[go: up one dir, main page]

WO2015017336A1 - Combinaison médicamenteuse et procédé d'administration à un animal - Google Patents

Combinaison médicamenteuse et procédé d'administration à un animal Download PDF

Info

Publication number
WO2015017336A1
WO2015017336A1 PCT/US2014/048446 US2014048446W WO2015017336A1 WO 2015017336 A1 WO2015017336 A1 WO 2015017336A1 US 2014048446 W US2014048446 W US 2014048446W WO 2015017336 A1 WO2015017336 A1 WO 2015017336A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
polyphenol
plant material
animal
plant extract
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/048446
Other languages
English (en)
Inventor
Neil E. Forsberg
Steven B. PUNTENNEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Omnigen Research LLC
Original Assignee
Omnigen Research LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Omnigen Research LLC filed Critical Omnigen Research LLC
Publication of WO2015017336A1 publication Critical patent/WO2015017336A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This disclosure concerns embodiments of a combination for administration to an animal for health maintenance, as well as methods of making the combination and administering the combination to animals.
  • Inflammatory diseases and disorders can arise from nutritional issues, general inflammatory processes, the aging process, infections, and/or in conjunction with immunosuppressive diseases.
  • Inflammatory diseases and disorders that occur in animals include, but are not limited to, osteoarthritis, laminitis, founder, dermatitis (atopy, flea-allergy dermatitis, food-allergy dermatitis, contact dermatitis, juvenile dermatitis), eczema, atherosclerosis, cystitis, inflammatory bowel disease, hemorrhagic gastroenteritis, otitis, meningitis-arteritis, encephalitis, acquired myasthenia gravis (with neuromuscular junction inflammation), hepatitis, pancreatitis, gingivitis, degenerative neurological conditions, diabetes, obesity, and combinations thereof.
  • Embodiments of a combination and method for administration to an animal are disclosed.
  • the combination includes (a) polyphenol-containing plant material or a plant extract derived from polyphenol-containing plant material, and (b) Composition A, where Composition A comprises glucan, silica, mineral clay, mannans, or any combination thereof.
  • Composition A comprises glucan, silica, mineral clay, and mannans.
  • Composition A may further comprise an endoglucanohydrolase.
  • the polyphenol-containing plant material and/or plant extract also may include non-polyphenolic compounds, including polyphenol degradation products such as gallic and trans-caftaric acids.
  • Suitable plant materials may be obtained from, but are not limited to, apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, plums, pomegranates, quillaja, raspberries, strawberries, yucca, and combinations thereof.
  • the plant material is grape pomace or green tea.
  • Composition A includes 15-40 wt silica, 1.0-5.0 wt glucans, 1.0-8.0 wt mannans, and 50-81 wt mineral clay.
  • the combination may have a ratio of polyphenol-containing plant materiakComposition A from 10,000: 1 to 1 : 100 by weight.
  • the combination includes a dried plant extract.
  • the dried plant extract may include 0.01 wt to 25 wt total polyphenols.
  • the combination has a ratio of dried plant extract: Composition A ranging from 10,000: 1 to 1 : 1,000 by weight.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof may be blended with Composition A, or one or more components of Composition A, to form a blended composition.
  • the blended composition may be in the form of a solid blend, a solution, or a liquid suspension, where the solid blend is a powder or a pellet.
  • the combination is a liquid suspension or a mixture of pellets comprising Composition A and pellets comprising the polyphenol-containing plant material, the plant extract, or mixture thereof.
  • Embodiments of the disclosed method include administering the polyphenol-containing plant material, the plant extract, or mixture thereof and one or more components of Composition A to an animal.
  • Administration may reduce the in vivo level of at least one inflammation biomarker in the animal.
  • the biomarker may be associated with an inflammatory disease or disorder.
  • administration may change the in vivo level of at least one immune system biomarker in the animal.
  • the animal may be any mammal or avian species.
  • the animal is a companion animal, such as a dog, cat, ferret, guinea pig, rat, gerbil, hamster, mouse, or rabbit.
  • the animal is a hoofed animal.
  • the polyphenol-containing plant material the plant extract, or mixture thereof and
  • Composition A component(s) may be administered (e.g. , daily or on alternating days) to the animal for an effective period of time to promote a reduction in the level of the inflammation biomarker or a change in the level of the immune system biomarker.
  • the effective period of time is at least one day.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A component(s) are administered to a hoofed animal for 0-60 days or 3- 21 days, prior to a ration change.
  • Composition A is administered to the animal for a first period of time, Composition A then is discontinued for a second period of time, and subsequently the polyphenol- containing plant material, plant extract, or mixture thereof is administered to the animal for a third period of time.
  • the polyphenol-containing plant material the plant extract, or mixture thereof and
  • Composition A may be administered to the animal in an amount ranging from 1 mg/kg body weight per day to 20 g/kg body weight per day. In some examples, a first portion of a target amount is administered to the animal, and a subsequent portion of the target amount subsequently is administered to the animal.
  • Dried plant extract and Composition A may be administered in a ratio from 1,000:1 to 1:1,000 by weight, and in an amount sufficient to provide the animal with 1-100 mg dried plant extract per kilogram body weight.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A may be administered to the animal in an amount sufficient to provide 0.1-100 mg polyphenols per kilogram of body weight.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof and/or one or more components of Composition A may be mixed into the animal's feed or water.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A may be mixed into the animal's feed in an amount ranging from 0.1 to 20 kg per ton of feed, or in an amount ranging from 0.01% to 2.5% by weight.
  • a sufficient amount of polyphenol-containing plant material, plant extract, or a mixture thereof is administered to the animal to provide 1-100 mg polyphenols per kilogram of body weight, and a sufficient amount of Composition A is administered to the animal to provide 0.001-1 gram per kilogram of body weight.
  • administering a sufficient amount of one or more components of Composition A may be performed simultaneously or sequentially in any order.
  • the steps may be performed sequentially within a time period effective to promote a reduction in the level of the inflammation biomarker in the animal.
  • the animal is a sheep and administering the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A comprises administering 0.1-10 grams of the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A to the sheep daily.
  • the animal is a bovine, and
  • administering the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A comprises administering 0.5-100 grams of the polyphenol-containing plant material, the plant extract, or mixture thereof and Composition A to the bovine daily.
  • a supplement composition is prepared by obtaining plant material comprising one or more polyphenols, and combining the plant material with glucan, silica, mineral clay, mannans, or a combination thereof.
  • the plant material may include plant matter obtained from apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, plums, pomegranates, quillaja, raspberries, strawberries, yucca, and combinations thereof.
  • Exemplary polar solvents include water, a water-miscible alcohol, water-miscible ester, or a combination thereof.
  • the polar solvent may be water, methanol, ethanol, isopropanol, ethyl acetate, or a combination thereof.
  • the solution includes 0.05-0.15 (v/v)% hydrochloric acid, citric acid, acetic acid, or a combination thereof.
  • the liquid phase may be concentrated to provide the plant extract.
  • Nonpolar components may be extracted from the plant material before extracting at least some of the polyphenols.
  • the plant extract is dried before combining the plant extract with glucan, silica, mineral clay and mannans.
  • the method also may include, before combining the plant extract with glucan, silica, mineral clay and mannans, combining the plant extract with a carrier selected from diatomaceous earth, silica, maltodextrin, ground grain, soybean meal, cottonseed meal, distiller's dried grains, rice hulls, wheat mill run, or clay to produce combined plant extract and carrier; drying the combined plant extract and carrier to produce dried combined plant extract and carrier, and grinding the dried combined plant extract and carrier.
  • a carrier selected from diatomaceous earth, silica, maltodextrin, ground grain, soybean meal, cottonseed meal, distiller's dried grains, rice hulls, wheat mill run, or clay to produce combined plant extract and carrier
  • drying the combined plant extract and carrier to produce dried combined plant extract and carrier, and grinding the dried combined plant extract and carrier.
  • FIG. 1 is a bar graph showing Trolox® equivalents of three plant extracts (green tea, Pinot gris, and Pinot noir) following aqueous extraction ("W") and ethanol extraction ("E”). Pure quercetin and catechin are included as controls. Each of the test extracts and controls were tested at five dilutions (1:100,000, 1:10,000, 1: 1000, 1:100, and 1:10).
  • FIG. 2 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE (CTP-5 + GPE) on L-selectin mRNA concentration in rat neutrophils following a 6-day study. L-selectin mRNA was expressed as a proportion of a housekeeping gene ( ⁇ -actin mRNA).
  • FIG. 3 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract
  • GPE GPE
  • CTP-5 + GPE CTP-5 + GPE
  • FIG. 4 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE (CTP-5 + GPE) on L-selectin mRNA concentration in rat neutrophils following a 28-day study.
  • the _y-axis represents L-selectin mRNA/beta actin mRNA (with control set to 1.0).
  • L-selectin mRNA was expressed as a proportion of a housekeeping gene ( ⁇ -actin mRNA).
  • FIG. 5 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE (CTP-5 + GPE) on IL8R mRNA concentration in rat neutrophils following a 28-day study.
  • the _y-axis represents IL8R mRNA/beta actin mRNA (with control set to 1.0).
  • IL-8R mRNA was expressed as a proportion of a housekeeping gene ( ⁇ -actin mRNA).
  • FIG. 6 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE (CTP-5 + GPE) on zymosan-mediated expression of reactive oxygen species in rat neutrophils following exposure to the diet regimens for 6 days.
  • the _y-axis represents free radicals (nanomolar).
  • DCF dichlorofluorescein.
  • FIG. 7 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE on zymosan-mediated expression of reactive oxygen species in rat neutrophils following exposure to the diet regimens for 28 days.
  • the _y-axis represents free radicals (picomolar).
  • DCF dichlorofluorescein.
  • FIG. 8 is a bar graph showing the effects of Composition A (CTP-5), grape pomace extract (GPE), and the combination of Composition A and GPE (CTP-5 + GPE) on serum concentrations of C-reactive protein (CRP) in rats following feeding for 6 days.
  • the _y-axis is CRP (pg/mL).
  • FIG. 9 is a bar graph showing the effects of pre-feeding sheep with embodiments of the disclosed supplement compositions prepared with Pinot noir pomace, Pinot gris pomace and green tea extracts on the concentration of Cox-2 mRNA, an inflammatory marker, in corium of lactic acid-infused sheep.
  • LA lactic acid.
  • Cox-2 mRNA was expressed as a proportion of a
  • FIG. 10 is a bar graph showing the effects of pre-feeding sheep with embodiments of the disclosed compositions prepared with Pinot noir pomace, Pinot gris pomace and green tea extracts on the concentration of macrophage inflammatory protein 1 a (MIP) mRNA, an inflammatory marker, in corium of lactic acid-infused sheep.
  • MIP macrophage inflammatory protein 1 a
  • LA lactic acid.
  • MIP mRNA was expressed as a proportion of a housekeeping gene (RPL-19 mRNA).
  • FIG. 11 is a bar graph showing the effects of infusing cows with oligofructose, and of pre- feeding one embodiment of the disclosed anti-inflammatory products 7 days prior to oligofructose infusion, on concentration of macrophage inflammatory protein 1-a (MIP) in the corium.
  • Data represent mean values of both the front and rear left hooves.
  • NC represents “negative control” (Group 1).
  • PC represents “positive control” (Group 2).
  • “Treatment” represents Group 3, animals that were pre-fed a supplement composition.
  • MIP mRNA was expressed as a proportion of a housekeeping gene (RPL-19 mRNA).
  • FIG. 12 is a bar graph showing the effects of infusing cows with oligofructose, and of pre- feeding one embodiment of the disclosed anti-inflammatory products 7 days prior to oligofructose infusion, on concentration of Cox-2 in the corium. Data represent mean values of both the front and rear left hooves. "NC” represents “negative control” (Group 1). “PC” represents “positive control” (Group 2). “Treatment” represents Group 3, animals that were pre-fed a supplement composition. Cox-2 mRNA was expressed as a proportion of a housekeeping gene (RPL-19 mRNA).
  • FIG. 13 is a bar graph showing the effects of feeding the three test rations on hyperemia score in corium. Data are given for the left front hoof, the left rear hoof and the combined hooves. Data represent six cows per group. Negative "control” (Group 1) represents animals fed hay only. “Positive control” (Group 2) animals were dosed with oligofructose. “Test product” (Group 3) represents animals pre-fed with one embodiment of the disclosed supplement composition for 7 days prior to oligofructose administration. The _y-axis represents the hyperemia score on a scale of 0-4.
  • FIG. 14 is a bar graph showing the effects of feeding the three test rations on dermal edema score in corium. Data are given for the left front hoof, the left rear hoof and the combined hooves. Data represent six cows per group. Negative "control” (Group 1) represents animals fed hay only. “Positive control” (Group 2) animals were dosed with oligofructose. “Product test” (Group 3) represents animals pre-fed with a supplement composition for 7 days prior to oligofructose administration. The _y-axis represents the dermal edema score on a scale of 0-4.
  • FIG. 15 is a bar graph showing the effects of feeding the three test rations on lamellar stretching score in corium. Data are given for the left front hoof, the left rear hoof and the combined hooves. Data represent six cows per group. Negative "control” (Group 1) represents animals fed hay only. “Positive control” (Group 2) animals were dosed with oligofructose.
  • Product test (Group 3) represents animals pre-fed with a supplement composition for 7 days prior to oligofructose administration.
  • the _y-axis represents the lamellar stretching score on a scale of 0- 4.
  • FIG. 16 is a graph showing temporal analysis of locomotion scores of cows on the three regimens following infusion of oligofructose in Groups 2 and 3 of the cows. Dashed lines track individual group 2 cows. Solid lines track individual Group 3 (supplement composition-fed) cows. X-axis is time following administration of oligofructose in hours. F-axis represents locomotion score as outlined in Table 4.
  • This disclosure concerns embodiments of a combination (also referred to herein as a "supplement composition” or “supplement combination”) for administration to an animal, as well as methods of making the combination and administering the combination to animals.
  • the combination may aid in maintaining the animal's health.
  • the combination may ameliorate the effects of an inflammatory disorder.
  • Administering Administration by any route to the animal. As used herein, administration typically refers to oral administration.
  • Alkyl refers to a hydrocarbon group having a saturated carbon chain.
  • the chain may be cyclic, branched or unbranched.
  • the term lower alkyl means the chain includes 1-10 carbon atoms.
  • Effective amount A quantity or concentration of a specified compound or composition sufficient to achieve a desired effect in a subject.
  • the effective amount may depend at least in part on the species of animal being treated, the size of the animal, and/or the nature of the desired effect.
  • Ester A chemical compound derived from an organic acid (general formula: RCO2H) where the hydrogen of the -OH (hydroxyl) group is replaced by an aliphatic, alkyl or aryl group.
  • RCO2H A chemical compound derived from an organic acid
  • a general formula for an ester derived from an organic acid is shown below:
  • R and R' denote virtually any group, including aliphatic, substituted aliphatic, aryl, arylalkyl, heteroaryl, etc.
  • Mannans A class of polysaccharides including the sugar mannose.
  • the mannan family includes pure mannans (i.e., the polymer backbone consists of mannose monomers), glucomannans (the polymer backbone comprises mannose and glucose), and galactomannans (mannans or glucomannans in which single galactose residues are linked to the polymer backbone). Mannans are found in cell walls of some plant species and yeasts.
  • Mineral Clay According to the AIPEA (Association Internationale pour l'Etude des Argiles (International Association for the Study of Clays)) and CMS (Clay Minerals Study) nomenclature committees, the term “mineral clay” refers to a mineral that imparts plasticity to a clay and hardens upon drying or firing. Mineral clays include aluminum silicates, such as aluminum phyllosilicates. Mineral clays usually include minor amounts of impurities, such as potassium, sodium, calcium, magnesium, and/or iron. Mineral clays typically have a two-layer sheet structure including tetrahedral silicate sheets and octahedral hydroxide sheets or a three-layer structure including a hydroxide sheet between two silicate sheets.
  • Polyphenols A class of organic compounds characterized by the presence of a plurality of phenol structural units.
  • a commonly accepted definition is the White-Bate-Smith-Swain-Haslam (WBSSH) definition (Natural Products Reports, 11(1), 41-66, (1994)), which describes polyphenols as (1) generally moderately water-soluble compounds, (2) with a molecular weight of 500-4000 Daltons, (3) with more than 12 phenolic hydroxyl groups, and (4) with 5-7 aromatic rings per 1000 Daltons.
  • WBSSH White-Bate-Smith-Swain-Haslam
  • Other definitions include variations on the range limits, such as fewer phenolic hydroxyl groups.
  • tannic acid is tannic acid:
  • polyphenols include, but are not limited to, anthocyanins, astragalin, catechins, ellagic acid, ellagitannin, epicatechin, isoquercetin, proanthocyanins, resveratrol and theaflavin-3- gallate.
  • Pomace The solids remaining after fruits are pressed for juice or oil. Pomace includes the skins, pulp, seeds, and stems of the fruit.
  • Trolox ® assay Trolox ® is a trade name for 6-hydroxy-2,5,7,8-tetramethyl-chroman-2- carboxylic acid, a water-soluble derivative of vitamin E.
  • a Trolox ® assay measures the antioxidant capacity of a given substance as compared to Trolox ® .
  • Embodiments of a combination include (i) a polyphenol-containing plant material, a plant extract prepared from polyphenol-containing plant material, or a mixture thereof; and (ii)
  • Composition A wherein Composition A comprises glucan, silica, mineral clay, mannans, or any combination thereof.
  • Composition A may comprise glucan, silica, mineral clay, and mannans. In any or all of the above embodiments, Composition A may further comprise an
  • the combination may further comprise polyphenol degradation products.
  • the polyphenol-containing plant material may comprise plant matter obtained from apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, plums,
  • the polyphenol-containing plant material is grape pomace or green tea.
  • Composition A may comprise 1-40 wt silica, 1- 25 wt glucan and mannans, and 30-92 wt mineral clay.
  • the combination may have a ratio of polyphenol- containing plant material: Composition A ranging from 10,000: 1 to 1 : 100 by weight.
  • the plant extract is a dried plant extract, and the combination comprises dried plant extract and Composition A in a ratio from 1,000: 1 to 1 : 1,000 by weight.
  • the dried plant extract may comprise 0.01 wt to 25 wt total polyphenols.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof may be blended with Composition A to form a blended composition.
  • the blended composition is a solid blend, a solution, or a liquid suspension of the blended composition, where the solid blend is a powder or a pellet.
  • the combination may be a mixture of pellets comprising Composition A and pellets comprising the polyphenol-containing plant material, the plant extract, or mixture thereof.
  • Embodiments of a method comprise administering to an animal a polyphenol-containing plant material, a plant extract prepared from polyphenol-containing plant material, or a mixture thereof; and administering Composition A to the animal, wherein Composition A comprises glucan, silica, mineral clay, mannans, or any combination thereof. In some embodiments, Composition A comprises glucan, silica, mineral clay, and mannans. In any or all of the above embodiments, Composition A may further comprise an endoglucanohydrolase. In an independent embodiment, the animal is a hoofed animal. In an independent embodiment, the animal is a companion animal.
  • administering the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and administering Composition A to the animal for an effective period of time may promote a reduction in an in vivo level of at least one inflammation biomarker.
  • the biomarker may be associated with an inflammatory disorder.
  • the inflammatory disorder is arthritis, a hoof disorder, dermatitis, eczema, atherosclerosis, cystitis, inflammatory bowel disease, hemorrhagic gastroenteritis, meningitis-arteritis, encephalitis, acquired myasthenia gravis hepatitis, pancreatitis, gingivitis, a degenerative neurological condition, diabetes, obesity, or a combination thereof.
  • the inflammatory disorder is a hoof disorder.
  • administering the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and administering Composition A to the animal for an effective period of time may change an in vivo level of at least one immune system biomarker.
  • the effective period of time may be at least one day.
  • administering may comprise administering daily.
  • administering may comprise administering the polyphenol- containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A on alternate days.
  • the method may further comprise administering the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A to the hoofed animal for an effective period of time prior to a ration change, where the ration change increases energy content of feed in the ration.
  • the effective period of time is 0-60 days.
  • the method may further comprise administering a first portion of a target amount of the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A to the animal, and subsequently administering a subsequent portion of the target amount to the animal.
  • the polyphenol-containing plant material, the plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A may be administered to the animal in a total amount ranging from 1 mg/kg body weight per day to 20 g/kg body weight per day.
  • the method may further comprise administering dried plant extract and Composition A in a ratio from 1,000: 1 to 1 : 1,000 by weight, and in an amount sufficient to provide the animal with 1-100 mg dried plant extract per kilogram body weight.
  • the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A may be administered to the animal in an amount sufficient to provide 0.1-100 mg polyphenols per kilogram of body weight.
  • administering the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A may further comprise mixing the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A into the animal's feed, water, or both feed and water.
  • administering the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A may further comprise mixing the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A into the animal's feed in an amount ranging from 0.1 to 20 kg per ton of feed.
  • administering the polyphenol- containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A may further comprise mixing the polyphenol-containing plant material, plant extract prepared from polyphenol-containing plant material, or mixture thereof and Composition A into the animal's feed in an amount ranging from 0.01% to 2.5% by weight of feed.
  • the method may further comprise administering a sufficient amount of the polyphenol-containing plant material, plant extract, or mixture thereof to the animal to provide 1-100 mg polyphenols per kilogram of body weight, and administering a sufficient amount of Composition A to the animal to provide 0.001-1 gram per kilogram of body weight.
  • steps of administering a sufficient amount of the polyphenol- containing plant material, plant extract, or mixture thereof and administering a sufficient amount of Composition A are performed simultaneously.
  • the polyphenol-containing plant material, the plant extract, or mixture thereof may be blended with Composition A to form a blended composition, and the blended composition may be administered to the animal.
  • the animal is a sheep and administering the blended composition comprises administering 0.1-10 grams of the blended composition to the sheep daily.
  • the animal is a bovine, and administering the blended composition comprises administering 0.5-100 grams of the blended composition to the bovine daily.
  • steps of administering the polyphenol-containing plant material, plant extract, or mixture thereof and administering Composition A may be performed sequentially in any order. In some embodiments, the steps of administering the polyphenol-containing plant material, plant extract, or a mixture thereof and administering
  • Composition A are performed sequentially within a time period effective to promote a reduction in the level of the inflammation biomarker.
  • the method may further comprise administering Composition A to the animal on a daily basis for a first period of time, discontinuing administration of Composition A for a second period of time, and subsequently administering to the animal the polyphenol-containing plant material, a plant extract prepared from polyphenol-containing plant material, or a mixture thereof on a daily basis for a third period of time.
  • the second period of time may be from 1 to 60 days.
  • a method comprises administering to an animal a polyphenol-containing plant material, a plant extract prepared from polyphenol-containing plant material, or a mixture thereof; and administering to the animal glucan, silica, mineral clay, mannans, or any combination thereof.
  • a method for making a supplement composition comprises obtaining a plant material comprising one or more polyphenols, and combining the plant material with glucan, silica, mineral clay, mannans, or a combination thereof to produce the supplement composition.
  • the plant material comprises plant matter obtained from apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, plums, pomegranates, raspberries, strawberries, and combinations thereof.
  • the method may further comprise extracting at least some of the polyphenols from the plant material to produce a plant extract, and combining the plant extract with glucan, silica, mineral clay, mannans, or a combination thereof to produce the supplement composition.
  • extracting at least some of the polyphenols from the plant material comprises (i) combining the plant material with a solution comprising 25-100% polar solvent and 0.01% to 1% acid to form a mixture, (ii) mixing the mixture, (iii) separating the mixture into a solid phase and a liquid phase, and (iv) recovering the liquid phase to provide the plant extract.
  • the polar solvent is water, a water-miscible alcohol, a water- miscible ester, or a combination thereof. In another embodiment, the polar solvent is water, methanol, ethanol, isopropanol, ethyl acetate, or a combination thereof. In any or all of the foregoing embodiments, the solution may comprise 0.05-0.15 (v/v)% hydrochloric acid, citric acid, acetic acid, or a combination thereof. In any or all of the foregoing embodiments, the method may further comprise concentrating the liquid phase to provide the plant extract.
  • the method may further comprise extracting nonpolar components from the plant material before extracting at least some of the polyphenols. In any or all of the above embodiments, the method may further comprise drying the plant extract before combining the plant extract with glucan, silica, mineral clay, mannans, or a combination thereof.
  • the method may further comprise, before combining the plant extract with glucan, silica, mineral clay, mannans, or a combination thereof: combining the plant extract with a carrier selected from diatomaceous earth, silica, maltodextrin, ground grain, soybean meal, cottonseed meal, distiller's dried grains, rice hulls, wheat mill run, or clay to produce combined plant extract and carrier; drying the combined plant extract and carrier to produce dried combined plant extract and carrier; and grinding the dried combined plant extract and carrier.
  • a carrier selected from diatomaceous earth, silica, maltodextrin, ground grain, soybean meal, cottonseed meal, distiller's dried grains, rice hulls, wheat mill run, or clay to produce combined plant extract and carrier
  • drying the combined plant extract and carrier to produce dried combined plant extract and carrier
  • grinding the dried combined plant extract and carrier may further comprise, before combining the plant extract with glucan, silica, mineral clay, mannans, or a combination thereof: combining the plant extract with a carrier selected
  • Embodiments of the disclosed supplement compositions comprise a plant extract and one or more components of Composition A.
  • Composition A comprises glucan (e.g. , ⁇ -1,3 (4)glucan), silica, mineral clay, mannans, or any combination thereof.
  • Composition A may comprise glucan, silica, mineral clay, and mannans.
  • Composition A further comprises an endoglucanohydrolase, such as ⁇ -1,3 (4)-endoglucanohydrolase, Suitable sources of silica include, but are not limited to, sand, quartz, diatomaceous earth, and synthetic silica.
  • the mannans comprise glucomannan.
  • Composition A The components of Composition A are prepared by methods commonly known in the art and can be obtained from commercial sources. At least some components of Composition A (e.g. , silica, mineral clay) also may be present in the environment. Diatomaceous earth is available as a commercially-available, mined product primarily comprising silica and with its remaining components not assayed but comprising primarily ash (minerals) as defined by the Association of Analytical Chemists (AOAC, 2002). The mineral clays (e.g. , aluminosilicates) used in
  • Composition A may be any of a variety of clays including, but not limited to, commercially available clays such as montmorillonite clay, bentonite and zeolite.
  • Glucan and mannans can be obtained from plant cell walls, yeast (e.g. , Saccharomyces cerevisiae, Candida utilis), certain fungi (e.g. , mushrooms), algae, and bacteria.
  • the glucans include soluble and/or insoluble ⁇ -glucans, such as (1,3/1,4) ⁇ -glucan ( ⁇ -1,3 (4) glucan), (1,3/1,6) ⁇ -glucan, or a combination thereof.
  • yeast cell wall extract derived from inactivated yeast (Saccharomyces cerevisiae).
  • the yeast cell wall extract may have a composition including 0-8% moisture, 92-100% dry matter, 10-55 % protein, 0-25 % fats, 0-2% phosphorus, 10-30% ⁇ -glucan, 0-25% mannans, and 0-5% ash.
  • the yeast cell wall extract had the following composition: 2-3% moisture, 97-98% dry matter, 14-17% proteins, 20-22% fats, 1-2% phosphorus, 22-24% mannans, 24-26% ⁇ -1,3 (4) glucan, and 3-5% ash.
  • ⁇ -1 ,3 (4)-endoglucanohydrolase may be produced from submerged fermentation of a strain of Trichoderma longibrachiatum.
  • Composition A examples include 1 -40 wt% silica, 1 -25 wt% glucan and mannans, and 30-92 wt% mineral clay. In one embodiment, Composition A includes 1-40 wt% silica, 1-25 wt glucan and mannans, and 40-92 wt mineral clay. In one embodiment,
  • Composition A comprises 5-40 wt silica, 2-15 wt glucan and mannans, and 40-80 wt mineral clay. In another embodiment, Composition A comprises 20-40 wt silica, 2-10 wt glucan and mannans, and 50-70 wt mineral clay. In another embodiment, Composition A comprises 20- 30 wt silica, 2-5 wt glucan and mannans, and 60-70 wt mineral clay. In another embodiment, Composition A comprises 15-40 wt silica, 1-15 wt glucans, 0-10 wt mannans, and 50-81 wt mineral clay. In another embodiment, Composition A comprises 20-30 wt silica, 1.0- 3.5 wt glucans, 1.0-6.0 wt mannans, and 60-75 wt mineral clay.
  • ⁇ -glucans and mannans are obtained from yeast cell wall extract, and Composition A comprises 1-40 wt silica, 1-30 wt yeast cell wall extract, 40-92 wt mineral clay. In one embodiment, Composition A comprises 10-40 wt silica, 5-20 wt yeast cell wall extract, and 40-80 wt mineral clay. In another embodiment, Composition A comprises 15- 30 wt silica, 5-15 wt yeast cell wall extract, and 55-70 wt mineral clay. In another embodiment, Composition A comprises 20-40 wt silica, 2-10 wt glucan and mannans, and 50- 70 wt mineral clay. In another embodiment, Composition A comprises 15-40 wt silica, 1.0-
  • Composition A comprises 20-30 wt silica, 1.0-3.5 wt glucans, 1.0-6.0 wt mannans, and 60-
  • Composition A may further comprise an
  • Composition A may include from at least 0.05 wt endoglucanohydrolase to 5 wt endoglucanohydrolase, such as from 0.05-3 wt ⁇ -1,3 (4)-endoglucanohydrolase.
  • Composition A consists essentially of 0.1-3 wt ⁇ -1,3 (4)-endoglucanohydrolase, 20-40 wt silica, 2-20 wt glucan and mannans, and 50-70 wt mineral clay.
  • the silica may be provided by diatomaceous earth.
  • the glucans may be ⁇ -glucans.
  • the mannans may comprise glucomannan.
  • Composition A consists essentially of 0.1-3 wt , ⁇ -1,3 (4)-endoglucanohydrolase, 20-40 wt diatomaceous earth, 2-20 wt ⁇ -glucan and glucomannans, and 50-70 wt mineral clay.
  • Composition A comprises 0.1-1 wt ⁇ -1,3 (4)-endoglucanohydrolase, 20-40 wt diatomaceous earth, 5-20 wt yeast cell wall extract, and 40-80 wt mineral clay.
  • Composition A comprises 0.1-0.5 wt ⁇ -1,3 (4)-endoglucanohydrolase, 20- 30 wt diatomaceous earth, 5-15 wt yeast cell wall extract, and 60-70 wt mineral clay.
  • Composition A comprises 0.1-0.3 wt ⁇ -1,3 (4)-endoglucano-hydrolase, 24- 25 wt diatomaceous earth, 10-11 wt yeast cell wall extract, and 63-64 wt mineral clay.
  • Composition A includes additional components. Additional components may be used for any desired purpose, such as a substantially biologically inert material added, for example, as a filler, or to provide a desired beneficial effect.
  • Composition A may include a carbonate (including a metal carbonate such as calcium carbonate), kelp, a vitamin (such as a niacin supplement or vitamin B-12 supplement), biotin, d-calcium pantothenate, choline chloride, thiamine mononitrate, pyridoxine hydrochloride, menadione dimethylpyrimidinol bisulfite, riboflavin-5-phosphate, folic acid, soybean oil, calcium aluminosilicate, rice hulls, mineral oil, or any combination thereof.
  • Composition A may be formulated in any suitable form, including a powder, a granule, a pellet, a solution, or a suspension.
  • Composition A is a dry, free-flowing powder suitable for direct inclusion into a commercially-available feed, food product or as a supplement to a total mixed ration or diet.
  • the powder may be mixed with either solid or liquid feed or with water.
  • Composition A is formed into pellets.
  • Composition A has an average particle size selected to be compatible with a feedstuff or other components with which Composition A may be admixed, including a ⁇ -agonist.
  • compatible means that the particle size is sufficiently similar to reduce or eliminate particle size segregation when Composition A is admixed with the feedstuff or other components. For example, if Composition A is admixed with a feedstuff or component having an average particle size of 50-200 ⁇ , Composition A may have a similar average particle size, e.g. , from 80-120% of the feedstuff/component particle size with which Composition A is admixed.
  • Composition A when incorporated directly into feeds, Composition A may be added in amounts ranging from 0.1 to 20 kg per ton (2000 pounds) of feed. In some embodiments,
  • Composition A is added to animal feedstuff s or to food in amounts from 0.5 kg to 10 kg per ton of feed. In certain embodiments, Composition A may be added to feeds in amounts ranging from 1 to 5 kg per ton of feed.
  • Composition A When expressed as a percentage of dry matter of feed, Composition A may be added to animal feedstuffs or to foods in amounts ranging from 0.01 to 2.5% by weight, such as from 0.0125% to 2% by weight of feed. In one embodiment, Composition A is added to animal feedstuffs or to food in amounts from 0.05 to 1.5% by weight, such as from 0.06% to 1 % by weight of feed. In another embodiment, Composition A is added in amounts from 0.1 to 0.7% by weight, such as from 0.125% to 0.5% by weight of feed.
  • Composition A may be fed directly to mammalian animals as a supplement in amounts up to 20 gram per kilogram of live body weight, such as from greater than 0.01 gram to 20 gram per kilogram of live body weight, from 0.01 gram to 10 gram per kilogram of live body weight, from 0.01 gram to 1 gram per kilogram of live body weight, from 0.01 gram to 0.5 gram per kilogram of live body weight, or from 0.02 gram to 0.4 gram per kilogram of live body weight per day.
  • Composition I may be provided for use with many mammalian species in amounts of from 0.05 grams to 0.20 grams per kilogram of live body weight per day.
  • Embodiments of the disclosed plant extracts are prepared from polyphenol-containing plant material.
  • the plant material also may include non-polyphenol compounds, including polyphenol degradation products. Degradation can occur, for example, through oxidative and/or biological processes. Both the polyphenols and the non-polyphenol compounds may have biological activity.
  • Suitable plant materials include, but are not limited to, apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, quillaja (e.g. , Quillaja saponaria), plums, pomegranates, raspberries, strawberries, and yucca (e.g., Yucca schidigera).
  • the plant extract may be prepared from a single plant material (e.g. , grapes) or from a combination of plant materials.
  • the plant extract is prepared from a pressed plant material, such as grape pomace, a dried plant material, such as tea, or a combination thereof.
  • Pomace may be obtained substantially immediately post-pressing or as an ensiled product, i.e. , pomace collected and stored for up to several months post-pressing.
  • Suitable plants have a plurality of polyphenols and/or other non-polyphenolic compounds, including but not limited to non-polyphenolic organic acids (such as gallic acid and/or trans-caftaric acid), flavanols, gallate esters, flavanodiols, phloroglucinol, pyrogallol, and catechol.
  • the plant extract is prepared from Pinot noir pomace, Pinot gris pomace, or green tea.
  • pressed or dried plant material is ground to a fine powder prior to, or during, extraction. Pressed plant materials may be frozen to facilitate grinding.
  • Polyphenols and other non-polyphenolic compounds may be extracted for administration to hoofed animals.
  • polyphenols and other non-polyphenolic compounds may be extracted from the powder using a solution comprising a polar solvent, such as water, an alcohol, an ester, or a combination thereof.
  • the solution comprises a water-miscible alcohol, ester, or combination thereof, such as a lower alkyl alcohol, lower alkyl ester, or a combination thereof.
  • the solution is water or an aqueous solution comprising 25-99% solvent, such as 25-95% solvent, 30-80% solvent, or 50-75% solvent, and water.
  • the solution is an aqueous solution comprising methanol, ethanol, isopropanol, ethyl acetate, or a combination thereof.
  • the solution may be acidified, by addition of an acid.
  • the acid may prevent or minimize oxidative degradation of biologically-active polyphenols and other non-polyphenolic compounds in the extract.
  • the acid may be any suitable acid, such as a mineral acid (e.g., hydrochloric acid), or an organic acid such as citric acid or acetic acid.
  • the solution comprises from 0.01 % to 1% acid, such as 0.02-0.5%, 0.025-0.25%, or 0.05-0.15%. In some examples, the solution included 0.1% hydrochloric acid.
  • Extraction may be performed at a temperature ranging from 0-100 °C. In some embodiments, extraction is performed at a temperature ranging from 20-70 °C, or at ambient temperature. Extraction may be performed for a duration ranging from several minutes to several days.
  • the plant material and solution may be mixed or agitated during extraction, such as by grinding the plant material during extraction, stirring the mixture, shaking the mixture, or homogenizing the mixture.
  • the extraction may be repeated one or more times with fresh solution to increase recovery of polyphenols and other non- polyphenolic compounds from the plant material. The liquid phases from each extraction cycle are combined for further processing.
  • the liquid phase is recovered, and the residual solids, or pulp, are discarded.
  • Recovering the liquid phase may comprise decanting the liquid from the remaining solids and/or filtering the liquid phase to remove residual solids.
  • the solvent (alcohol, ester, or combination thereof) is removed from the liquid solution by any suitable means, such as evaporation (e.g. , roto- evaporation), to produce an aqueous extract containing the biologically-active components in a mildly acidic solution.
  • an initial extraction of nonpolar components may be performed before extracting the polyphenols and other polar, non-polyphenolic compounds.
  • Nonpolar components may be extracted by homogenizing the plant material in a nonpolar solvent, e.g. , hexanes, heptanes, or a combination thereof. The solvent layer including the extracted nonpolar components is separated from the plant material and discarded.
  • the aqueous plant extract may be further purified by suitable means, e.g. , extraction, chromatographic methods, distillation, etc., to remove non-polyphenolic compounds and/or to increase the concentration of polyphenols relative to other compounds in the extract.
  • suitable means e.g. , extraction, chromatographic methods, distillation, etc.
  • the aqueous plant extract may be dried, for example by freeze-drying or other low- temperature drying methods, and ground to a powder to provide a dried plant extract.
  • the dried plant extract comprises 0.01 wt% to 25 wt% total polyphenols, such as 0.01 wt% to 10 wt%, 0.01 wt% to 5 wt%, 0.01 wt% to 2.5 wt%, 0.01 wt% to 1 wt%, 0.01 wt% to 0.5 wt%, 0.02 to 0.25 wt%, or 0.03-0.1 wt% total polyphenols.
  • the dried plant extract further comprises non-polyphenolic compounds.
  • the dried plant extract may comprise 0.01-1 mg/g gallic acid, such as 0.05-0.5 mg/g or 0.09-0.25 mg/g gallic acid, and/or 0.001-0.1 mg/g trans-caftaric acid, such as 0.005-0.05 mg/g or 0.01-0.025 mg/g trans-caftaric acid.
  • the aqueous plant extract may be concentrated to a smaller volume, e.g. , by evaporation, and used as an aqueous plant extract.
  • the aqueous plant extract is mixed with a carrier before drying and grinding.
  • Suitable carriers include, for example, diatomaceous earth, silica, maltodextrin, ground grain (e.g. , corn), meals (e.g. , soybean or cottonseed meal) byproducts (e.g. , distiller's dried grains, rice hulls, wheat mill run), clays (e.g. , bentonite), and combination thereof.
  • the plant extract may be combined with a carrier in a ratio ranging from 10: 1 to 1 : 10 by weight, such as from 5: 1 to 1 :5.
  • the plant extract may be mixed with diatomaceous earth in a ratio of 3 : 1 by weight.
  • a supplement combination comprises (a) polyphenol-containing plant material, an embodiment of a plant extract as described above, or both, and (b) glucan, silica, mineral clay, mannans, or any combination thereof, such as an embodiment of Composition A as described above.
  • the plant material and/or extracts may further include non-polyphenolic compounds with biological activity, including polyphenol degradation products.
  • a supplement combination consists essentially of (a) polyphenol-containing plant material, an embodiment of a plant extract as described above, or both, and (b) an embodiment of Composition A as described above.
  • a supplement combination consists of (a) polyphenol-containing plant material, an embodiment of a plant extract as described above, or both, and (b) an embodiment of Composition A as described above.
  • the combination components may be separate, e.g. , pellets of polyphenol-containing plant material and/or plant extract, and pellets of Composition A.
  • the components may be mixed or blended to produce a blended composition comprising the components.
  • the blended composition is a substantially homogeneous composition comprising (a) polyphenol-containing plant material, an embodiment of a plant extract, or both, and (b) one or more components of Composition A, such as an embodiment of Composition A.
  • the supplement combination may comprise plant extract and one or more components of Composition A.
  • the supplement combination comprises dried plant extract and Composition A.
  • the ratio of dried plant extract: Composition A components may range from 10000: 1 to 1 : 1000 by weight, such as from 1000: 1 to 1 : 1000, 500: 1 to 1 :500, 100: 1 to 1 : 100, 5: 1 to 1 :500, 1 : 1 to 1 : 100, 1 : 10 to 1 : 100, 1 : 1 to 1 : 10, 1000: 1 , 100: 1, 50: 1, 10: 1, 5:1 , 3: 1 , 1 : 1, 1 :5, 1 : 10, 1 :25, 1 :50, 1 : 100, 1 :250, 1 :500, or 1 : 1000.
  • the ratio of dried plant extract: Composition A is selected to provide a ratio of polyphenols Composition A ranging from 10000: 1 to 1 : 1000 by weight, such as from 1000: 1 to 1 : 1000, 500: 1 to 1 :500, 100: 1 to 1 : 100, 5: 1 to 1 :500, 1 : 1 to 1 : 100, 1 : 1 to 1 : 10, 1000: 1, 100: 1, 50: 1, 10: 1, 5: 1, 3: 1, 1 : 1, 1 :5, 1 : 10, 1 :25, 1 :50, 1 : 100, 1 :500, or 1 : 1000.
  • the supplement combination may comprise 0.001 to 99.99 wt% dried plant extract, such as 0.01 to 99 wt , 0.1 to 90 wt , 0.1 to 50 wt , 1 wt to 50 wt , 1 wt , 5 wt , 10 wt , 20 wt , 25 wt , 50 wt , or 90 wt% dried plant extract.
  • the supplement combination may comprise 0.001-0.5 wt polyphenols.
  • a supplement combination can be formulated by blending dried plant extract with
  • Composition A to form a supplement composition.
  • dried plant extract may be blended with appropriate amounts of one or more components of Composition A (i.e., glucan, silica, mineral clay, mannans) to form a supplement composition.
  • Blending the plant extract with Composition A can be accomplished by any suitable means, such as agitating, shaking, stirring, grinding, ball-milling, etc.
  • Aqueous plant extract can be mixed with one or more components of Composition A and then dried to create a supplement composition.
  • Composition A is premixed prior to adding the aqueous plant extract.
  • appropriate amounts of one or more components of Composition A may be combined with the aqueous plant extract and then dried to form the supplement composition.
  • 1 ,000 mL of aqueous extract may be combined with 1 ,000 g of Composition A and then dried to form the supplement composition.
  • the ratio of aqueous plant extract to Composition A will depend on the concentration of polyphenols and other non-polyphenolic compounds in the aqueous plant extract, as well as the desired final ratio of dried plant extract: Composition A.
  • the supplement combination may comprise polyphenol-containing plant material and one or more components of Composition A as described above.
  • Suitable plant materials include, but are not limited to, apples, blackberries, black chokeberries, black currants, black elderberries, blueberries, cherries, cranberries, grapes, green tea, hops, onions, plums, pomegranates, quillaja, raspberries, strawberries, yucca, and combinations thereof.
  • the plant material is in the form of pomace, e.g., grape pomace.
  • the plant material is dried plant material.
  • the plant material can be mixed with one or more components of Composition A to form a supplement composition.
  • Composition A is premixed prior to adding the plant material.
  • appropriate amounts of one or more components of Composition A may be combined with the plant material. If the plant material is not previously dried before mixing with Composition A component(s), the supplement composition may be dried after mixing.
  • the components may be mixed to form a substantially homogeneous composition.
  • the supplement composition is a free-flowing powder.
  • the supplement composition may be formed into pellets or mixed with a suitable liquid (e.g., water) to form a liquid suspension or solution.
  • the ratio of plant material:Composition A components in the supplement composition may range from 10000:1 to 1:100 by weight, such as from 1000:1 to
  • the supplement composition may comprise 1 wt% to 99.9 wt% plant material, such as such as 1 to 99 wt , 1 to 50 wt , 1 wt , 5 wt , 10 wt , 20 wt , 25 wt , 50 wt% , 90 wt , 99 wt , or 99.9 wt% plant material.
  • the supplement combination may be formed into pellets comprising plant material and/or plant extract, and pellets comprising Composition A.
  • the ratio of plant material pellets to Composition A pellets in a mixture of pellets may range from 10,000:1 to 1:100, such as 1000:1 to 1:100, 100:1 to 1:100, 50:1 to 1:50, 25:1 to 1:25, or 10:1 to 1:10.
  • the components of the supplement combination may be mixed with a suitable liquid (e.g., water) to form a liquid suspension or solution.
  • Acute inflammation is a response to tissue injury that produces characteristic symptoms and usually resolves spontaneously. Blood vessels are more permeable leading to increase in immune cells in the tissue, edema (swelling) and heat. Neutrophils and other leukocytes primarily mediate acute inflammation.
  • Chronic inflammation contributes to pathogenesis of many health issues and is generated by cellular dysfunction and stress.
  • the development of degenerative diseases causing loss of cellular function may be linked to chronic stress.
  • Oxidative stress, toxin exposure, pathogen exposure and improper dietary energy balance can contribute and lead to chronic inflammation.
  • Monocytes, macrophages and lymphocytes primarily mediate chronic inflammation. Multiple exposure or sequential exposure to causative agents will lead to chronic inflammation that persists resulting in tissue damage, reduction in productivity and acceleration of the aging process.
  • Certain biomarkers are indicative of an acute or chronic inflammatory response.
  • Inflammation biomarkers include, but are not limited to, tumor necrosis factor alpha (TNF-a), nuclear factor kappa B (NF- ⁇ ), interferon gamma (IFN- ⁇ ), interleukin-6 (IL6), interleukin-8 (IL8), interleukin- 1 ⁇ (IL- ⁇ ), cellular COX-2 gene expression, L-selectin, interleukin-8 receptor (IL8R), cellular lipoxygenase (LOX), C-reactive protein (CRP), macrophage inflammatory protein 1 -alpha (MIP) gene expression, eicosanoids (localized cellular products produced by COX and LOX), alpha- 1 -antitrypsin (AAT), haptoglobin, fibrinogen, uric acid/urate, homocysteine, adiponectin, and/or toll-like receptors (TLRs).
  • TNF-a tumor necrosis factor alpha
  • NF- ⁇ nuclear factor kappa
  • Anti-inflammatory disorders include, but are not limited to, arthritis (e.g. , osteoarthritis, immune-mediated arthritis (erosive (e.g. , rheumatoid arthritis) or non-erosive), infectious arthritis (e.g. , rickettsial arthritis, canine ehrlichiosis, spirochetal arthritis), neoplastic arthritis, crystalloid arthritis, traumatic arthritis, genetic arthritis, metabolic arthritis), a hoof disorder (laminitis, founder), dermatitis (e.g.
  • atopy flea-allergy dermatitis, food allergy dermatitis, contact dermatitis, juvenile dermatitis
  • eczema atherosclerosis, cystitis, inflammatory bowel disease, hemorrhagic gastroenteritis, meningitis-arteritis, encephalitis, acquired myasthenia gravis, hepatitis, pancreatitis, gingivitis, degenerative neurological conditions, diabetes (e.g. , insulin-deficient diabetes), obesity, and combinations thereof.
  • a particular inflammatory disorder common to both ruminant animals (dairy cows, beef cows, sheep, goats) and horses is the development of inflammatory hoof disorders following their ingestion of high energy feeds.
  • this condition also known as laminitis
  • laminitis is a natural consequence of feeding high energy rations that are designed to maximize either milk production (in dairy cows) or enhance growth (in beef cows).
  • a hoof degeneration disorder (founder, also known as chronic laminitis) is a frequent consequence of accidental ingestion of large amounts of high energy feeds (cereal grains) or fresh growing pastures.
  • causes of hoof disorders caused by ingestion of high energy feeds in ruminants and horses are not fully understood.
  • Laminitis and founder exist as syndromes whereby a combination of factors must act to bring about a hoof degeneration condition.
  • laminitis is the second primary reason for culling in dairy industries (following mastitis). Net losses to the US dairy industry resulting from laminitis are estimated at about $1.8 billion annually. A conservative estimate is that 15 percent of horses in the United States are afflicted by laminitis during their lifetimes. Up to 75 percent of horses affected with laminitis eventually develop severe or chronic lameness and debilitation.
  • Laminitis is a non-infectious inflammation of the laminae, or tissues, that form a strong and durable bond between an animal's hoof wall and the coffin bone (also known as the pedal bone). Laminitis is also known as "pododermatitis aseptic diffusa" (Nocek, /. Dairy Sci. , 80: 1005-1028, (1997)). Laminitis is a debilitating disease that causes the delamination, or separation, of an animal's hoof. As the layers of the hoof wall delaminate, or separate, they cause extreme pain in the sensitive tissues underneath the hoof wall. Laminitis may be diffuse, acute, subacute, or chronic, and usually involves the tissues of more than one hoof.
  • Clinical signs include lameness, inflammation, and increased temperature in the hooves. Severe cases of chronic laminitis are characterized by flattened, broad claws with a concave furrowed dorsal wall, widening, discoloration and softening of the white line, sole and white line hemorrhage, double sole and ulcerations.
  • Untreated laminitis may lead to founder, or chronic laminitis, which is a condition that occurs when the bond between the sensitive and insensitive laminae in the hoof completely fails. Founder causes the coffin bone attachment to the hoof to break down, damaging arteries and veins and crushing the remaining living tissues around the coffin bone. In extreme cases, as the whole weight of the animal bears down on the coffin bone, it will rotate downwards and through the hoof sole to the ground. In some instances, the terms laminitis and founder are used interchangeably, although not all animals with laminitis will develop founder.
  • a primary cause of both laminitis and founder is nutritional (Nocek, /. Dairy Sci. 80: 1005- 1028, 1997).
  • Sequelae to the ingestion of high amounts of carbohydrates include the development of ruminal acidosis, altered populations of ruminal (or cecal) microorganisms, enhanced delivery of starches to the lower gastrointestinal tract (small and large intestine), and changes in small intestinal microbial populations.
  • Lactobacilli include the activation of matrix metalloproteinase (MMP) activities within the hoof (Hendry et al , J. Dairy Res. 70: 19-27, 2003; French et al, Equine Vet. J. 36:261-266, 2004).
  • MMP matrix metalloproteinase
  • Matrix metalloproteinases are extracellular proteinases responsible for remodeling of extracellular matrix proteins in normal animals; however, their pathologic activation can result in damage to the extracellular matrix and loss of support functions.
  • MMPs matrix metalloproteinases
  • endotoxins are thought to accelerate the digestion of the suspensory ligaments in the hoof supporting the coffin (pedal) bone.
  • the pedal bone thereby loses its support and rotates downward toward the base of the hoof and, in doing so, creates a visible hemorrhagic lesion. In severe cases the loss of support becomes so severe that the coffin bone ruptures through the sole and thereby provides a portal for infection (a sole ulceration).
  • a second contributing element to laminitis and founder is oxygen supply to hoof tissues.
  • ROS reactive oxygen species
  • Carbohydrate ingestion causes rapid molecular and histological changes in hoof tissues. Specifically, Morrow et al (1973) reported histological changes to the hoof of the sheep within
  • the laminitis models used herein include the ovine lactic acid infusion model (Morrow et al, Am. J. Vet. Res. 34: 1305-1308, 1973, incorporated by reference herein) and the oligofructose dosing method (Danscher et al., J. Dairy Sci. 92:607-616, 2009, incorporated by reference herein).
  • Embodiments of the disclosed supplement compositions also were administered to rodents to study the immunological, anti-inflammatory, and/or synergistic properties of the compositions.
  • Biomarkers correlated with laminitis include altered microbial populations, accumulation of white blood cells such as neutrophils in damaged laminar tissues, increased MMP activity, generation of reactive oxygen species, and increases in a number of pro-inflammatory molecules, such as COX-2, interleukin- 1 beta (IL- ⁇ ⁇ ), tumor necrosis factor alpha (TNF-a), interleukin-8 receptor (IL8R), and L-selectin. VII. Amounts and Methods of Administration
  • the supplement combination is administered to an animal, such as a mammal or avian species.
  • the animal is an animal raised for human consumption such as livestock (e.g., feed or dairy cattle) or pigs, or avians, such as domestic fowl (e.g. , chicken, turkey, goose, duck, Cornish game hen, quail, pheasant, guinea-fowl, ostrich, emu, swan, or pigeon).
  • livestock e.g., feed or dairy cattle
  • pigs or avians, such as domestic fowl (e.g. , chicken, turkey, goose, duck, Cornish game hen, quail, pheasant, guinea-fowl, ostrich, emu, swan, or pigeon).
  • domestic fowl e.g. , chicken, turkey, goose, duck, Cornish game hen, quail, pheasant, guine
  • the animal is a ruminant, such as a bovine, a sheep, a goat, a horse, a bison, a buffalo, a deer, a llama, or an alpaca.
  • the animal is a domestic animal, e.g. , a companion animal, such as a dog, cat, ferret, guinea pig, rat, gerbil, hamster, mouse, or rabbit.
  • the animal is a hoofed animal.
  • the supplement combination supports the animal's overall health and wellbeing.
  • the supplement combination when administered to the animal, may help reduce an in vivo level of at least one inflammation biomarker.
  • the biomarker may be associated with an inflammatory disorder. By promoting a reduction in the level of an inflammation biomarker, administration of the supplement may consequently ameliorate one or more signs or symptoms of the inflammatory disorder.
  • the inflammatory disorder is arthritis, laminitis, founder, dermatitis (e.g.
  • the animal is a hoofed animal and the inflammatory disorder is laminitis or founder.
  • the animal is a hoofed ruminant.
  • the animal is a bovine, a sheep, a goat, or a horse. The animal may have, or be at risk of, developing laminitis or founder.
  • the supplement combination is a blended composition comprising
  • polyphenol-containing plant material and/or plant extract (a) polyphenol-containing plant material and/or plant extract, and (b) one or more components of Composition A.
  • the polyphenol-containing plant material/plant extract and Composition A are separate components that are administered to the animal simultaneously or sequentially in any order. Additionally, individual components of Composition A may be administered simultaneously or sequentially in any order.
  • the polyphenol-containing plant material and/or plant extract may further comprise biologically active non-polyphenolic compounds, such as polyphenol degradation products.
  • composition A or one or more components of Composition A, may be administered followed substantially immediately (e.g. , within several minutes to an hour) by the polyphenol-containing plant material/extract.
  • the animal could be
  • the first and subsequent times may be, e.g. , a first feeding period of a day and a subsequent feeding period of the day.
  • the polyphenol-containing plant material/plant extract and Composition A, or one or more components of Composition A may be administered sequentially within a time period effective to help reduce an in vivo level of at least one inflammation biomarker in the animal.
  • the effective time period may range from 1 hour to 60 days, such as from 1 day to 60 days, from 1 day to 45 days, from 1 day to 30 days, from 1 day to 20 days, from 1 day to 15 days, or from 1 day to 10 days.
  • administration of the polyphenol-containing plant material/plant extract and Composition A is performed on alternating days.
  • administration of Composition A is discontinued the day prior to administering the polyphenol-containing plant material/plant extract, leading to an interval of one day between suspension of Composition A administration and initiation of plant material/plant extract administration.
  • the beneficial effects of Composition A may persist beyond
  • the interval between suspension of Composition A administration and initiation of polyphenol-containing plant material/plant extract administration may be up to 60 days, such as from 1 day to 60 days, from 1 day to 45 days, from 1 day to 30 days, from 1 day to 20 days, from 1 day to 15 days, or from 1 day to 10 days.
  • Composition A may be administered regularly (e.g. , daily) for a period of time, such as for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 14 days, or at least 30 days before suspension.
  • the polyphenol-containing plant material/plant extract may be administered regularly (e.g. , daily) for a subsequent period of time, such as for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 14 days, at least 30 days, or from 1 day to 60 days.
  • the animal is administered a sufficient amount of the supplement combination to provide a dried plant extract amount of 1-100 mg/kg body weight per day (mg/kg BW/d).
  • the target amount may be 1 mg/kg BW/d of plant extract, 5 mg/kg BW/d, 7 mg/kg BW/d, 10 mg/kg BW/d, or 50 mg/kg BW/d.
  • an animal may be administered an amount of the supplement combination ranging from 1 mg/kg BW/d to 20 g/kg BW/d, such as 1 mg/kg BW/d, 10 mg/kg BW/d, 50 mg/kg BW/d, 100 mg/kg BW/d, 500 mg/kg BW/d, 1 g/kg BW/d, 5 g/kg BW/d, 10 g/kg BW/d, or 20 g/kg BW/d.
  • 1 mg/kg BW/d such as 1 mg/kg BW/d, 10 mg/kg BW/d, 50 mg/kg BW/d, 100 mg/kg BW/d, 500 mg/kg BW/d, 1 g/kg BW/d, 5 g/kg BW/d, 10 g/kg BW/d, or 20 g/kg BW/d.
  • the animal is administered a sufficient amount of the supplement combination to provide a total polyphenol amount of 0.1-100 mg/kg BW/d, such as a polyphenol amount of 1 mg/kg BW/d, 7 mg/kg BW/d, 10 mg/kg BW/d, 50 mg/kg BW/d, or 100 mg/kg BW/d.
  • the combination may be administered as an admixed composition comprising dried plant extract and Composition A, or the components (dried plant extract and Composition A) may be administered separately with administration occurring simultaneously and/or sequentially in any order.
  • the combination is administered as separate components whereby the animal is administered a total polyphenol amount of 1-100 mg/kg BW/d and a Composition A amount of 0.01-1 g/kg BW/d.
  • the amount of the supplement combination fed can vary depending upon the animal species and size of the animal, the ratio of plant materiakComposition A or dried plant extract: Composition A, and/or type of the feedstuff to which the supplement combination is added.
  • the supplement combination may be provided to sheep in the range of from 0.1 grams per head per day to 10 grams per head per day, or to bo vines in the range of from 0.5 grams per head per day to 100 grams per head per day.
  • a supplement composition is administered to sheep at a target plant extract amount of 50 mg per sheep per day.
  • a sheep may be administered 5 g per day of a supplement composition comprising a 1 : 100 ratio of dried plant extract: Composition A.
  • the supplement combination is administered to cows at a target plant extract amount of 7 mg/kg BW/d, or 5 grams per cow per day.
  • a cow may be administered 10 g/day of a supplement composition comprising a 1:1 mass ratio of dried plant extract: Composition A.
  • the supplement combination may be mixed with either solid or liquid feed or with water; alternatively, one component (plant material/plant extract or Composition A) may be mixed with solid feed and the other component may be mixed with liquid feed or water.
  • the supplement combination is formed into pellets; the pellets may include a combination of plant material plant extract and Composition A, or individual pellets of plant material/plant extract and individual pellets of Composition A may be formed.
  • the supplement combination when incorporated directly into feeds, is added in amounts ranging from 0.1 to 20 kg per ton (2000 pounds) of feed. In some embodiments, the supplement combination is added to animal feedstuff s or to food in amounts from 0.5 kg to 10 kg per ton of feed. In certain embodiments, the supplement combination may be added to feeds in amounts ranging from 1 to 5 kg per ton of feed.
  • the supplement combination When expressed as a percentage of dry matter of feed, the supplement combination may be added to animal feedstuffs or to foods in amounts ranging from 0.01 to 2.5% by weight, such as from 0.0125% to 2% by weight. In one embodiment, the supplement combination is added to animal feedstuffs or to food in amounts from 0.05 to 1.5% by weight, such as from 0.0625% to 1% by weight. In another embodiment, the supplement combination is added in amounts from 0.1 to 0.7% by weight, such as from 0.125% to 0.5% by weight of feed.
  • the supplement combination may be fed directly to animals as a supplement in amounts of from 0.01 gram to 20 gram per kilogram of live body weight per day, such as from 0.01 gram to 10 gram per kilogram, 0.01 gram to 5 gram, 0.01 gram to 1 gram, or 0.015 gram to 1 gram.
  • the supplement combination is fed to animals in an amount that provides 1-100 mg/kg of total polyphenol per day, such as 1-50 mg/kg, 1-25 mg/kg, 1-10 mg/kg or 5-10 mg/kg.
  • a target daily amount of the supplement combination is administered to the animal in a single administration.
  • the target daily administration is split and administered to the animal in two or more separate administrations, e.g. , half the target daily amount may be administered in a first daily feeding and half the target daily amount may be administered in a subsequent feeding.
  • the target daily amount is added to the animal's feed and the animal is permitted to consume the feed ad libitum throughout the day.
  • the supplement combination is included in the animal's diet on a daily basis. In other embodiments, the supplement combination is included in the animal's diet for an effective period of time prior to changing the animal's diet or ration.
  • the effective period of time may be from 0-60 days, such as from 1-30 days, 3-21 days, 5-15 days, or 7-10 days. In some examples, animals were pre-fed the supplement combination for 7 days before a change in ration.
  • a therapeutic agent effective for treating inflammatory disorders is co-administered with the supplement combination.
  • Co-administration refers to concurrent (e.g. , simultaneous or substantially simultaneous) or sequential administration.
  • Therapeutic agents suitable for co-administration include, but are not limited to, fluid therapy, cryotherapy, heat therapy, antimicrobials (e.g. , antibiotics, antifungals), anti-endotoxin agents, anticoagulants, anti-inflammatory agents (e.g. , corticosteroids, non-steroidal anti-inflammatory drugs), glycosaminoglycans (e.g. , glucosamine, chondroitin), vasodilators, dimethyl sulfoxide, mineral oil (typically via nasogastric tube), supplements (fish oil, herbs (e.g.
  • proteinase inhibitors e.g. , proteinase inhibitors that target hoof wall matrix metalloproteinases.
  • Exemplary therapeutic agents include, but are not limited to, acetylpromazine, phenoxybenzamine, phenylbutazone, flunixin meglumine, ketoprofen, carprofen, etodolac, deracoxib, meloxicam, isoxsuprine, pentoxifylline, isoxuprine hydrochloride, ace promazine, glyceryl trinitrate, aspirin, heparin, L-arginine, nitroglycerin, glucosamine, chondroitin, tramadol, gabapentin, doxycycline, and combinations thereof.
  • Other modalities may include dietary restrictions (e.g.
  • modalities also may include stabling the animal on soft ground, treating abscesses, use of heel wedge cuffs, and foot trimming.
  • biomarkers include, but are not limited to, tumor necrosis factor alpha (TNF-a), nuclear factor kappa B (NF- ⁇ ), interferon gamma (IFN- ⁇ ), interleukin-6 (IL6), interleukin-8 (IL8), interleukin- 1 ⁇ (IL- ⁇ ⁇ ), cellular COX-2 gene expression, L-selectin, interleukin- 8 receptor (IL8R), cellular lipoxygenase (LOX), C-reactive protein (CRP), macrophage inflammatory protein 1 -alpha (MIP) gene expression, eicosanoids (localized cellular products produced by COX and LOX), alpha- 1 -antitrypsin (AAT), haptoglobin, fibrinogen, uric acid/urate, homocysteine, adiponectin, and/or toll-like
  • Administering an embodiment of the disclosed supplement combinations and compositions to an animal may promote a reduction in an in vivo level of at least one biomarker, thereby helping to maintain the animal's overall health by helping to reduce the prevalence and/or severity of symptoms or signs associated with an inflammatory disorder characterized by an elevation in one or more of these biomarkers including, but not limited to, arthritis, hoof disorders, dermatitis, eczema, atherosclerosis, cystitis, inflammatory bowel disease, hemorrhagic gastroenteritis, meningitis-arteritis, encephalitis, acquired myasthenia gravis, hepatitis, pancreatitis, gingivitis, degenerative neurological conditions, diabetes, and obesity.
  • Embodiments of the disclosed supplement combinations and compositions also may augment the animal's health by enhancing the animal's immune system (i.e., the innate and/or adaptive immune system).
  • some embodiments of Composition A affect levels of immune system biomarkers including, but not limited to, neutrophil L-selectin, IL- ⁇ ⁇ and/or gene expression of Crp, Mbl2, Apes, 115, Ifnal , Ccll2, Csf2, 1113, 1110, Gata3, Stat3, C3, Tlr3, Ccl5, Mx2, Nfkbl, Nfkbia, Tlr9, CxcllO, Cd4, 116, Ccl3, Ccr6, Cd40, Ddx58, 1118, Jun, Tnf, Traf6, Statl, Ifnbl , Cd80, Tlrl, Tlr6, Mapk8, Nod2, Ccr8, Iraki, Cdldl,
  • Composition A also augment an animal's adaptive immune system, e.g. , by increasing response to a vaccine; antibody levels, such as IgG levels, may be increased, relative to an animal that has received a vaccine but has not been administered Composition A.
  • Embodiments of the disclosed supplement combinations and compositions may be administered to an animal for an effective period of time to help reduce an in vivo level of at least one inflammatory biomarker or help change an in vivo level of at least one immune system biomarker.
  • the effective period of time may be at least 1 day, at least 3 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 30 days, or at least 60 days.
  • the effective period of time is 1-60 days, 1-45 days, 1-30 days, 1-21 days, 3-60 days, 3-45 days, 3-30 days, 3-21 days, 7-60 days, 7-45 days, 7-30 days, 7-21 days, 10-60 days, 10- 45 days, 10-30 days, or 10-21 days.
  • composition A and grape plant extract exerted pro-inflammatory properties as measured by expression of two key inflammatory markers in neutrophils, i.e. , L-selectin and IL8R
  • the combination of Composition A and grape plant extract significantly reduced expression of both L-selectin and IL8R (see. e.g. , FIGS. 2-5).
  • L-selectin and IL8R significantly reduced expression of both L-selectin and IL8R
  • embodiments of the disclosed supplement combinations may maintain an animal's health and wellbeing by ameliorating inflammatory responses.
  • a supplement combination as disclosed herein, fewer neutrophils that are present in the blood are recruited to a non-infectious site of tissue damage (e.g. , the corium following a laminitic challenge). As a result, neutrophil- mediated damage of the tissue will be lowered or substantially eliminated during periods of excessive carbohydrate challenge.
  • the supplement combination can help protect animals from neutrophil-mediated damage to tissue and maintains their health and wellbeing.
  • neutrophils When fed an embodiment of the disclosed supplement combinations, neutrophils up- regulate their ability to produce pathogen-killing ROS species. Therefore, in a non-infectious clinical presentation (such as non-infectious laminitis), less tissue damage will result as a result of reduced neutrophil infiltration in the tissue (e.g. , corium tissue). However, should an infectious agent actually be present (either in corium or in other tissue to which neutrophils are recruited), the supplement combination may support health by enhancing killing ability of individual neutrophils by increasing their ability to manufacture ROS.
  • C-reactive protein is an acute phase protein, which is synthesized in the liver and plays an important role in initiating the complement cascade.
  • Effects of the disclosed supplement combination on CRP expression demonstrate that the combination may synergistically enhance complement function. These synergistic responses essentially mimic those detected with the combination's effects on zymosan-mediated ROS generation.
  • Embodiments of the disclosed supplement combination have been demonstrated to attenuate some aspects of the inflammatory response, while at the same time synergistically enhancing other elements of the immunological response (e.g. , ROS generation and hepatic formation of CRP/complement activation).
  • Some embodiments of the disclosed supplement combinations when administered to sheep or cows, demonstrated clear health benefits compared to a control diet without the supplement combination.
  • sheep were fed a control diet or an embodiment of the supplement combination comprising Pinot noir extract, Pinot gris extract, or green tea extract for 7 days, and then DL-lactic acid was administered to sheep via ruminal infusion to induce laminitis symptoms.
  • Subsequent examination of the animals' corium showed that the supplement combination substantially lessened the inflammatory response in the corium as measured by Cox-2 and MIP mRNAs (FIGS. 9 and 10).
  • This protective effect would be expected to reduce the extent of self- mediated tissue damage of the corium that would occur in a grain overload/laminitis event and thereby protect the integrity and function of the hoof.
  • feeding the product for an effective period of time e.g. , one week
  • a diet change can maintain the animal's health by ameliorating debilitating effects of tissue auto-digestion that occurs in the corium.
  • cows in a test group were administered a bolus comprising an embodiment of the supplement combination twice daily for 7 days, and then oligofructose was administered directly into the rumen to induce laminitis symptoms. Over the next 48 hours, the cows continued to receive the supplement combination twice daily. A control group received the oligofructose, but did not receive the supplement combination.
  • the supplement combination also caused marked reduction in hyperemia and dermal edema, as well as a reduction in lamellar stretching compared to animals in the positive control group that received oligofructose but did not receive the supplement combination (FIGS. 13-15).
  • Extractions may be performed for a duration of several minutes to several days; in the examples, extractions typically were performed for 1 hour.
  • Any acidifying agent may be used in place of HC1, including, for example, citric acid;
  • aqueous phase (contains biologically-active polyphenolic and non-polyphenolic components) and discard pulp. In some instances, the pulp is extracted one or more additional times before being discarded, and the aqueous phases are combined;
  • This product may then be dried via freeze-drying or via low-temperature drying, and then ground to a fine powder to produce a dried extract.
  • the aqueous plant extract may be mixed with a carrier such as diatomaceous earth or maltodextrin, and then dried.
  • the liquid extract from step 5 is combined with Composition A, and the combination is subsequently dried to form a supplement composition.
  • the ratios of 1) dried plant extract: Composition A and 2) the four ingredients comprising Composition A can be varied as disclosed herein.
  • Plant materials (Pinot gris pomace, Pinot noir pomace and dried green tea) were extracted with both aqueous- and ethanol-based systems. In each case, the ratio of plant material to solvent was 1 :9 (weight:volume).
  • the solvent in the water-based system was water with 0.1 % HC1.
  • the solvent in the ethanol-based system was 70% ethanol, 30% water and 0.1% HC1. The extractions were typically performed for 1 hour.
  • the concentrations of antioxidants in the extracts were determined in vitro using a "Trolox equivalents" assay (FIG. 1). Antioxidant concentrations of extracts were compared to well-known antioxidant molecules (catechin and quercetin) at five different concentrations (1 : 10, 1 : 100, 1 : 1000, 1 : 10,000 and 1 : 100,000). All plant extracts possessed anti-oxidant activities (expressed as Trolox equivalents). Aqueous- and ethanol-based extraction systems provided similar recoveries of antioxidant activity, although for green tea extraction, ethanol extraction appeared more efficacious at 1 : 100,000 through 1 : 10,000 dilutions. The results showed that there were similar amounts of antioxidants in both Pinot noir and Pinot gris pomace.
  • ⁇ Polyphenol degradation products included gallic acid (2.2 mg/100 ml) and trans-caftaric acid (0.23 mg/100 ml).
  • Composition A was provided to Groups 2 and 4 at 0.5% w/w of the diet (Harlan Teklad 8604, Harlan Laboratories). Grape pomace extract was provided to Groups 3 and 4 to provide a daily amount of 6.25 mg of total polyphenol/rat/day. Animals were maintained on these regimens for 6 or 28 days after which they were anesthetized, and blood samples were taken via cardiac puncture.
  • ROS reactive oxygen species
  • L-selectin included L-selectin, interleukin-8-receptor (IL8R) and ⁇ -actin mRNAs.
  • L-selectin and IL8R mRNAs were expressed as a proportion of a house-keeping gene ( ⁇ -actin) according to the method of Livak and Schmittgen ⁇ Methods 25, 402-408 (2001)).
  • FIGS. 2 and 3 Effects of short-term (6-day) exposure of rats to these four regimens on neutrophil L- selectin and IL8R mRNAs are shown in FIGS. 2 and 3.
  • Feeding Composition A CTP-5 alone caused small increases in concentrations of both L-selectin and IL8R mRNAs.
  • feeding the grape pomace extract GPE alone caused massive increases in the expression of both of these biomarkers (FIGS. 2 and 3).
  • Composition A when fed alone, increased expression of two inflammatory markers: L-selectin and IL8R.
  • the grape extract product even though considered to be an anti-inflammatory product, also exerted inflammatory properties in the neutrophils.
  • antioxidant polyphenols are regarded to function as anti-inflammatory agents.
  • FIGS. 2-5 clearly demonstrate that the grape polyphenolic extract, when fed alone, exerted pro-inflammatory properties in the rat model.
  • ROS reactive oxygen species
  • C-reactive protein is an acute-phase protein, which is synthesized in the liver and plays an important role in initiating the complement cascade.
  • Effects of Composition A (CTP-5) in combination with grape extract on CRP expression imply that the combination product would synergistically enhance complement function.
  • These synergistic responses mimic those detected with the combination product' s effects on zymosan- mediated ROS generation.
  • the combination product appears to surprisingly attenuate some aspects of the inflammatory response (e.g., neutrophil recruitment potential) while, at the same time synergistically enhancing other elements of the immunological response (e.g., ROS generation and hepatic formation of
  • Composition A and extract were combined in a ratio of 100: 1.
  • the combined product approximately 5 g per sheep, was added to the sheep's regular feed and consumed throughout the day.
  • Development of inflammatory markers in corium was determined 48 hours following ruminal infusion of DL-lactic acid.
  • effects of combination products prepared with Pinot noir, Pinot gris and green tea were assessed.
  • the RPL-19 mRNA was used as a housekeeping gene, and amounts of Cox-2 and MIP mRNAs were expressed as a proportion of RPL-19 mRNA according to the methods of Livak and Schmittgen (Methods 25, 402-408 (2001)). Effects of lactic acid infusion on Cox-2 and MIP mRNAs are shown in FIGS.
  • Pre-feeding the experimental product for 7 days prior to the lactic acid challenge substantially lessened the inflammatory response of corium (FIGS. 9 and 10).
  • the one that was prepared from the Pinot noir pomace exerted the greatest efficacy in ameliorating the lactic acid induced inflammatory events of the corium.
  • This protective effect would be expected to help reduce the extent of self -mediated tissue damage of the corium that would occur in a grain overload/laminitis event, and thereby protect the integrity and function of the hoof.
  • animals in Group 3 were administered experimental product daily in two bolus amounts (AM and PM feeding) administered directly into the rumen via a feeding tube.
  • the experimental product included a 1 : 1 mass ratio of Composition A and dried plant extract. The product was suspended in water for infusion into the rumen. Each amount was estimated to provide 5 g of total polyphenol to each animal.
  • animals in Groups 2 and 3 were administered oligofructose directly into the rumen. The oligofructose dose was 15g/kg body weight (roughly 20 lbs of oligofructose/cow).
  • cows in Group 3 received intraruminal administration of product in morning and afternoon to simulate intake.
  • mice Forty-eight hours after oligofructose administration, animals were locomotion-scored ⁇ i.e., walking ability was assessed qualitatively). Furthermore, animals were individually placed on a hoof-trimming cart, turned sideways and samples of corium were taken aseptically via biopsy of the left front and rear hooves. The corium samples were divided into two pieces. One piece was preserved in formalin for histological examination, and the other piece was preserved in Trizol for later quantification of molecular markers of corium inflammation.
  • MIP and Cox-2 were calculated relative to the RPL-19 housekeeping gene according to the methods of Livak and Schmittgen (Methods 25, 402-408 (2001)). Histological analysis was completed blind by a board-certified veterinary pathologist. Samples of corium were scored on an objective scale for degree of damage and inflammation as described below in results. Once samples had been scored histologically, data were compiled and regimen effects assessed.
  • FIGS. 11 and 12 Effects of the three regimens on biomarkers of molecular inflammation (MIP and Cox-2 mRNAs) are shown in FIGS. 11 and 12, respectively. Data presented are means of both samples from the front and rear hooves.
  • NC represents “negative control” (Group 1).
  • PC represents “positive control” (Group 2).
  • Teatment represents Group 3, animals that were pre-fed experimental product. Infusion of oligofructose into Group 2 animals increased expression of both MIP and Cox-2 mRNAs in corium. Pre-feeding of product for 7 days prior to oligofructose administration helped reduce the oligofructose-mediated elevation in both MIP and Cox-2 mRNAs.
  • locomotion scoring allows one to objectively quantify the overall "health" of the hoof for an animal or for a herd. For example, a quick evaluation of locomotion scores within a herd informs an individual about dietary, housing and other issues that may adversely be affecting hoof health and cow comfort.
  • Table 4 A summary of the scoring system used in locomotion scoring is given in Table 4.
  • FIG. 16 Effects of oligofructose infusion on locomotion scores of Group 2 and 3 cattle are shown in FIG. 16 (Group 1 cattle were not locomotion scored). Dashed lines track individual group 2 cows. Solid lines track individual Group 3 (experimental product-fed) cows.
  • X-axis is time following administration of oligofructose in hours. F-axis represents locomotion score as outlined in Table 3. For Group 2 cows (i.e., those infused with oligofructose but no protective product), locomotion scores were elevated at 20-72 hours post-infusion, demonstrating that the oligofructose infusion protocol effectively provided a model of experimentally-induced laminitis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Mycology (AREA)
  • Rheumatology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Inorganic Chemistry (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des modes de réalisation de l'invention concernent une combinaison médicamenteuse et un procédé d'administration à un animal. L'animal peut être atteint d'un trouble inflammatoire ou présenter le risque de développer un trouble inflammatoire. La combinaison médicamenteuse comprend (a) un matériau végétal contenant du polyphénol, un extrait végétal dérivé du matériau végétal contenant du polyphénol, ou un mélange de ceux-ci, et (b) du glucane, de la silice, un minéral argileux, des mannanes, ou toute combinaison de ceux-ci.
PCT/US2014/048446 2013-07-29 2014-07-28 Combinaison médicamenteuse et procédé d'administration à un animal Ceased WO2015017336A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361859689P 2013-07-29 2013-07-29
US61/859,689 2013-07-29

Publications (1)

Publication Number Publication Date
WO2015017336A1 true WO2015017336A1 (fr) 2015-02-05

Family

ID=51355650

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/048446 Ceased WO2015017336A1 (fr) 2013-07-29 2014-07-28 Combinaison médicamenteuse et procédé d'administration à un animal

Country Status (3)

Country Link
AR (1) AR097111A1 (fr)
TW (1) TW201601730A (fr)
WO (1) WO2015017336A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017207481A1 (fr) * 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Indazoles substitués utiles pour le traitement et la prévention de maladies allergiques et/ou inflammatoires chez des animaux
WO2018140450A1 (fr) * 2017-01-24 2018-08-02 Costigan Timothy E Complément alimentaire en granulés et ses procédés de fabrication et d'utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114177187B (zh) * 2021-12-10 2024-10-22 西北大学 富含α2，6-唾液酸修饰的羊乳酸性游离寡糖在制备免疫调节药物或功能食品中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10143146A1 (de) * 2001-09-03 2003-03-27 Mfe Marienfelde Gmbh Unternehm Antiarthrotische Zubereitung und deren Verwendung
WO2007011674A2 (fr) * 2005-07-15 2007-01-25 Baker Donald J Compositions et methodes de traitement et de prevention de processus inflammatoires et/ou degeneratifs chez l'homme et l'animal
WO2010097643A1 (fr) * 2009-02-24 2010-09-02 Novatech Istrazivanje D.O.O. Formulation à base de zéolithe micronisée, d'extrait de thé vert et de génistéine en tant qu'agent thérapeutique pour réduire le poids corporel et la cellulite
WO2014055672A1 (fr) * 2012-10-02 2014-04-10 Oil-Dri Corporation Of America Produits d'argile et utilisations de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10143146A1 (de) * 2001-09-03 2003-03-27 Mfe Marienfelde Gmbh Unternehm Antiarthrotische Zubereitung und deren Verwendung
WO2007011674A2 (fr) * 2005-07-15 2007-01-25 Baker Donald J Compositions et methodes de traitement et de prevention de processus inflammatoires et/ou degeneratifs chez l'homme et l'animal
WO2010097643A1 (fr) * 2009-02-24 2010-09-02 Novatech Istrazivanje D.O.O. Formulation à base de zéolithe micronisée, d'extrait de thé vert et de génistéine en tant qu'agent thérapeutique pour réduire le poids corporel et la cellulite
WO2014055672A1 (fr) * 2012-10-02 2014-04-10 Oil-Dri Corporation Of America Produits d'argile et utilisations de ceux-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Y. WANG ET AL: "Ability of a commercial feed additive to modulate expression of innate immunity in sheep immunosuppressed with dexamethasone", ANIMAL, vol. 1, no. 07, 1 August 2007 (2007-08-01), pages 945, XP055143696, ISSN: 1751-7311, DOI: 10.1017/S1751731107000365 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017207481A1 (fr) * 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Indazoles substitués utiles pour le traitement et la prévention de maladies allergiques et/ou inflammatoires chez des animaux
CN109219603A (zh) * 2016-06-01 2019-01-15 拜耳动物保健有限责任公司 用于治疗和预防动物的过敏性和/或炎症性疾病的取代吲唑
TWI781935B (zh) * 2016-06-01 2022-11-01 德商拜耳動物保健有限公司 經取代之吲唑於治療及預防動物之疾病之用途
US12459916B2 (en) 2016-06-01 2025-11-04 Bayer Pharma Aktiengesellschaft Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals
WO2018140450A1 (fr) * 2017-01-24 2018-08-02 Costigan Timothy E Complément alimentaire en granulés et ses procédés de fabrication et d'utilisation
CN110325051A (zh) * 2017-01-24 2019-10-11 奥姆尼根研究有限责任公司 颗粒状饲料补充剂及其制造和使用方法
AU2018212566B2 (en) * 2017-01-24 2022-11-24 OmniGen Research, L.L.C. Granulated feed supplement and methods for making and using

Also Published As

Publication number Publication date
TW201601730A (zh) 2016-01-16
AR097111A1 (es) 2016-02-17

Similar Documents

Publication Publication Date Title
Giri et al. Effects of bioactive substance from turmeric on growth, skin mucosal immunity and antioxidant factors in common carp, Cyprinus carpio
US11419888B2 (en) Composition and method for promoting reduction of heat stress in animals
Wu et al. Effects of dietary Radix Rehmanniae Preparata polysaccharides on the growth performance, immune response and disease resistance of Luciobarbus capito
Ragaa et al. Studying the effect of formic acid and potassium diformate on performance, immunity and gut health of broiler chickens
DE60212964T2 (de) Zusammensetzungen zur behandlung von tierischen krankheiten und syndromen mit transferfaktor
Ou et al. Dietary supplementation with zinc oxide decreases expression of the stem cell factor in the small intestine of weanling pigs
Van Eps et al. Equine laminitis induced with oligofructose
Dai et al. Sodium butyrate ameliorates high-concentrate diet-induced inflammation in the rumen epithelium of dairy goats
US8697148B2 (en) Milk yield and/or milk quality improving agent, perinatal disease preventive or therapeutic agent, and reproductivity improving agent for ruminant
O’Doherty et al. Novel marine polysaccharides and maternal nutrition to stimulate gut health and performance in post-weaned pigs
WO2018049243A1 (fr) Additif pour aliment pour animaux comportant de l'allicine
JP2017532369A (ja) 抗微生物剤耐性を回避する抗下痢製剤
JP2023532029A (ja) コクシジウム症の予防と治療に対する、動物飼料によるプラスの潜在的効果
Idowu et al. Effects of a multicomponent microbial feed additive containing prebiotics and probiotics on health, immune status, metabolism, and performance of newly weaned beef steers during a 35-d receiving period
Ren et al. Supplementation of dietary crude lentinan improves the intestinal microbiota and immune barrier in rainbow trout (Oncorhynchus mykiss) infected by infectious hematopoietic necrosis virus
WO2015017336A1 (fr) Combinaison médicamenteuse et procédé d'administration à un animal
Ochiogu et al. Serum luteinising hormone, testosterone and total cholesterol levels, libido and testicular histomorphology of male West African Dwarf goats orally or subcutaneously treated with monosodium L-glutamate.
Qi et al. Effect of coated-benzoic acid on growth performance, immunity, and intestinal functions in weaned pigs challenged by enterotoxigenic Escherichia coli
WO2018148563A1 (fr) Composition comprenant de la silice, de l'argile minérale, du glucane et des mannanes et son administration à des mammifères
El-Kholy et al. Study on the optimal crude papaya latex content of growing rabbit diet under summer conditions: Effects on growth performance and immune status
US20250345361A1 (en) Compositions and methods to improve calf growth and reduce incidence of scours
JP7519661B2 (ja) 腸管細胞の炎症抑制剤
KR100327966B1 (ko) 수용성 키토산을 함유하는 양돈용 영양제 및 이의 사용방법
Fei et al. Optimal Isatidis Radix extract enhances growth, immunity, modifies immune-gene action and intestinal health in hybrid snakehead (Channa maculata♀× Channa argus♂) against rhabdovirus
WO2025120326A1 (fr) Arabinogalactane

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14752495

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14752495

Country of ref document: EP

Kind code of ref document: A1