Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/116—Heterocyclic compounds
  • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/168—Steroids
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/184—Hormones
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/60—Feeding-stuffs specially adapted for particular animals for weanlings
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
  • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S426/00—Food or edible material: processes, compositions, and products
  • Y10S426/805—Pet food for dog, cat, bird, or fish
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S426/00—Food or edible material: processes, compositions, and products
  • Y10S426/807—Poultry or ruminant feed

Definitions

• the present invention relates to an animal feed composition that comprises free indole acetic acid (free IAA) or a derivative thereof.
• the invention also relates to a method for enhancing animal growth by feeding the animal with a composition according to the invention.
• the invention also relates to the use of free IAA or a derivative thereof in a method of therapy of animals in need of a growth-promoting treatment, such as immunocompromised animals, animals with a growth deficit or slow growing animals.
• the invention also relates to the use of free IAA or a derivative thereof for the preparation of a therapeutical composition for increasing the growth rate and/or the feed conversion rate and/or the immunity of animals in need of such a treatment, in particular immunocompromised or slow growing animals.
• a composition according to the invention may preferably be in the form of a food or feed supplement.
• One of the means to improve the productivity is to develop feed compositions that enhance animal growth.
• estrogens as growth-promoting agents presents certain inherent difficulties and hazards. Thus, estrogens frequently downgrade the animal to which they are administered. Another disadvantage is that some of the estrogenic material may remain in the edible portions of the animal and could presumably produce an adverse effect on an individual when consumed. Further, the known substances have principally been administered by injection or implantation procedures, which are both costly and time-consuming and are ofyen disliked by consumers.
• An object of the invention is to provide an animal feed composition. Another object of the invention is to provide a feed composition that would enhance animal growth. A further object of the invention is to provide a method for enhancing animal growth by feeding the animal with the feed composition. Another object of the invention is to provide a method for the preparation of an animal feed composition.
• Free IAA and its derivatives are known compounds. Free IAA is a naturally-occurring plant growth phytohormone which has been extensively studied. In plants, most of the IAA occurs in a conjugated form (Slovin et al. 1999, Biochemistry and molecular biology of plant hormones, Elsevier, Amsterdam. P115-140), either conjugated to sugars via ester linkages or to amino acids and peptides via amide linkages.
• free IAA is used herein to indicate that the free IAA is in the free or acid form, whereas the term “conjugated IAA” refers to IAA that is conjugated via ester linkages or via amide linkages.
• EP 1,296,676 describes the use of free IAA as a pharmaceutical, in particular for treating neoplastic disease in humans.
• WO 02/080906 describes the use of free IAA for treating endometriosis in women.
• Nachson et al. Food and Chemical Toxocology 41, 745-752
• researchers reported the effect of some free IAA derivates (indole-3-carbinol and 3,3′-diindolylmethane) on the proliferation and induction of apoptosis in human prostate cancer cell lines whereas Rossiter et al.
• the invention therefore provides a method of raising non-human animals by administering free IAA to the animal, preferably via a feed.
• the free IAA or a derivative thereof may be fed to the animal and is most effective when administered within clearly defined concentrations in the animal feed and/or water. Injection and/or implantation is unnecessary and the animals orally ingest the free IAA or a derivative thereof of their own free choice with their feed.
• an animal feed composition that enhances animal growth which comprises free IAA or a derivative thereof.
• Such an animal feed composition can be a conventional feed composition supplemented with free IAA or a derivative thereof in a concentration sufficient to allow a daily intake of between 25 and 1000 microgram per kg life weight per day (ug/kg LW/day).
• Such a feed composition may then contain between 0.2 mg and 10 g free IAA or a derivative thereof per kg feed.
• a feed composition containing more than 0.24 mg free IAA or a derivative thereof per kg feed such as a feed composition containing more than 0,30 mg free IAA or a derivative thereof per kg feed, or a feed composition containing more than 0,40 mg free IAA or a derivative thereof per kg feed, such as more than 0,6, 0.8, 1, 5, 10, 20, 30, 50, 100, 200 or 500 mg free IAA or a derivative thereof per kg feed.
• the invention therefore relates to an animal feed composition comprising more than 240 microgram of free IAA or a derivative thereof per kilogram.
• the upper limit of the concentration of free IAA or a derivative thereof is for a large part determined by the intended use.
• the feed composition may be in the form of a feed or food additive that has to mixed into the animal feed at a convenient rate. In this case the concentration of free IAA or a derivative thereof may be as high as 10%, i.e. 100 g/kg.
• the feed composition may also be in the form of a ready to use mixture. In that case the upper limit is determined by the desired dose for the animal, once the daily intake of feed of the animal is known. In, daily practice, feed compositions containing 1, 2, or 4% (10 to 40 g/kg) free IAA or a derivative thereof proved to be most practical for storage in the form of a stock feed additive.
• a preferred storage form of a feed composition to be mixed into a ready to use feed or into a feed additive is therefore a mixture of about 1-4% free IAA or a derivative thereof with other dry material suitable for ingestion.
• the invention therefore relates to a feed composition comprising up to 40 g of free IAA or a derivative thereof per kilogram.
• Preparations containing between 100 mg and 1000 mg, such as 500 mg free IAA or a derivative thereof/kg feed additive were most practical when used to correctly dose the free IAA or a derivative thereof into the ready to use feed composition.
• the invention therefore also relates to a feed composition comprising between 100 and 1000 mg of free IAA or a derivative thereof per kilogram.
• the amount of free IAA in the ready to use feed has to be adjusted in order to supply the animal with an effective amount of free IAA.
• an estimate has to be made of the feed intake of an animal or animal group.
• a skilled person is aware of the feed intake of a (particular kind or group of) animal(s), usually the feed intake per day is between 0,5 and 10% of the body weight of the animal, with occasional exceptions as high as 20% such as for instance in young chickens. An animal will normally ingest twice the unit volume of water as it will ingest feed.
• an animal will ingest the same amount of free IAA when fed with a feed composition containing 10 milligram free IAA/kg as it will by drinking water with a concentration of 5 mg/l or a combined concentration of 2.5 mg/l in water plus 5 mg/kg in feed.
• An animal feed composition as used herein comprises a composition for animal nutrition, in solid or in liquid form. Feed is the main source of energy and of nutrition for animals and is usually of animal or plant origin. Thus feed may be defined as a substance with sufficient nutritional value to allow for growth and maintenance of adequate body conditions of an animal.
• an animal feed composition consists of pellets, meal, grains, extruded or expanded grains, tablets, powder or bolus forms.
• a particularly advantageous feed composition comprises a foodstuf selected from the group consisting of dry forages and roughages, energy feeds, protein feeds, mineral feeds, vitamin feeds, yeast products, normal premix, cornmeal, cotton seed wheat gluten, maize silage rutabaga, sugar beet pulp, apple pulp, ryegrass, fescue grass, alfalfa feed concentrate and feed supplement.
• the free IAA or a derivative thereof may be mixed with any suitable base feed material, such as rape seed, cotton seed, soybean, fish meal, wheat bran, wheat feed meal, minerals, vitamins and binders or prepared as a premix with, for example amino acids, salts, phosphorous or cornmeal.
• the feed or feed additive is in a form and/or composition approved by a governmental institution such as the FDA, the US dept. of agriculture or the Canadian Food Inspection Agency.
• a governmental institution such as the FDA, the US dept. of agriculture or the Canadian Food Inspection Agency.
• CAC Codex Alimentarius Commission
• AWA Animal Welfare Act
• the invention concerns an animal feed within the definition of “animal feed” in section 201(x) of the FFDCA, supplemented with free IAA.
• Free IAA or a derivative thereof is conveniently incorporated directly in the animal feed and/or water. Any suitable method for dispersing the material in the feed can be used. The amount of free IAA or a derivative thereof added to the animal feed and/or water may be varied within the limits stated in order to obtain the maximum benefits.
• the invention therefore comprises a method for the preparation of animal feed comprising the steps of providing an animal feed stuff and mixing said feed stuf with an effective dose of free IAA.
• composition according to the invention may be in the form of a capsule, but other dosage forms, preferably oral dosage forms, such as tablets, suspensions, emulsions, fluids, powders, lozenges, pastilles, pills, etc., are also possible.
• the composition may for example take the form of a feed supplement, a feed additive or a pharmaceutical composition.
• a method for promoting the growth of non-human animals and/or improving the feed efficiency and/or the feed conversion rate and/or the immunity of a non-human animal that comprises administering to the animals an animal feed composition according to the invention.
• a liquid such as water containing more than 120 ug free IAA or a derivative thereof per litre fluid is administered to the animals, such as 240, 500, or more than 1000 ug/l.
• Feedstuffs and/or water supplemented with free IAA or a derivative thereof according to the invention are particularly suitable for the commercial rearing of farm animals such as fish, cattle, poultry and swine. They may also be used for pet animals such as rabbits, horses, birds such as pigeons, fish such as koi fish, cats and dogs. By utilising such supplemental diets, it is not only possible to greatly accelerate the growth of non-human animals but also the efficiency of feed conversion (i.e. the number of kg of feed needed to produce one kg gain in animal weight) is greatly increased, resulting in greater economic benefits.
• the animal feed composition and methods according to the invention may also be applied to animals that have a growth deficit.
• animal experiments it was shown that the weight of poorly growing animals increased to normal levels when fed with free IAA or a derivative thereof. These experiments are illustrative of the fact that the compounds and methods of the invention lead to an increased appetite and/or improved feed conversion.
• growth deficit in this respect is to be regarded as a growth that substantially lacks behind the normal growth of the species.
• Such animals exhibit a life weight that is more than 10%, such as more than 25, 40, 60 or 80% below the median of the normal weight distribution of animals with the same age within the species.
• Immunocompromised animals are herein defined as non-human animals with an impaired or weakened immune system. Such animals are usually characterised by a lowered level of IGF-1 in their serum. Lowered IGF-1 serum levels are herein defined as levels of IGF-1 that are more than 10% below the normal median of the healthy subjects in the species, such as more than 25%, 40%, 60% or more than 80%. A weakened immune system is often the cause of an elevated death rate caused by disease or adverse living conditions.
• the invention is also useful for the treatment of animals showing various other indications that are associated with a lowered serum level of IGF-1. It is therefore a further object of the present invention to provide a means for increasing the IGF-1 serum level in a non-human animal suffering from a condition associated with a lowered IGF-1 serum level.
• the invention thus relates to the use of free IAA and a derivative thereof for the preparation of a therapeutical composition for increasing the growth rate and/or immunity in immunocompromised animals and/or animals with a growth deficit. This may lead to an increased body weight of the animal and/or a reduced death rate caused by diseases or adverse living conditions.
• a slightly higher dose is often required.
• Particularly good results were obtained with a dose of 50-1000 ug free IAA/kg LW/day, in particular 250-1000 ug free IAA/kg LW/day, more in particular 400-1000 ug free IAA/kg LW/day such as 500 or 750-1000 ug free IAA/kg LW/day during a short period of time such as less than 6 weeks, 4 weeks but more in particular less than 3 weeks, such as 2 weeks.
• Optimal dosage of free IAA or a derivative thereof may be determined empirically, and may, within the limits defined herein, depend to some extend on the particular type of feed, species and farming conditions. A person skilled in the art knows how to set up a schedule for such dosing experiments, the experimental design of example 7 may be helpful therein.
• the key compound of the invention is thus free indole acetic acid.
• equivalent result may be achieved by using derivatives of free IAA.
• Derivatives of free IAA are herein defined as compounds that lead to an increased level of free IAA in the body of the non-human animal in comparison to the level of free IAA in the same animal body prior to administration of the compound. These derivatives can be divided into various categories.
• Conjugated IAA may appear in the form of IAA conjugated via ester linkages, for example to sugars such as for example IAA-glucose, IAA-alfa-aspartic acid 1N-glucoside, IAA-inositol, IAA-myoinositols or IAA linked to various other carbohydrates.
• IAA may also be conjugated via amide linkages for instance to amino acids and peptides.
• Examples thereof are acetamide, alfa-leucine, alfa-alanine, alfa-aspartate (most important conjugate of IAA in plants), alfa-glutamate, alfa-lysine, alfa-glycine, alfa-valine, alfa-phenylalanine or slow release amide conjugates with lysine or tryptophan. Conjugation with peptides is common, whereas also conjugates with other amino acids occur in different plants.
• this group comprises 3-acetonitrile derivatives, which easily are converted into the corresponding acid, like indole-3-acetonitrile that decomposes in free IAA both chemically (under basic conditions) and enzymatically (by nitrilase activity
• this conjugated IAA must be converted to free IAA. This may be achieved by simultaneous admission of enzymes such as esterases, amidases or nitrilases to the animal. This may for instance be achieved by admixing enzymes together with the conjugated IAA into the animal feed composition.
• the invention thus relates to an animal feed composition as described above, additionally comprising an enzyme capable of converting a derivative of free IAA into free IAA.
• conjugated IAA may also be added to the feed and/or administered to the animal as such, thereby by relying on the enzyme activities naturally present in the circulation or gastro-intestinal tract of the animal for the conversion of conjugated IAA into free IAA.
• Free IAA is liberated from the amides by amidases (amidohydrolysases). Free IAA may be released from the glucosides by glucosidases. In plants, considerable amounts of conjugated IAA can be present, which can be liberated either by enzymatic hydrolysis (such as glucosidases or amidases) or chemical hydrolysis. Of the total IAA pool in plants, amide linked IAA in general constitutes 90%, whereas approximately 10% is ester linked and less than 1% is free IAA. In plants, levels of free+bound free IAA as high as about 1.2 ug/g Dry Weight may be found such as in 9 days old Arabidopsis . Later in the life cycle of the plant these levels drop. A maximum of about 1% of this is free IAA.
• hydroxylated, phosphorylated, methoxylated, N-oxides and N-methylated indole derivatives can be found. These compounds can also be converted into free IAA, either in the stomach, gut, liver or elsewhere in the body. This conversion can be enzymatic or chemical. Thus the invention also relates to these compounds that can be converted to free IAA, either directly or indirectly through metabolic conversion.
• precursors are for example 4-hydroxy-IAA, 4-methoxy-IAA, 5-hydroxy-IAA, 5-methoxy-IAA, 6-hydroxy-IAA, 6-methoxy-IAA, 7-hydroxy-IAA, 7-methoxy-IAA.
• the term derivative may also comprise IAA with other substituents, compounds that may be either naturally occurring or synthetic.
• naturally occurring also encompasses the result of metabolism by living cells such as plants, micro-organisms, mammalian cells and the human or animal body.
• halogenated indole alkaloids can be found, particularly in marine organisms (i.e. 6-bromoindigotin).
• All types of substituents can synthetically be introduced on the aromatic ring, e.g. methyl, amino, nitro, fluoride, chloride, bromide, and iodide on the positions 4, 5, 6 and 7. These compounds may all be used to increase the level of free IAA in an animal.
• derivatives may also encompass precursors from which free IAA and analogues as listed above could be formed, such as tryptophan, 4-hydroxytryptophan, 4-methoxytryptophan, 5-hydroxytryptophan, 5-methoxytryptophan, 6-hydroxytryptophan, 6-methoxytryptophan, 7-hydroxytryptophan7-methoxytryptophan, hypaphorine, tryptamine, 4-hydroxytryptamine, 4-methoxytryptamine, psilocin (4-hydroxy, dimethyl tryptamine), psilocybin (4-phosphate, dimethyl tryptamine), baeocystin, serotonin (5 hydroxytryptamine), 5-methoxytryptamine, bufotenine (dimethylserotonine), O-methylbufotenine, melatonin (5-methoxy, acetamide function on tryptamine NH 2 ), 6-hydroxytryptamine, 6-methoxytryptamine
• derivatives may also encompass compounds that are analogues or metabolites of free IAA that may be converted back into free IAA. These compounds also encompass the above mentioned 4-, 5-, 6- and 7-hydroxy- and methoxy-derivatives. These compounds are for example indole, indole-3-acetaldehyde, indole-3-ethanol, indole-3-aldehyde, indole-3-methanol, indole-3-carboxylic acid, 3-methylindole (skatole), indole-3-acetaldoxime, 3-aminomethylindole, N-methylaminomethylindole, Gramine (N-dimethylaminomethylindole).
• derivatives may also encompass compounds with changed indole chromophore, such as indoxyls (indicans), indoleninones, 3-methylene-2-oxindole, abrine, isotan B, isatin, indican, indigo, indurubin, indigotins,3-indolylmethyl (skatolyl), niacin and 2-oxindole-3-acetic acid.
• indoxyls indicans
• indoleninones 3-methylene-2-oxindole
• abrine isotan B
• isatin indican
• indigo indigo
• indurubin indigotins
• indigotins 3-indolylmethyl (skatolyl)
• niacin 2-oxindole-3-acetic acid
• derivatives may also encompass compounds that are commonly found in plants or vegetable tissue, such as 3-methylene-2-oxindole, oxindole-3-methanol, oxindole-3-aldehyde, oxindole-3-carboxylic acid and 3-methyloxindole.
• the invention also relates to the use of conjugates (esters and amides) of other natural IAA derivatives such as 2-oxindole derivatives and 4-, 5-, 6- or 7-hydroxyderivatives: dioxindole-3-acetic acid, 3-O-beta-glucosyl-dioxindole-3-acetic acid 7-hydroxy-2-oxindole-3-acetic acid-7′-O-beta-d-glucopyranoside, glucopyrasonyl-beta-1,4-glucopyranosyl-beta-1-N-oxindole-3-acetyl-N-aspartic acid, glucopyranosyl-beta-1-N-oxindole-3-acetyl-N-aspartic acid, 2-indolone-3-acetyl aspartic acid, 3-(O-beta-glucosyl)-2-indolone-3-acetyl aspartic acid, 3-hydroxy-2-indo
• derivatives of free IAA are preferably molecules that can be synthesised into free IAA in one step, either by chemical synthesis or by enzymatic conversion.
• examples of such derivatives are indole-3-acetaldehyde (IAAId) that can be converted into free IAA by action of IAAId oxidase (AAO1) or indole-3-acetonitrile (IAN) that can be converted into free IAA by nitrilases NIT1, NIT2, or NIT3 (Bartel et al., J. Plant growth Regul (2001) 20; 198-216).
• derivatives of free IAA may be molecules that can be synthesised into free IAA in two steps.
• IAOx indole-3-acetaldoxime
• derivatives of free IAA may be molecules that can be synthesised into free IAA in three or more steps.
• the invention therefore relates to an animal feed composition
• an animal feed composition comprising a derivative of free IAA wherein the derivative can be converted into free IAA in more than 3 steps, preferably in 3, more preferably in 2 and most preferably in 1 step.
• Free IAA is readily available as a commercial product. It may be synthesised chemically or prepared in a biological way. IAA producing micro-organisms are widespread in nature. Yeast, fungi and many bacteria as well as plants are known to convert precursors of IAA into free IAA. In addition to the L-tryptophan conversion by bacteria, also L-tryptophan independent biochemical routes towards free IAA are described extensively (J. Plant Growth Regul (2001) 20: 198-216).
• a well known bacterium, capable of producing free IAA is Azospirillum Brasilense (AB).
• AB Azospirillum Brasilense
• a small amount of synthetic free IAA may be added to the media.
• the micro-organism may be lysed and a powder enriched in free IAA may be obtained by spray drying or any other convenient way of drying the culture broth. Other techniques may be used to remove liquids partly or completely.
• Free IAA or a derivative thereof may be obtained from any commercial source. Alternatively, free IAA may be produced in a microbiological way.
• Azospirillum brasilence Sp7 was obtained as an agar culture in a culture tube.
• LB medium was used to grow the strain overnight at 28° C. at 175 rpm.
• Glycerol was added to the culture up to 10%, mixed and divided over Nalgene creovials and frozen at ⁇ 80° C. Stocks were stored at ⁇ 80 ° C. in creovials.
• a 10 litre fermentor was rinsed with water and the pH electrode was calibrated.
• Nine litre of LB medium was prepared and 1 g/l L-Tryptophan and 0.1 g/l free IAA was added.
• the medium was entered into the fermentor together with 2 ml of anti foam.
• the fermentor was sterilised for 30 min at 121° C. After cooling down to 28° C., the O2 probe is calibrated with N2 and O2, 0 and 100% air saturation respectively.
• the seed culture is transferred to the fermentor via a flask and tubing which are separately sterilised in an autoclave.
• the tubing and flask are removed and the fermentation is started with the following parameters: Stirrer speed 400 rpm Temperature 28° C. Aeration 0.75 Nl/min PH 7
• the first (control) group consisted of normal well growing piglets.
• the B group consisted of 78 poor growers, these were treated with free IAA.
• the X group consisted of 52 poor growers that were not treated.
• the B group received free IAA in the feed, starting on day 5 of the trial.
• the feed for the B group was prepared by first mixing free IAA with dextrose which was then mixed with the feed. For that purpose, 4 gram of pure free IAA (Aldrich) was mixed with 96 gram dextrose and the mixture was then dispersed in the feed.
• the piglets were weaned for two days at the start of the trial. Blood samples for IGF-1 measuring were taken from each group at day 5 of the trial and at the end of the trial. Two pens (13 piglets) of the B and X group, were weighed at day 5 and at the end of the trial. Quantification of IGF-1 was performed using an immunoradiometric assay (IRMA)(DSL-5600 ACTIVETM, DSL, Germany GmbH, Germany). Intra- and inter-assay variance was: 4.0% and 9.2% for GH; 3.0% and 1.5% for IGF-1.
• IRMA immunoradiometric assay
• IGF-1 levels were low, between 0.8 and 13.1 with an average of 4.6.
• IGF-1 levels were low, between 0.8 and 13.1 with an average of 4.6.
• Pen B 3L(eft) grew on average 850 grams more then their neighbours from pen X 4 L(eft).
• Pen B 3 R(ight) gained on average as much weight as their neighbours from pen X 4R(ight), but weighed 310 grams less at the start of the trial.
• the treated group gained (for the pens that were weighed) almost 0.5 kg more over a period of 21 days (table 2).
• the treated birds were force fed daily with a capsule with 400 ug free IAA/kg LW/DAY which corresponds to 10 mg/kg LW/DAY of a 4% mixture of free IAA in dextrose. Treatment was continued until the hens started laying. The two groups were weighed every week.
• the treated birds were force fed daily with a capsule with 400 ug free IAA/kg LW/DAY which corresponds to 10 mg/kg LW/DAY of a 4% mixture of free IAA in dextrose. Treatment was continued until the hens started laying. The different group were weighed every week.
• free IAA does not seem to induce a resistance in hens to it's mode of action at the dosage of 400 ug free IAA/kg LW/DAY.
• the average IGF-1 concentration in group R rose in two weeks from 9.9 nmol/l to 15.72.
• the average IGF-1 concentration in this group rose in 10 days from 1.6 to 9.36 nmol.
• the test was carried out on a large commercial farm with 1400 sows in which poor growing piglets were selected.
• the selected piglets were not suffering form any specific disease and piglets on the farm were tested negative for antibodies against PRRS (sows were vaccinated against PRRS).
• 39 Piglets were selected from a group of 600 at day 21 of age, 7 days before weaning. These piglets were at random divided in 3 groups over 3 fostering sows until weaning.
• Two groups of piglets received free IAA in the prestarter feed in the farrowing period at a dose of 500 ug free IAA/kg LW/day. After weaning, free IAA was supplemented to these 2 groups in the starter feed at the same dose until 14 days after weaning. The amount of free IAA added to the feed was based on the estimated weights and feed intake.
• the third group received the same feed, but without free IAA.
• Feed was prepared by mixing free IAA with basic feed in the concentrations indicated in Table 13. There was a fixed amount of feed given to the fish each day corresponding to 2.5% of the biomass. TABLE 13 Feed given (mg free Dose based on actual feed IAA/kg intake of 2.5% of live weight Group feed) (ug free IAA/kg LW/day) 1 0 0 2 40 1360 3 16 544 4 6.4 218
• the feed additive according to table 15 may be added to animal feed in appropriate amounts to ensure the desired dose to be administered to an animal. It may be apparent that the concentration in the feed may vary depending on the daily intake of feed of the animal as well as on the animal's weight. In order to supply an animal of 10 kg with a daily intake of 500 ug free IAA per kg LW, an amount of 10 grams of the mixture of table 15 may be mixed with the amount of feed that the animal ingests per day.

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