on taking it for a long period of time. <P>SOLUTION: This agent contains at least one of uridylic acid, uridine and uracil as an active ingredient. By administering the uridylic acid, etc., it is newly found out that a blood uric acid value is lowered, and by the administration of the uridylic acid, etc., the prevention and/or treatment of hyperuricemia, gout, urinary calculus, renal dysfunction, etc., can be enabled. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention includes uridylic acid, uridine, uracil as active ingredients, and an agent that prevents and / or ameliorates at least one of hyperuricemia and gout by reducing blood uric acid levels, and uses the same Therefore, the present invention relates to a method for preventing and / or improving at least one of hyperuricemia and gout.

  Uric acid is the final metabolite of purines. Purine, which is an indispensable substance for DNA synthesis, is a substance that forms the basis of uric acid, is contained in cells and foods, and is finally decomposed into uric acid by metabolism, energy consumption, etc., and discharged into urine.

  Hyperuricemia refers to a condition in which the amount of uric acid present in the blood exceeds the normal range, and a blood uric acid level of 7.0 mg / dl or more is diagnosed as hyperuricemia. In addition, if this value exceeds 8.0 mg / dl, treatment is required regardless of the presence or absence of symptoms. There are about 5 million hyperuricemia patients in Japan.

  Hyperuricemia develops when the balance between uric acid production and excretion in the body is lost. Although there are many cases where the clear cause is unknown, lifestyle habits such as overeating, preference for high pudding / high fat / high protein diet, regular drinking, or lack of exercise are considered to be obvious risk factors. Hyperuricemia is positioned as a lifestyle-related disease and therefore usually does not develop in the younger generation. Hyperuricemia often accompanies other lifestyle-related diseases and is often accompanied by complications such as obesity (visceral fat-type obesity), hyperlipidemia, impaired glucose tolerance, and hypertension. . Such a phenomenon is not only seen in humans, but recently, animals such as pets have also come to be seen in these animals due to their long life and long life.

  There are three types of hyperuricemia: a case in which excretion of uric acid is greatly reduced, a case in which production is increased, and a case in which these are mixed. Cases where uric acid excretion is reduced account for 60%, and it is said that heredity, obesity, and stress are involved. The production of uric acid is increased in 10%, and excessive uric acid is caused by excessive intake of foods containing a large amount of purines or violent exercise. Furthermore, these mixed types are said to be 30%.

  Examples of the pathological condition involving uric acid include urinary calculus, renal dysfunction, coronary artery disease, ischemic heart disease and the like in addition to hyperuricemia, which is a basic disease of gout.

  In 2002, the guidelines for the treatment of hyperuricemia and gout (Non-Patent Document 1) were published for the first time in the world, and with these guidelines, hyperuricemia is a common disease that can be handled by general clinicians. It has become.

  High blood uric acid levels are also known to increase the risk of ischemic heart disease. In two major cohort studies in Japan, hyperuricemia is an independent risk factor for cardiovascular and cerebrovascular diseases. It is shown that there is. (Non-Patent Document 1)

  From the above, the prevention and improvement of diseases such as hyperuricemia, urinary calculus, renal dysfunction, coronary artery disease, ischemic heart disease, gout, etc. involving uric acid by lowering blood uric acid level It is thought that you can.

  There are two methods for lowering blood uric acid levels: methods by improving lifestyle such as eating, drinking, and exercising, and methods using drugs. In particular, the former is important for reducing the risk of coronary artery disease, ischemic heart disease and the like and is an essential method for all patients, but the burden on the patients is large.

  Drugs that lower uric acid include uric acid excretion promoters and uric acid production inhibitors. The former includes probenecid, bucolome, benzpromalone, and the latter includes allopurinol. Uric acid excretion enhancers inhibit URAT1 (uric acid transporter), which is responsible for the reabsorption of uric acid in the tubules, suppress the physiological reabsorption of uric acid, increase the ability to excrete uric acid from the kidney, Reduce. However, it is always necessary to pay attention to the development of urinary calculus during use, and side effects include gastrointestinal disorders, headache, and lightheadedness. Furthermore, serious liver damage may occur when administered to idiosyncratic patients (Non-patent Document 1).

  On the other hand, as a uric acid production inhibitor, allopurinol has been introduced and widely used for the treatment of gout. This allopurinol inhibits xanthine oxidase, which acts in the final stage of the purine metabolic pathway, and reduces the uric acid excretion in the urine as well as the blood uric acid level. However, when overdosed to a patient with renal failure, oxypurinol accumulates in the blood in large amounts and may cause a fatal poisoning syndrome (Non-patent Document 1).

  Based on these facts, we have established prevention and treatment methods that are highly safe and have no side effects such as not burdening patients against hyperuricemia, which will become an increasingly social issue in Japan. It is requested to do.

In general, some nucleic acid-related substances such as nucleotides and nucleosides are known to be useful as seasonings and pharmaceuticals, but there are no reports that the use of uracil nucleotides alone has lowered blood uric acid levels. .
“Guideline for treating hyperuricemia and gout, digest version” published by the Japanese Society of Gout and Nucleic Acid Metabolism (September 1, 2002), p1-7

  The present invention has been made for the purpose of developing a new system that is effective and safe for preventing and / or improving hyperuricemia and gout, without the risk of side effects even after long-term ingestion. .

  As a result of extensive studies to solve the above problems, the present inventors have focused on naturally derived substances from the viewpoint of safety, and as a result of extensive screening, they have focused on uridylic acid. The effect of acid on blood uric acid levels was examined, and as a result, it was found for the first time that blood uric acid levels were decreased by uridylic acid.

  The present invention was finally completed as a result of further research based on these useful new findings, and it lowers the blood uric acid level containing at least one of uridylic acid, uridine, and uracil as an active ingredient. An agent for preventing and / or improving hyperuricemia and / or gout is a basic technical idea. In the present invention, “prevention and / or improvement” refers to at least one of prevention, improvement and treatment, and “agent” refers to a human drug or a non-human animal drug. Non-human animals include monkeys, chimpanzees, gorillas, baboons and other primates; cattle, horses, donkeys, goats, sheep, camels, buffalos, pigs, minks, weasels, martens, etc .; rats, mice, Rodents such as hamsters, guinea pigs; pets such as rabbits, dogs, cats, squirrels, ferrets, mongooses; animals kept in zoos; experimental animals; chickens, ducks, geese, ostriches, pigeons, parakeets, parrots, Birds such as quail, pheasant and madrid; reptiles are included.

  Embodiments of the present invention are exemplified below.

(1) An agent having an effect (action) of lowering blood uric acid level, characterized by comprising one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil as active ingredients.
(2) Prevent and / or improve at least one of hyperuricemia and gout characterized by comprising as an active ingredient one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil. Agent.
(3) The agent according to any one of claims 1 to 2, wherein the agent is for humans or animals.

(4) A human having an effect (action) of reducing blood uric acid level, characterized by containing one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil as an active ingredient Food and drink for animals.
(5) Prevention and / or improvement of at least one of hyperuricemia and gout characterized by containing as an active ingredient one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil. A food or drink for humans or animals that has the effect (action) to do.

(6) Reducing blood uric acid levels in humans or non-human animals characterized by orally or parenterally administering one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine and uracil How to make.
(7) Gout and / or high uric acid in humans or non-human animals, characterized in that one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine and uracil are orally or parenterally administered A method for preventing and / or improving blood glucose.

  The present invention has been found for the first time that a nucleic acid-related substance having uracil as a base, such as uridylic acid, directly lowers blood uric acid levels. By this action, in addition to hyperuricemia, gout, urinary tract It can be used for the prevention and treatment of various diseases such as stones, renal dysfunction, coronary artery disease, ischemic heart disease, and the reduction or improvement of disease states.

  In the present invention, since a nucleic acid-related substance having uracil such as uridylate as a base as an active ingredient is used as an active ingredient, it is extremely characteristic in that it has no special side effects and is highly safe. is there. In the present situation where conventional uric acid lowering drugs are numerous and serious side effects are unavoidable as described above, the present invention can be said to have a very remarkable effect and should be highly evaluated. is there.

  In addition, the present invention does not indirectly prevent and / or treat gout by promoting uric acid excretion or suppressing uric acid production, but reduces the uric acid level in blood by administration of the nucleic acid-related substance. By doing so, gout is directly prevented and / or treated, and its action mechanism is also characteristic.

  Moreover, the drop in blood uric acid level produced by the present invention is extremely high, and as is apparent from the description of the examples and drawings, the plasma uric acid concentration is reduced to about ½ compared to the control. (In other words, the reduction effect is about twice), and the effect is extremely high. Therefore, since the blood uric acid level lowering effect produced by the present invention is extremely high as described above, the remarkable effect that the amount of the active ingredient used can be reduced is also achieved.

  Therefore, the present invention can provide an anti-gout agent, an antihyperuricemia agent, and a blood uric acid lowering agent that are excellent medicaments.

  In addition, the active ingredient according to the present invention is safe and can be administered orally, and furthermore, has an excellent physiological action such as anti-gout action, anti-hyperuricemia action, blood uric acid lowering action. Therefore, the present invention can also be provided as a food / drink for humans and a food / drink for animals (feed, feed additive) excellent in functionality.

  In the present invention, a nucleic acid-related compound having uracil as a base is used as an active ingredient, and examples of the nucleic acid-related compound include at least one selected from uracil, uridine, and uridylic acid. The nucleic acid-related compounds of the present invention include pharmaceutically acceptable salts of these nucleic acid-related compounds, and salts of uridylic acid (uridine monophosphate) (for example, alkali metal salts, alkaline earth metal salts, etc.) Is preferable, and uridine monophosphate disodium salt is exemplified as a preferable example.

  The origin of the nucleic acid-related compound is not particularly limited and may be a synthetic product, but those derived from natural products such as yeast, bacteria, milk, seafood, animals and plants are preferred. The method for purifying nucleic acid-related compounds is not particularly limited, and a completely purified product can be used as well as a crude product or a contained product. A liquid or suspension-treated product can be widely used. Commercial products can also be used as appropriate, and for example, those commercially available as food additives such as uridine monophosphate disodium salt are also preferably used. In addition, in this invention, although a nucleic acid related substance includes a nucleic acid related compound, both may be used synonymously.

  The present invention has a great feature in that the effectiveness (that is, functionality, physiological activity or physiological action) of uridylic acid was directly confirmed using rats. Specifically, blood was collected after intranasal administration of uridylic acid to rats, and the plasma samples were analyzed to actually and directly confirm the physiological effects. In addition, uridylic acid is related to nucleic acids derived from other bases. It is very characteristic in that it is actually confirmed that it is effective only by using uridylic acid, not in combination with nucleic acid-related compounds derived from other bases.

  According to the present invention, the above-described nucleic acid-related compound as an active ingredient, pharmaceuticals for humans or non-human animals, foods and drinks, supplements, prepared milk powder, enteral nutrition, health foods and drinks, feed additives, feeds, etc. It can be put to practical use as various types of compositions.

  The compounding amount of the active ingredient may be arbitrary, but may be appropriately determined according to the purpose of use (prevention or treatment). However, in the case of ingestion for the purpose of health maintenance or health maintenance over a long period of time, the amount may be smaller than the above range, and since this active ingredient has no safety problem, it is used in a larger amount than the above range. But it does n’t matter. As a result of a 10-day acute toxicity test using mice, no death was observed even at an oral dose of 1000 mg / kg.

  When used as a human and / or veterinary drug, the active ingredient is administered in various forms. Examples of the dosage form include oral administration using tablets, capsules, granules, powders, syrups and the like. These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. Can be formulated using known adjuvants. The amount used varies depending on symptoms, age, body weight, administration method, dosage form, etc., but usually 0.01 mg to 1000 mg per kg body weight can be administered to adults when administered intravenously per day. In the case of administration, 0.01 mg to 1000 mg can also be administered. In the case of oral administration, it is preferably administered in the range of 0.5 mg to 2000 mg, preferably 1 mg to 1000 mg (1 mg to 40 mg is particularly preferable). Further, when used as a feed or a feed additive, it may be produced by blending an active ingredient with a commonly used feed, milk substitute, drinking water or the like in the same manner as described above. The dose may be appropriately defined according to the above.

  Hyperuricemia is positioned as a lifestyle-related disease. Therefore, subjects who administer nucleic acid-related substances according to the present invention become those who develop lifestyle-related diseases, and infants, children and other young people are not targeted. The age at which lifestyle-related diseases develop varies from person to person and cannot be uniformly defined. However, adults who are middle-aged and aged and are generally 32 to 35 years of age or older are targeted by the present invention. The pharmaceuticals, feeds, and foods and drinks according to the present invention are intended for adults, adults, adults, and adults, not young people and young animals, and are often administered for a long time. Therefore, the present invention can be safely administered over a long period of time, and the present invention is excellent also in this respect.

  Furthermore, the present invention has been found for the first time that the nucleic acid-related substance has a new use for lowering blood uric acid levels, and can be referred to as a novel use invention. By using the above as an active ingredient, it is characterized as an antihyperuricemia food or drink, and is used for prevention and / or improvement.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited only to an Example.

Example 1
Thirty Wistar Rat males (250 g) were used. A control group, a uridylic acid 30 mg administration group, and a uridylic acid 60 mg administration group were set, and 10 animals were assigned to each test group, and a Western diet (oriental yeast) (Table 1), which is a high calorie diet, was freely ingested. As uridylic acid, uridine monophosphate 2Na was used (hereinafter referred to as uridylic acid: the same applies to Examples 2 and 3).

(Table 1)
Western food (Oriental yeast)
High-fat feed <F2HFD2> (paste-like feed for mice and rats)
Lard 58%
30% fish meal
Defatted soybean 10%
2% vitamin and mineral mixture
Approximate nutrient content (in 100g)
Total calories 640kcal
Protein 24.5g
Fat 60.0g
Carbohydrate 7.5g

  After the acclimation period of 3 days, 30 mg / day / head uridylic acid was dissolved in 30 mg uridylic acid administration group, and 60 mg / day / head uridylic acid was dissolved in 1 ml distilled water in 60 mg uridylic acid administration group. It was forcibly administered. In the control group, physiological saline (0.9%) was similarly administered at 1 ml / day / head for 10 days, and water was freely consumed.

  Blood was collected at the end of the administration period, plasma was separated and plasma uric acid concentration was measured. A significant difference test between the control group, the 30 mg uridylic acid administration group, and the 60 mg uridylic acid administration group was performed by Duncan's multiple range test.

As a result, the uric acid concentration in plasma significantly decreased in both the 30 mg uridylic acid administration group and 60 mg uridylic acid compared to the control group (FIG. 1). In addition, comparing the 30 mg uridylic acid administration group and the 60 mg uridylic acid group, the uric acid concentration in the 60 mg administration group was lower.
As is clear from the drawing, the uric acid concentration in plasma decreased to 1/2 to 1/3 in the uridylic acid administration group as compared to the control group.

  From the above, it was found that uridylic acid decreases blood uric acid level in a concentration-dependent manner when ingesting a high-calorie diet. Moreover, since free uridylic acid, uridine, and uracil are nucleic acid-related substances having uracil or uracil as a base in the same manner as uridylic acid, the same effects as uridylic acid are sufficiently exerted.

(Example 2)
Lactose (1.5 kg), corn starch (0.5 kg), and methylcellulose (0.2 kg) were added to uridylic acid (1 kg), mixed in a mixing pan for 10 minutes, water (1 kg) and ethanol (1 kg) were added, and kneaded with a speed kneader for 2 minutes. Thereafter, the particles were sized with a speed mill equipped with a punch metal screen, dried at 60 ° C. to a moisture content of 5% or less, and sieved with a 30 mesh sieve. After sieving, 0.3 kg of powdered eggshell was added, mixed for 1 minute in a mixing pan, and tableted by tableting with a rotary tableting machine.

(Example 3)
50 g of uridylic acid was added to and mixed well with 20 g of precipitated calcium carbonate, 20 g of vitamin C, 40 g of granulated sugar, and 20 g of a mixture of equal amounts of corn starch and lactose. The obtained mixture was divided into 100 equal parts and packed in bags, and 1.5 g of a stick-like calcium health food composition was produced.

The present invention is summarized as follows.
That is, the present invention provides a novel system effective in preventing and / or improving and / or treating at least one of hyperuricemia and gout that has no risk of side effects even after long-term ingestion and is highly effective and highly safe. It was made as an issue to develop.

  The above-mentioned problem is a nucleic acid-related substance (compound), that is, an agent (medicine, animal medicine) or a food or drink (animal food or drink, feed, feed) containing at least one of uridylic acid (including salt), uridine, and uracil Additives, including drinking water).

  The present invention has been found for the first time that blood uric acid levels can be reduced by administration of uridylic acid or the like, thereby preventing or improving diseases such as gout, and is intended exclusively for adults, not in urine but in blood. The uric acid level of the uric acid is decreased (not adjusted by lowering or increasing the uric acid level). Here, the uric acid level in urine is different from the uric acid level in blood, and depending on the type of hyperuricemia, the way in which the value changes may be different in both cases. Therefore, there is not always a correlation between the uric acid level in urine and the uric acid level in blood. As described above, the present invention prevents and treats diseases such as gout by lowering the blood uric acid level. In other words, the present invention intends to participate in gout by lowering only the blood uric acid level, and thus is not directly related to the urinary uric acid level.

The concentration of uric acid in blood collected after the end of the administration period is shown (a, b: significant difference between different symbols, P <0.01).

Claims (7)

  1. An agent having an action of lowering blood uric acid level, characterized by comprising one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil as active ingredients.   An agent for preventing and / or improving at least one of hyperuricemia and gout characterized by comprising one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine and uracil as active ingredients.   The agent according to any one of claims 1 to 2, wherein the agent is for humans or animals.   A food or drink for humans or animals having an action of reducing blood uric acid level, characterized by containing one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil as an active ingredient.   An action to prevent and / or improve at least one of hyperuricemia and gout characterized by containing as an active ingredient one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil. A food or drink for humans or animals.   A method for lowering blood uric acid level, comprising orally or parenterally administering one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil.   Preventing and / or improving at least one of hyperuricemia and gout characterized by orally or parenterally administering one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil Method.

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