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    公开号:ES2545867T9
    申请号:ES11826088.4T
    申请日:2011-09-19
    公开日:2017-02-17
    发明作者:María Pilar Herrero；Warren E. Shafer
    申请人:Valent BioSciences LLC；
    IPC主号:
    专利说明:

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    Description
    Compositions of abscisic acid for animal health Field of the invention
    The present invention generally relates to compositions comprising abscisic acid and / or salts thereof, and methods for its preparation and administration for and / or nutraceutical use in animals.
    Background of the invention
    Absclsic acid is a naturally occurring plant hormone and a safe non-toxic substance. The chemistry and physiology of abscisic acid and its analogs are described by Milborrow, Ann. Rev. Plant Physiol. 1974, 25, 259-307. The enantiomeric form of natural origin of abscisic acid is (S) - (+) - abscisic acid. The stereochemistry of the side chain of the main part of the naturally occurring abscisic acid is 2-cis-, 4-trans-, since it is the isomer that is produced biosynthetically in all green plants and in some microorganisms.
    Certain salts of abscisic acid, and / or derivatives and analogs thereof, as described in United States applications 12 / 011,846, 12 / 011,825,61 / 083,202, 61 / 083,203 and PCT / US08 / 01203, however, have demonstrated high concentrations of abscisic acid in its compositions.
    Commercial formulations comprising abscisic acid are used in agriculture and horticulture in or around crops and plants to improve stress tolerance, decrease growth speed, adjust the flowering phase. It has also been reported that abscisic acid has qualities for insect inhibition. See United States patents nums. 4,434,180 and 4,209,530. Others have reported possible medicinal properties of abscisic acid, for example, United States patent application no. 2006/0292215 describes methods for using abscisic acid for anti-cancer purposes, and international application num. WO 2007/042983 describes anti-inflammatory activity of abscisic acid. United States patent application num. 2007/0184060 describes the use of ABA for the treatment of autoimmune diseases.
    Here, applicants have surprisingly discovered that abscisic acid and / or salts thereof, have nutraceutical properties in animals.
    Summary of the invention
    The present invention is generally directed to compositions comprising absclsic acid and / or salts thereof (collectively referred to as "ABA" in the present description), of which the (S) - (+) - absclsic acid is an enantiomer (of hereinafter "S-ABA"), and methods to use as nutraceuticals. Applicants found that ABA compositions can be used as a nutraceutical.
    The compositions of the present invention generally comprise ABA. Other components that enhance the biological activity of ABA may optionally be included.
    In one embodiment, the present invention is directed to a method of increasing the postnatal survival rates of the crla which comprises administering to a genitor animal or the crla a therapeutically effective amount of absclsic acid and / or salts thereof.
    Another embodiment of the present invention is directed to a method for increasing postnatal weight gain which comprises administering to a animal in need, or lactating genitor of an animal in need thereof, a therapeutically effective amount of abscisic acid and / or salts of East.
    Finally, in another Modality, the present invention is directed to a method for increasing the number of crla per litter comprising administering to a genitor animal a therapeutically effective amount of absclsic acid and / or salts thereof.
    Detailed description of the invention
    The present invention is generally directed to compositions comprising ABA, of which S-ABA is an enantiomer, and methods for use as nutraceuticals. Applicants found that ABA compositions can be used as nutraceuticals, in infant formula or as a food ingredient.
    S-ABA is the preferred compound of the compositions and uses in the present description and has the following structure:
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    image 1
    Abscisic acid
    The compositions and methods of the inventions encompass racemic mixtures, enolic forms, solvated and non-solvated forms and acceptable salts of the described abscisic acids. Examples of suitable salts that can be used include inorganic salts such as ammonium, lithium, sodium, potassium, magnesium, and potassium salts and organic amine salts such as triethanolamine, dimethanolamine and ethanolamine salts. In one embodiment, the organic amine salt is triethanolamine salt. In another embodiment, the organic amine salt is dimethylethanolamine salt. In yet another embodiment, the organic amine salt is ethanolamine salt. These examples of salts are not limiting when other salts may also be suitable for use in the present invention. A currently preferred salt is ammonium salt. Other preferred salts are sodium and potassium salts. The salts can be prepared by contacting the acid form with a sufficient amount of the desired base to produce a salt in a conventional manner. The free acid forms can be regenerated by treating the salt with a suitable dilute aqueous acid solution such as dilute aqueous sulfuric, hydrochloric or phosphoric acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as their solubilities in polar solvents, but the salts are equivalent to their respective free acid forms for the purposes of the invention. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977)).
    Definitions
    The term "Animal" refers to any animal, or crla of the animal, that receives and / or is administered the composition. The term "crlas" refers to the progeny or descendants of the animal, and includes born progeny, fetuses and embryos. "Animals" shall include but not limited to poultry, which include chickens, which include broilers and laying hens and male and female breeding stock, geese, duck, turkey, pheasant, Cornish hens, pig, cow, which includes the production of meat and milk, sheep, and goats. Additionally, "animals" will also include catfish, carp, tilapia, trout, astaco, shrimp, lobster, crab, aquatic mammals, salmon, and whitefish.
    The term "composition" includes a product comprising ABA (and in the amounts specified, if indicated), which includes products with exogenous or positively regulated ABA, as! as well as any product that results, directly or indirectly, from the combination of ABA with the ingredients specified in the specified quantities.
    The term "administer" or "administration" includes any means to introduce the ABA of the invention and other therapeutic agents, into the body.
    The term "effective amount" means an amount of a compound that, when administered to an animal to achieve a desired result, is sufficient to exert such a desired result. The "effective amount" will vary depending on the compound, the desired health benefit, the desired result, the age and relative health of the animal, the route and method of administration, the criteria of the attending physician or the person in charge or caregiver. The animal, and other factors. The amount of ABA that is "effective" will vary from composition to composition, depending on the particular use, the particular ABA, salts, and the like. Therefore, it is not always possible to specify an exact "effective amount". However, a suitable "effective amount" in an individual case can be determined by the person skilled in the art through the use of routine experimentation.
    As used herein, the terms "reduce", "suppress" and "inhibit" have their commonly understood meaning of reducing or decreasing. As used in the present description, the term "progression" means increasing the range or severity, progress, growth or worsening. As used in the present description, the term "recurrence" means the return of a pre-treatment state after a period of remission.
    As used herein, the term "nutraceutical" is commonly understood to refer to any substance that contains ABA that is a food or liquid, part of a food or liquid, or addition to the food or liquid, which triggers a physiological response. independent or in excess of a substance that does not contain exogenous or positively regulated ABA. Such products may be in the range of isolated nutrients, dietary supplements, specific diets, foods designed by genetic engineering, herbal products, and processed foods, such as cereals, soups, nutritional bars, beverages, tablets, capsules, solutions, emulsions, bars , gels, milkshakes, yogurts, breads, juices, and other nutraceuticals.
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    As used herein, all numerical values that refer to amounts, weight percentages and the like are defined as "approximately" or "approximately" each particular value, specifically, more or less 10%. For example, the phrase "at least 5% by weight" should be understood as "at least 4.5% to 5.5% by weight." Therefore, the amounts within 10% of the claimed values are covered by the scope of the claims.
    Compositions for administration
    In some embodiments, the compositions of the present invention may be included in a vehicle suitable for oral ingestion. Suitable acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound is present in such compositions in an amount sufficient to provide the desired effect.
    The compositions contemplated for use in the practice of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the active ingredients in admixture with an organic or inorganic carrier or excipient suitable for nasal, enteral, or parenteral applications.
    The active ingredients can be combined, for example, with the usual non-toxic carriers, physiologically acceptable for tablets, granules, capsules, troches, tablets, aqueous or oily suspensions, powders or dispersible granules, suppositories, solutions, emulsions, suspensions, hard capsules or soft, oblong tablets or syrups or elixirs and any other form suitable for use. Possible carriers include glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talcum, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and others carriers suitable for use in the preparation of preparations, in solid, semi-solid, or liquid form. In addition, auxiliary, stabilizing, thickening and coloring agents can be used.
    In another embodiment, the compositions of the present invention may be formulated for intranasal, intravenous, transdermal or ophthalmic administration. It is within the experience of the person skilled in the art to formulate the compositions for such administration.
    In a different embodiment, the compositions of the present invention can be formulated with food products for oral consumption. In another embodiment, the composition of the present invention can be formulated as a nutritional supplement for consumption, for example, as a solid or liquid, such as a tablet, capsule, solution, emulsion, stick, gel, milkshake or the like. In other embodiments, the compositions of the present invention can be formulated with yogurts, cereals, breads, juices and other nutraceuticals. In more embodiments, the compositions of the present invention may be incorporated with yogurts, cereals, breads, juices and other nutraceuticals that include, but are not limited to, food products that provide health benefits.
    In a different embodiment, the compositions of the present invention can be formulated in a liquid composition for oral consumption. It is within a person skilled in the art to formulate the compositions in liquid compositions for oral consumption.
    In other embodiments, the compositions of the present invention can be administered through a breeding infant genitor, through transplacental transfer from the father to the offspring, by IV, or in a infant formula for breeding.
    The present invention is directed to reproduction and more specifically to methods for increasing survival rates and postnatal weight comprising administering to a animal in need thereof a therapeutically effective amount of ABA.
    A preferred range of a therapeutically effective amount of ABA for the different methods is from about 0.1 mg / kg / day to about 1000 mg / kg / day. A more preferred range of a therapeutically effective amount of ABA is from about 10 mg / kg / day to about 1000 mg / kg / day. An especially preferred range of a therapeutically effective amount of ABA is from about 50 mg / kg / day to about 500 mg / kg / day. An especially preferred range of a therapeutically effective amount of ABA is from about 50 mg / kg / day to about 200 mg / kg / day.
    The preferred composition comprises S-ABA.
    A Modality of the present invention are liquid compositions that can be prepared either as ready-to-use dilutions or dilutable concentrates. The embodiment of the present invention may be a solution containing from 0.5% to as much as 50% by weight of ABA. Dilutable concentrates can be diluted in water directly to a final application concentration or to any intermediate dilution, without risk of precipitation of the active ingredient. Aqueous formulations according to one embodiment of the present invention are cheap to manufacture, safe to handle and use, and the active ingredient of ABA is stable under storage and transport conditions. A
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    A person who has experience in the field may be able to determine how to prepare the final concentration of the aqueous solution for direct application to animals without excessive experimentation, without any risk of causing the precipitation of the active ingredient, and without long and laborious agitation. to leave the active ingredient in solution.
    The compositions of the present invention can be prepared as a single unit dose or as a plurality of single unit doses. As used herein, a "unit dose" means a discrete amount of the composition comprising a predetermined amount of the active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that could be administered to an animal or a fraction thereof.
    The compositions of the present invention may be liquid or lyophilized or in any other dry formulations and include diluents of various buffer content (eg, Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (for example, Tween 20 ™, Tween 80 ™, Pluronic F68 ™, bile acid salts), solubilizing agents (eg, glycerin, polyethylene glycerin), antioxidants (for example, ascorbic acid, sodium metabisulfite), preservatives (for example, Thimerosal ™, benzyl alcohol, parabens), fillers or tonicity modifiers (e.g., lactose, mannitol), covalent bonding of polymers such as polyethylene glycol to prothene, complex formation with metal ions, or incorporation of the material into or on particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc., or in liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, in vivo release rate, and in vivo elimination rate. Controlled or sustained-release compositions include formulation in lipophilic deposits (eg, fatty acids, waxes, oils).
    Additionally, as used herein, those skilled in the art know acceptable carriers and include, but are not limited to, 0.01-0.1 M and preferably 0.05M phosphate buffer or 0.9% saline solution. In addition, such acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline solution and buffered media.
    Parenteral vehicles include sodium chloride solution, Ringer dextrose, dextrose and sodium chloride, fixed oils and Ringer lactate. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like.
    Sustained or controlled release compositions according to the invention include formulation in lipophilic deposits (eg, fatty acids, waxes, oils). Also encompassed by the invention are compositions in particles coated with polymers (for example poloxamers or poloxamines) and the compound coupled to antibodies directed against specific tissue receptors, ligands or antigens or coupled to ligands of tissue specific receptors. Other embodiments of the compositions according to the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various administration routes, including parenteral, pulmonary, nasal and oral,
    It is known that compounds modified by the covalent bonding of water soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone or polyproline exhibit substantially a longer half-life in blood after intravenous injection. than the corresponding unmodified compounds. Such modifications may further increase the solubility of the compound in aqueous solution, eliminate aggregation, improve the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, in vivo biological activity can be achieved by the administration of such polymer-compounds less frequently or in smaller doses than with the unmodified compound.
    The preparation may comprise ABA, alone, or may additionally include a pharmaceutically acceptable carrier, and may be in solid or liquid form such as tablets, powders, capsules, granules, solutions, suspensions, elixirs, emulsions, aerosols, gels, creams, or suppositories, which include rectal or urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof. The preparation containing ABA can be administered to an animal, for example, by subcutaneous implantation of a granule. The preparation can also be administered by intranasal, intravenous, intraarterial, or intramuscular injection of a liquid preparation. Administration can be carried out with the use of a rectal suppository or urethral suppository.
    Preparations administrable by the invention can be prepared by known processes of dissolution, mixing, granulation, or tabletting. For oral administration, ABA and the like are mixed with customary additives for this purpose, such as inert carriers, stabilizers, or diluents, and are converted by usual methods into suitable forms for administration, such as tablets, coated tablets, hard capsules or jelly
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    soft, aqueous, alcoholic or oily solutions. Examples of suitable inert vegetables are conventional tablet bases such as lactose, sucrose or maize starch in combination with binders such as acacia, maize starch, gelatin, with disintegrating agents such as maize starch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
    Examples of suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish liver oil. The preparations can be made as dry and wet granules. For parenteral administration (subcutaneous, intravenous, intra-arterial, or intramuscular injection), ABA and the like becomes a solution, suspension, or emulsion, if desired with the usual and suitable substances for this purpose, for example, solubilizers or Other auxiliaries Examples are sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable, or synthetic, for example, peanut oil, soybean oil, or mineral oil. Generally, water, saline solution, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
    The preparation of compositions containing an active component is well understood in the art. Such compositions can be prepared as injectables, as liquid solutions or suspensions; however, solid forms suitable for solution in, or suspension in, liquid before injection can also be prepared. The preparation can be emulsified. The active therapeutic ingredients are frequently mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerin, ethanol, or the like or any combination thereof).
    In addition, the composition may contain smaller amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents that improve the effectiveness of the active ingredient.
    Animal feed
    The composition of the invention may preferably take the form of animal feed and includes protein, fat, fiber, calcium, and phosphorus. A preferred food includes maize and / or wheat, soy flour, fat, animal by-product, meat and bone meal, and vitamins and minerals.
    The ABA may initially be mixed in a premix. The term "premix" means a food composition that is prepared as an initial mixture containing the active ingredient and, for example, a carrier, and then mixed in the final food. In the present invention, it is generally suggested that, for ease of calculation and use, the premix is mixed with approximately one metric ton (MT) of conventional feed, with the result that the necessary dosage requirements of the animals are provided to the animals. ABA When a metric ton (MT) of finished food is prepared, the premix of the invention preferably comprises about 1 to 2000, and more preferably, about 5 to 500 grams of aBa. The carriers for use in a premix are well known to those with experience in the art, and suitable concentrations can be readily determined.
    ABA can be added to the carrier as a dry powder or as a liquid solution or suspension. When added as a liquid, ABA can dissolve or be suspended in a liquid with stirring at room temperature. Such liquid may be water or a suitable solvent or other product used for animal feed that is already in liquid form. Due to ABA's liquid solubility characteristics, it can form a suspension. A predetermined amount of ABA is then added to the conventional premix, and it will not get too wet. Once the premix is prepared, the premix is then added to the final food, preferably at a rate in the range of a quarter of a pound (lb.) to five pounds (lbs.) Of the premix for a metric ton (MT) ) of food, to supply the ABA's daily requirement for poultry.
    The ABA solid or in solution or in liquid suspension can be added directly to the premix material, and then mixed. Mixing can be achieved by any known means, such as by a standard horizontal or vertical stirrer. The mixing time will vary again depending on the particular ingredients of the premix, and it may take as long as necessary to ensure that the ingredients blend perfectly.
    The premix is then incorporated into the feed that will be given to poultry. In a more preferred embodiment, the ABA is mixed with the carrier to form the premix, and the premix is mixed directly into the final food. While there is no evidence that the use of higher amounts would cause a toxicity problem in treated poultry, this will affect cost considerations. Because the mixture will generally be added to loads of one ton of food (as is common in the industry), the correspondence between one gram of ABA added to the premix yields approximately a concentration of 1 ppm of ABA in the food. Therefore, 5 grams of ABA added to a pound of the premix, which in turn is added to a metric ton (MT) of food, yields approximately an effective ABA concentration of 5 ppm.
    Although ABA can be mixed with a premix material before incorporation into the finished food,
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    the appropriate amount of ABA can be mixed directly into or sprayed on the food. The preferred additive range of ABA in the finished food, either added directly or through a premix, is approximately 1 to 2000 grams per metric ton (MT) of food; more preferably about 5 to 500 grams per metric ton (MT) of food.
    The food is prepared conventionally in a large tray or mixer in which the food ingredients are added in descending order of weight according to their prevalence in the final feed mixture. Therefore, broken or ground grain could be the primary ingredient. The minor ingredients are added later. The micro-ingredients are added last. These include vitamins, drugs, growth promoters, antibiotics, and, in the present case, ABA. Therefore, ABA can be one of the micro-ingredients and is added to the food in the final mixing stage. The food is mixed for conventional periods of time.
    The food comprising ABA is given to cattle and fish in a standard way, such as a pure, crumb or granule, and at standard feeding dosage intervals and rates.
    Another embodiment of the present invention are liquid compositions that can be prepared either as ready-to-use dilutions or dilutable concentrates. The embodiment of the present invention may be a solution containing from 0.5% to as much as 50% by weight of ABA. Dilutable concentrates can be diluted in water directly to a final application concentration or to any intermediate dilution, without risk of precipitation of the active ingredient. Aqueous formulations according to one embodiment of the present invention are cheap to manufacture, safe to handle and use, and the active ingredient of ABA is stable under storage and transport conditions. A person who has experience in the field may be able to determine how to prepare the final concentration of the aqueous solution for direct application to animals without excessive experimentation, without any risk of causing the precipitation of the active ingredient, and without long stirring and laborious to leave the active ingredient in solution.
    Another embodiment of the present invention is an aqueous ABA solution that serves as a source of water drink for animals. Such a supplemented aqueous solution could be prepared by dissolving dry ABA powder in drinking water or by using a liquid solution or an ABA suspension concentrate. The preferred additive range of ABA in drinking water is about 1 to 2000 parts per million (ppm) or about 1 to 2000 milligrams of ABA per liter of water; more preferably about 5 to 500 parts per million (ppm) or about 5 to 500 milligrams of ABA per liter of water. A person who has experience in the art may be able to determine how to prepare the final aqueous solution for direct application to animals without excessive experimentation, without any risk of causing the precipitation of the active ingredient, and without long and laborious agitation to leave The active ingredient in solution.
    In another embodiment of the present invention, ABA can be applied directly to animal feed once it has been prepared. For example, as may be the practice with some enzymes, ABA can be applied directly to the finished food. In a preferred embodiment, an aqueous solution of ABA is sprayed into the finished feed in its final form, such as a granule, before feeding the feed to the animals.
    The advantageous properties of this invention can be seen as a reference to the following examples illustrating the invention. These examples are provided for the purposes of illustration and are not intended to limit the scope of the present invention.
    EXAMPLES
    The tests were performed with (S) - (+) - abscisic acid according to standard guidelines and procedures as evidenced by the guidelines for EPA subchronic toxicity tests: 870.3050 - Repeated dose dla 28 - Oral toxicity study in rodents (July of 2000); 870.3100 - dla 90 Oral toxicity in rodents (August 1998); 870.3650 - Repeated combined dose toxicity study with Reproductive / Development toxicity screening test (July 2000); and 870.3200 - Days 21/28 Dermal toxicity (August 1998), as! as well as the guidelines of the Organization for Economic Co-operation and Development (OECD) for the test of chemical substances that include: test num. 407: Repeated dose dla 28 Study of oral toxicity in rodents; test num. 408: Repeated dose dla 90 Study of oral toxicity in rodents; test num. 416: reproduction toxicity of two generations; and test num. 410: Repeated dermal toxicity; study from 21/28.
    Examples of data from these studies are presented below.
    Reproductive toxicity study of two generations
    This study was conducted to determine the potential adverse effects of the test substance in reproduction in a 2nd generation study. This included determining the effects of the test substance on male and female reproductive processes, including gonadal function, estrous cyclicity, mating behavior, conception, pregnancy, childbirth, breastfeeding, weaning, and the growth and development of the crla. A minimum of 1 crla was produced in each generation.
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    Three groups of male and female were offered ABA, continuously on the diet for at least 70 consecutive days before mating. The concentrations of the target test substances were 10,000, 15,000, and 20,000 ppm for generations F0 and F1. A concurrent control group of 30 rats / sex was offered a continuous basal diet throughout the study. The F0 animals were approximately 7 weeks old at the start of the test diet administration. The test diet was administered to the offspring selected to become the F1 generation after weaning. Males F0 and F1 continued to receive the test substance during mating and continued until the day before euthanasia. Females F0 and F1 continued to receive the test substance during mating, pregnancy, and lactation, and continued until the day before euthanasia. For the two generations (F1 and F2), 8 cries per litter (4 per sex, when possible) were selected to reduce variability between litters. Crlas (30 / sex / group, if possible) from the pairing of F0 animals were selected to constitute the F1 generation. F0 males and females were exposed for 127-130 consecutive days and F1 males and females were exposed for 178-186 consecutive days.
    All animals were observed twice a day for appearance and behavior. The clinical observations, body weights and food consumption were recorded at appropriate intervals for males throughout the study and for females before mating and during pregnancy and lactation. All females F0 and F1 were allowed to feed and raise their young until weaning on day 21 of lactation. The clinical observations, body weights and sexes were recorded for F1 and F2 crols at appropriate intervals. F1 cries not selected and all surviving f2 crises underwent necropsy. The selected organs were weighed from 1 crla / sex / litter from F1 and F2 crises that underwent necropsy. Each animal F0 and F1 genitor survivor received a complete and detailed macroscopic autopsy after the weaning of the F1 and F2 weeds, respectively; the selected organs were weighed. Spermatogenic endpoints were recorded for all F0 and F1 males, and ovarian primordial follicle counts were recorded for all F0 and F1 females in the control and high exposure groups and all F0 and F1 females suspected of reduction of fertility Designated tissues of all F0 and F1 genitor animals were examined microscopically.
    Reproduction
    Table 1 demonstrates the increase in postnatal survival rates of crlas in response to treatments with S-ABA.
    Table 1
     POSTNATAL SURVIVAL (% PER BED)
     POSTNATAL DAY
     DOSE (PPM)    0 (RELATED TO # BORN) 0-1 1-4 (PRESET) 4 (POST-SELECTION) - 7 7-14 14-21 BIRTH-4 (PRESELECT) 4 (POST-SELECT) -21
     AVERAGE 98.4 98.0 99.5 98.6 99.5 100.0 95.9 98.1
     0  N 26 26 26 26 26 26 26 26
     AVERAGE 99.7 100.0 98.9 99.5 100.0 100.0 98.6 99.5
     10,000  N 25 25 25 25 25 24 25 24
     AVERAGE 96.1 98.5 98.5 99.6 98.7 100.0 93.2 98.2
     15,000  N 29 28 28 28 28 28 29 28
     AVERAGE 98.5 99.7 98.5 98.5 99.5 100.0 96.8 98.0
     20,000  N 25 25 25 25 25 25 25 25
    As a result of these test data, it is observed that S-ABA increases the survival rates of postnatal crises. For example, on days 4 to 7, a dose of 10,000 ppm resulted in an increase in average survival of 98.6% to 99.5% in rats.
    Table 2 demonstrates the weight gain of the crlas in response to treatments with S-ABA.
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     BREAST WEIGHT (grams)
     DOSE (PPM)      POSTNATAL DAY
     1 4 7 14 21
     AVERAGE 6.9 9.1 14.0 29.7 46.8
     male N 26 26 26 26 26
     MEDIUM 6.5 8.5 13.0 28.2 44.4
     0  female N 26 26 26 26 26
     MEDIUM 7.1 9.7 15.2 30.9 47.9
     male N 25 25 25 25 24
     MEDIUM 6.6 9.1 14.3 29.9 45.5
     10,000  female N 25 25 25 25 24
     AVERAGE 6.9 9.3 14.7 30.8 47.8
     male N 28 28 28 28 28
     AVERAGE 6.6 8.8 14.0 29.8 45.8
     15,000  female N 28 28 28 28 28
     MEDIUM 7.0 9.3 15.1 31.2 48.1
     male N 25 25 25 25 25
     MEDIUM 6.6 8.8 14.5 30.5 46.6
     20,000  female N 24 24 24 24 24
    As a result of this test data, we see that S-ABA increases the weight gain of the crlas. For example, on day 21, a dose of 10,000 ppm resulted in an increase in the average weight of the cries from 46.8 grams to 47.9 grams in male times. The corresponding increase in the average weight of the cries for female rats was 44.4 grams to 45.5 grams.
    This result also suggests that ABA could be replaced by prophylactic antibiotics that are often used in animal reproduction.
    Table 3 demonstrates the decrease in the mortality levels of the crlas in response to treatments with SABA.
    Table 3
     DOSE (PPM)  Crlas born They were found dead
     0  328 15
     10,000  322 4
     15,000  375 15
     20,000  327 11
    As a result of these test data, we see that S-ABA decreases the mortality of the crlas. For example, a dose of 10,000 ppm resulted in a decrease from 4.57% to 1.24%.
    Table 4 demonstrates the increase in average live crla per litter in response to S-ABA treatments.
    5
    10
    fifteen
    twenty
    25
    30
    35
    40
    Four. Five
    fifty
    55
    60
    65
     Dose (PPM)  0 10,000 15,000 20,000
     Half life  11.8 12.3 13.1 12.3
     Crlas born N  25 27 27 27
    As a result of this test data, we see that S-ABA increases the number of live crlas per litter. For example, a dose of 15,000 ppm resulted in an increase in the number of average cries from 11.8 to 13.1 per litter.
    More supporting data can be seen below in Tables 2 and 3 that show that in necropsy the numbers of fetus and size of the follicle increase with the addition of S-ABA.
    Table 5
     FETUS DATA IN THE PROGRAMMED NECROPSY
     GROUP  Sex
     MALE  FEMALE VIABLE FETOS
     one  N 154 179 343
     MEDIUM 5.5 7.2 13.7
     0 mg / kg / dla
     2  N 187 181 368
     MEDIUM 7.5 7.2 14.7
     500 mg / kg / dla
     3  N 188 166 354
     MEDIUM 7.5 6.6 14.2
     750 mg / kg / dla
     4  N 170 208 378
     1,000 mg / kg / dla  MEDIUM 6.8 8.3 15.1
    Table 6
     OVARIO PRIMARY FOLICLE COUNT
     FEMALE
     GROUP  0 PPM 10,000 PPM 15,000 PPM 20,000 PPM
     P RIMORDIAL FOLICULES
     HALF  120.1 257.5 214.0 270.3
     N  30 5 1 30
    Immune system health
    Reproductive toxicity studies of two generations of S-ABA in rats demonstrated the reduction of spleen weight in males and second generation cries as seen in Table 7 and 8.
    5
    10
    fifteen
    twenty
    25
    30
    35
     MALE
     GROUP 0 PPM  10,000 PPM 15,000 PPM 20,000 PPM
     BAZO WEIGHT (GRAMS)
     HALF  1.00 0.98 0.97 0.92
     % DIFFERENCE  -2.0 -3.0 -8.9
     N  30 30 28 30
    Table 8
     SUMMARY OF ORGAN WEIGHT AND RELATIVE ORGAN WEIGHTS
     SECOND GENERATION FRIES
     GROUP  0 PPM 10,000 PPM 15,000 PPM 20,000 PPM
     BAZO WEIGHT (GRAMS)
     HALF  0.2334 0.1989 0.1918 0.1979
     % DIFFERENCE  -14.8 -17.8 -15.2
     N  25 25 27 27
    The reduction in the size of the spleen, as shown in the tables / data above, may be directly related to the improvement in health and the improvement in mortality shown in the tables / data above.
    权利要求:
    Claims (3)
    [1]

    Claims
    10
    1. A method for increasing the postnatal survival rates of the crla which comprises administering to an animal genitor or the crla an effective amount of absclsic acid and / or salts thereof.
    [2]
    2. A method for increasing postnatal weight gain which comprises administering to an animal that needs it, or lactating genitor of an animal that needs it, an effective amount of abscisic acid and / or salts thereof.
    [3]
    3. A method for increasing the number of crla per litter comprising administering to an animal genitor an effective amount of abscisic acid and / or salts thereof.
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    US38402010P| true| 2010-09-17|2010-09-17|
    US384020P|2010-09-17|
    PCT/US2011/052178|WO2012037563A1|2010-09-17|2011-09-19|Compositions of abscisic acid for animal health|
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