JP4482493B2 - Rotavirus infection / proliferation inhibitor - Google Patents

Description

  The present invention relates to a rotavirus inhibitor, and more specifically, an agent that promotes the production of a specific antibody against rotavirus by using a nucleic acid-related substance such as uridylic acid and suppresses infection and proliferation of rotavirus. It is about.

  The present invention not only provides a rotavirus inhibitor, but also provides foods and drinks and animal feeds having the action of suppressing (including prevention and treatment) rotavirus. Applications of the present invention are humans and non-human animals, and the latter widely includes livestock, poultry, pets and the like. In the present invention, rotavirus suppression refers to suppression of rotavirus infection and / or proliferation, and broadly encompasses prevention and / or treatment of diseases caused by rotavirus.

  Calves suffer from diarrhea, respiratory diseases, and various infectious diseases from birth to weaning, affected by shortage of colostrum intake, changes in feeds fed, stress due to changes in transportation and environment, etc. Cheap. Calf diarrhea is the most common disease, accounting for about 75% of calf diseases, and causes significant economic losses for livestock farmers. Rotavirus is involved in nearly half of calf diarrhea. The economic loss due to calf diarrhea in the United States is said to reach 50 billion yen per year.

  Rotavirus is a virus that is a major cause of diarrhea in early life, and infects many mammals and birds including humans.

  Also in humans, rotavirus is said to be involved in over 70% of infants' winter diarrhea. By the age of 5, over 90% of infants are believed to be infected orally, and severe diarrhea that may require hospitalization may occur. In the United States, 3.5 million rotavirus infections are confirmed annually.

  Calves are usually infected with rotavirus within 7 days of age, and rotavirus diarrhea occurs within 15 days of birth. In order to grow calves healthy, it is necessary to take appropriate countermeasures against rotavirus immediately after birth.

  In cattle, since almost 100% of adult cattle carry antibodies against rotavirus, rotavirus is considered to be resident on many farms. However, rotavirus is highly resistant in the environment and is not inactivated by commonly used inverse soaps.

  Bovine maternal-infant immunization is performed via colostrum, but the quality of colostrum varies greatly from individual to individual, and even with the same IgG concentration, rotavirus neutralizing antibody titers are different and sufficient transfer antibodies cannot be obtained. There are many cases. Moreover, the antibody transferred from colostrum gradually decreases and disappears in about 6 weeks. For these reasons, there is a demand for natural materials that enhance the immune function of calves themselves and prevent infections caused by viruses.

Recent research on the prevention of infectious diseases in calves has focused on the development of vaccines and antibiotics, but no specific drug for rotavirus has yet been found. Under these circumstances, it has been recognized that it is more important to promote the establishment of a good immune system and prevent and treat diseases by nutritional management that fully understands the physiological functions of calves.
Although it is desirable to enhance the resistance to rotavirus by promoting the maturation of immune function in the early years by administration of nutritional materials, no suitable material has been found.

  The present invention has been made in view of the current state of the art, and as a result of intensive research, it is possible to suppress rotavirus by using uridylic acid, which is a pyrimidine nucleotide, not a purine nucleotide, and using uridylic acid alone. In addition, this effect has been directly confirmed using an actual calf, but such useful findings are not known at all and are novel.

  Regarding the physiological actions of nucleotides, it is known that a mixture of purine nucleotides lowers blood LDL cholesterol level and raises HDL cholesterol level in growing rats (for example, Non-Patent Document 1). In addition, there is no description about the effectiveness of nucleotides for the suppression of rotavirus, nor is there any description of the rotavirus suppression effect of using uridylic acid alone.

Also, from the viewpoint of feed, conventional methods for feeding livestock and poultry using nucleotides have been reported (for example, Patent Document 1). However, nucleotides are used in a mixture of four types. Moreover, the purpose is to reduce the mortality rate, and it does not suppress rotavirus caused by uridylic acid alone as in the present invention.
JP 2001-340055 A Nishizawa et al., The 70th Annual Meeting of the Japanese Society for Agricultural Chemistry, Abstract p. 15 (1996)

  The present invention has been made for the purpose of meeting the demand in the industry where prevention of infection by rotavirus is desired.

  In order to achieve the above-mentioned object, the present inventors have studied from various directions. As a result, various nucleotides are not used simultaneously (that is, mixed) as conventionally widely used, but specific nucleotides are used alone. Pay attention. And we studied the physiological functions of single nucleotides.

  In the course of the research, human breast milk has a low content of uracil nucleic acid-related substances, so these substances are less important in formulas for childcare aimed at mother emulsification, while in cow colostrum Focusing on the fact that uracil nucleic acid-related substances are prominently contained, we studied the physiological effects of uracil nucleic acid-related substances.

  In fact, uracil-based nucleic acid-related substances are abundantly contained in bovine colostrum, but the variation due to colostrum is very large. For example, the content of the uracil nucleic acid-related substance in colostrum is UDP galactose: 0.5 to 170 mg / 100 g, UDP glucose: 0.3 to 115 mg / 100 g, uridylic acid: 0.1 to 30 mg / 100 g. There are no findings on the effects of administration of these substances on rotavirus.

  The present invention has a very significant feature in that the effectiveness (physiological action) of a uracil-based nucleic acid-related substance is directly confirmed using a calf. Specifically, uridylic acid was orally administered to calves, rotavirus vaccine was administered at the time when the antibody transferred from colostrum disappeared, blood was collected from calves, and biological samples were analyzed. We found for the first time that the increase in the specific antibody titer against the substance was increased, and actually confirmed that it was effective only with uracil nucleic acid-related substances, not in combination with nucleic acid-related substances derived from other bases. This is very characteristic.

  The present invention has been completed as a result of further research based on the above-mentioned useful new findings, and a rotavirus inhibitory composition comprising at least one of uridylic acid, uridine, and uracil as an active ingredient is a basic technology. For example, the following aspects are included.

1. A rotavirus inhibitor characterized by comprising as an active ingredient one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil.
2. 2. The rotavirus inhibitor according to 1 above, which promotes the production of a specific antibody against rotavirus.
3. 3. The agent according to any one of 1 to 2 above, wherein the agent is for humans or animals.
4). A human food or animal feed or animal feed having rotavirus inhibitory activity characterized by containing, as an active ingredient, one or more selected from nucleic acid-related substances consisting of uridylic acid, uridine, and uracil.
5). 5. The agent or food / beverage product or animal feed according to any one of the above 1 to 4, wherein the active ingredient is at least one selected from a purified product, a crude product, and an inclusion.
6). A method for suppressing rotavirus, comprising administering a nucleic acid-related substance comprising uridylic acid, uridine, and uracil.

  In the present invention, one or more selected from uridylic acid, uridine, and uracil (hereinafter sometimes referred to as uracil-based nucleic acid-related substances or simply nucleic acid-related substances) have a novel physiological action of rotavirus inhibitory action. For the first time, the details of the mechanism must be further studied in the future, but at the present time, the present inventors have confirmed that nucleic acid-related substances produce specific antibodies against rotavirus using actual calves. This is the first successful development of a novel use of rotavirus inhibitors for nucleic acid-related substances, and relates to a novel use invention.

  In addition, although this invention is related to a novel use invention, it can be clearly distinguished from a conventionally known nucleic acid-related substance-containing product by, for example, displaying as follows.

  It contains at least one selected from uridylic acid (including metal salts), uridine, and uracil, has a rotavirus inhibitory action, and indicates that it is used for rotavirus suppression Attached human food or animal feed or animal feed.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the rotavirus suppression composition which uses a highly safe uridylic acid nucleic acid related substance as an active ingredient. INDUSTRIAL APPLICABILITY The present invention can provide a rotavirus inhibitor for humans or animals, a food or drink having rotavirus inhibitory activity, and the same feed, containing uridylic acid or the like as an active ingredient. Therefore, according to the present invention, it has become possible for the first time to achieve the object of developing a new system for suppressing rotavirus infection by utilizing a highly safe natural product.

  Hereinafter, the present invention will be described in detail.

  In the present invention, a nucleic acid-related substance having uracil as a base is used as an active ingredient, and at least one selected from uracil, uridine, and uridylic acid is exemplified. There are no particular restrictions on the origin of these nucleic acid-related substances, and they may be synthetic products, but those derived from natural products such as yeast, bacteria, milk, seafood, animals, plants are suitable, and commercially available products can also be used as appropriate. It is.

  According to the present invention, the above-mentioned nucleic acid-related substance as an active ingredient, various drugs such as pharmaceuticals for humans or non-human animals, foods and drinks, supplements, prepared milk powder, enteral nutrients, health foods and drinks, feed additives, feeds, etc. It can be used practically as a type of composition.

  The compounding amount of the active ingredient may be arbitrary, but may be appropriately determined according to the purpose of use (prevention, health, or treatment), and an amount of 0.0001 to 10% is appropriate. As the administration method, methods such as oral administration and intravenous administration can be used.

  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. In either case or in the case of administration as feed, 0.5 to 2000 mg per kg body weight may be administered once a day, desirably several times.

  When used as a feed or a feed additive, it may be mixed with a commonly used feed or milk substitute. For example, in the case of uridylic acid, the intake or dose is 4 to 10 days old Holstein newborn calf. About 0.1 to 20 g per day, preferably 0.5 to 10 g, and more preferably 1 to 5 g may be mixed with the milk substitute and administered. In the case of uridine and uracil, the amount used may be determined based on the above. Adult cows may be increased or decreased as appropriate according to the type, age, weight, and the like. Moreover, what is necessary is just to determine the quantity suitably also about animals other than a cow according to the above. In addition, since uracil-based nucleic acid-related substances are naturally derived components and have no safety problems, even if they are used in a large amount outside the above range, there is no problem. In fact, in a 10-day acute toxicity test using mice, no death was observed even after oral administration of 1000 mg / kg.

  In the present invention, a uracil-based nucleic acid-related substance is used as an active ingredient, and uridylic acid is one of typical examples. Uridylic acid used as an active ingredient in the present invention is a known compound, and is a commercially available product. Can be used. Note that uridylic acid may have a phosphate residue at any of the 2-position, 3-position or 5-position, but usually uridine 5-monophosphate having a phosphate residue at the 5-position is used. use. Such uridylic acid and / or uridine may be in a free form or a salt form. Examples of such salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. Various metal salts such as can be exemplified. Among such compounds, a particularly preferred one is disodium 5-uridylate (5-UMP-2Na) that has already been approved as a food additive.

  For example, in the case of a calf in the lactation period, 0.1 to 20 g of uridylic acid per day is mixed with milk replacer and orally administered to increase the increase in rotavirus-specific antibody titer when rotavirus is infected. it can. Insufficient transfer antibodies from colostrum often cause diarrhea due to rotavirus infection. Therefore, increasing the calf's own ability to produce rotavirus-specific antibodies is particularly effective in suppressing rotavirus.

  In addition, when a calf is inoculated with a vaccine against rotavirus, the combined use of uridylic acid can enhance the function of the vaccine, and thus there is a great practical advantage. In addition, the above-mentioned composition can be used not only as rotavirus but also as an inhibitor of various viruses such as poliovirus, influenza virus, norovirus, coronavirus.

  The novel physiological action of suppressing rotavirus infection and proliferation by administering uridylic acid according to the present invention was first found in calves, but this action by uridylic acid is not unique to calves. It is also found in adult cattle, and is widely found in other livestock (pigs, sheep, goats, horses, horses, etc.) and poultry (chicken, duck, duck, turkey, quail, etc.), and uridylic acid Other novel uridines and uracils have this new physiological effect.

  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the examples.

Example 1
Holstein newborn calves (12 heads) were fed colostrum from each mother cow immediately after birth, and then fed artificial colostrum until 3 days of age. Divide calves into 2 groups starting from 4 days of age, and replace milk containing uridylic acid (2 g / day) in the test group (6 animals) and normal milk substitute in the control group (6 animals) until reaching 65 days of age. Paid. In the meantime, all animals were allowed to freely ingest the calf formula feed (starter). Blood collection was performed at 3, 14, 28, and 42 days of age. Further, at the age of 49 days, rotavirus vaccine was administered to all calves, and thereafter blood was collected every 2 days until 59 days of age, and fluctuations in rotavirus-specific IgG antibodies in the plasma were measured.

  It was confirmed that the uridylic acid concentration contained in the colostrum of each mother cow fed immediately after birth was not different between the test group and the control group.

  Artificial colostrum was prepared by using colostrum powder and vegetable oil as main raw materials and adjusting the IgG content to 15.5%. The milk replacer used was a product (trade name: Premium Mayrak, component value, protein 24%, fat 20%) manufactured by Meiji Dairy Co., Ltd., which mainly uses milk protein and vegetable oils and fats. For the mixed feed for calves, products (trade name: Premium Meester, component value, protein 20%, digestible nutrient total amount 75%) of Meiji Feed Co., Ltd., which are mainly made of corn and soybean oil meal, were used.

  As the rotavirus vaccine administered at the age of 49 days, the "Microbiological Laboratory" "Kyoto Microken" cow diarrhea 5 mixed inactivated vaccine "was used.

  Plasma rotavirus-specific antibody titer was measured by ELISA. The plasma rotavirus-specific IgG antibody at 3, 14, 28, and 42 days of age was measured, and it was confirmed that there was no difference between sections. The obtained results are shown in Table 1 and FIG.

  As is clear from these results, as a result of administering the vaccine at 49 days of age, the increase in plasma rotavirus-specific IgG antibody significantly increased in the test group 2 days after the vaccine administration (51 days of age), and thereafter in the plasma Rotavirus specific IgG antibodies tended to be high. Therefore, it was shown that the effect of the vaccine was improved by the oral administration of uridylic acid, and the inhibitory power against rotavirus became stronger.

The rotavirus-specific IgG antibody titer in plasma at 3.14.28.42.49-59 days of age is shown.

Claims (5)

Inhibition of rotavirus as an orally administered pharmaceutical product for cattle, characterized by comprising only uridylic acid as an active ingredient and promoting the production of specific IgG antibodies against rotavirus, not in combination with other nucleic acid-related substances Agent.   The agent according to claim 1, wherein the active ingredient is at least one selected from a purified product, a crude product, and an inclusion.   The agent according to claim 1 or 2, wherein the cow is a calf. A method for suppressing bovine rotavirus, which comprises orally administering only uridylic acid to promote production of specific IgG antibody against rotavirus. A method for increasing the ability to produce a specific IgG antibody against bovine rotavirus, comprising orally administering only uridylic acid .

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