Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
  • A23C11/00—Milk substitutes, e.g. coffee whitener compositions
  • A23C11/02—Milk substitutes, e.g. coffee whitener compositions containing at least one non-milk component as source of fats or proteins
  • A23C11/04—Milk substitutes, e.g. coffee whitener compositions containing at least one non-milk component as source of fats or proteins containing non-milk fats but no non-milk proteins
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
  • A23L33/12—Fatty acids or derivatives thereof
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is directed to enteral formulations that contain long- chain polyunsaturated fatty acids (PUFAs) and to methods for maintaining gut integrity and enhancing the restitution of gut integrity. More specifically the present invention is directed to formulations and methods for reducing gut permeability and restoring damaged intestinal cells to maintain and enhance the restitution of gut integrity.
• PUFAs long- chain polyunsaturated fatty acids
• U.S. Patent No. 4,670,285 discloses a specific fat blend suitable for use in infant formulations.
• the fat blend contains at least one C 20 or C 22 n-6 fatty acid and one C 20 or C 22 n-3 fatty acid.
• the C 20 or C 22 n-6 fatty acid is present in a total amount of about 0.13 to 5.6% by weight of all fatty acids in the composition.
• the C 20 or C 22 n-3 fatty acid is included in a total amount of about 0.013 to about 4.44% by weight of all fatty acids in the composition.
• This patent discloses the use of egg lipids to supply the fatty acids.
• U.S. Patent No. 4,918,063 discloses formulations containing mixtures of phospholipids and neutral lipids for the prevention or treatment of ulcers and inflammatory bowel disease.
• This patent discloses a mixture of saturated or unsaturated phospholipids, together with saturated or unsaturated triglycerides and/or sterols as providing ulcer protection in experimental animal models.
• PCT International Publication No. WO96/10922 discloses a fat mixture for infant formula characterized in that arachadonic acid and docosahexanoic acid are present in the form of phospholipids.
• European Patent Application No. 0376628 Bl discloses an all vegetable oil fat blend which utilizes randomized palm oil or randomized palm olein oil as the sole palmitic acid oil source. It is disclosed that the compositions are particularly useful in infant formulas particularly for preterm or low birth weight infants.
• the present invention is directed to methods for maintaining gut integrity and enhancing the restitution of gut integrity in an individual in need thereof, comprising administering to the individual a formulation comprising at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid, to formulations for use in the method comprising an effective amount of at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid, and the to use of an effective amount of at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid in the manufacture of a medicament for use in maintaining gut integrity and enhancing the restitution of gut integrity in an individual in need thereof.
• Figure 1 compares plasma endotoxin levels in rats supplemented with the formulation of the invention to rats that have not been supplemented.
• Figure 2 shows the effect of the present formulation on intestinal PLA 2 mRNA expression levels.
• Figure 3 shows the effect of the present formula on intestinal PAF-receptor levels in RNA.
• the polyunsaturated fatty acids useful in the present invention include fatty acids of twenty carbons or more having at least two carbon-carbon double bonds.
• the number and position of double bonds in the fatty acids are designated by the nomenclature conventionally used.
• arachidonic acid has a chain length of 20 carbon atoms and 4 double bonds beginning at the sixth carbon from the end of the molecule. Accordingly, arachidonic acid is referred to as C 20 :4 n-6.
• docosahexanoic acid has a chain length of 22 carbon atoms with 6 double bonds beginning at the third carbon from the end of the molecule and is designated C 22 :6 n-3.
• the n-6 polyunsaturated fatty acid used in the present invention is arachidonic acid and the n-3 polyunsaturated fatty acid used in the present invention is docosahexanoic acid.
• the method of the present invention comprises administering to an individual having one or more disorders characterized by cell damage or destruction to gut tissue an effective amount of a formulation containing at least one n-6 polyunsaturated fatty acid and at least one n-3 polyunsaturated fatty acid. Effective amounts of the n-6 polyunsaturated fatty acid is about 5 to 61 mg and preferably 10 to 51 mg/kg body weight.
• effective amounts of the n-3 polyunsaturated fatty acid is about 5 to 61 and preferably 5 to 51 mg/kg body weight.
• the effective arachidonic acid: docosahexanoic acid ratio is about 1: 1 to 2.5:1, and preferably 1 :1 to 2:1. This is based on administration of 100 kcal/kg/day for a 1 kg infant.
• the formulations used in the present method should comprise about 4 to about 50, and preferably about 8 to about 41 mg/100 ml of polyunsaturated fatty acid.
• the formulations used in the present method should comprise about 4 to about 50, and preferably about 4 to about 41 mg/100 ml of the n-3 polyunsaturated fatty acid.
• the effective arachidonic acid: docosahexanoic acid ratio is 1:1 to 2.5: 1 and preferably 1 : 1 to 2: 1.
• the present invention is directed to methods for maintaining gut integrity and enhancing the restitution of gut integrity, to formulations for use in for maintaining gut integrity and enhancing the restitution of gut integrity and to the use of an effective amount at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid in the manufacture of a medicament for use in for maintaining gut integrity and enhancing the restitution of gut integrity.
• Gut integrity is compromised in a number of disease states which increase gut permeability, cause cell damage or destruction in the gut and cause bacterial translocation in the gut which may lead to endotoxemia.
• a preferred embodiment of this invention is a method or formulation for maintaining and enhancing the restitution of gut integrity in infants, particularly preterm infants. This method comprises enterally administering to the infants a nutritionally complete infant formula comprising proteins, carbohydrates, lipids and effective amounts of at least one n-6 polyunsaturated fatty acid and at least one n-3 polyunsaturated fatty acid.
• n-6 and n-3 polyunsaturated fatty acid examples include S-26, S-26 LBW and SMA available from Wyeth Nutritionals International.
• Fat Blend 1 Specific examples of fat blends containing appropriate amounts of n-6 and n-3 polyunsaturated fatty acids according to the present invention are set forth below: Fat Blend 1
• the method of the present invention was tested in a neonatal rat model of hypoxia induced gut injury. Reduced gut permeability is associated with reduced endotoxemia and a lowered intestinal phospholipase-2 (PLA 2 ) gene expression.
• PHA 2 intestinal phospholipase-2
• Rat pups were delivered via abdominal incision from time- dated pregnant Sprague-Dawley rats on the 21st day of gestation.
• the newborn rats were fed via the orogastric route 0.1 ml of formula (S26-LBW formula, available from Wyeth Nutritionals International, Burlington, VT) every three hours with the volume advanced as tolerated up to 0.4 ml by 72 hours of life.
• animals were stressed with asphyxia twice daily by breathing 100% nitrogen gas for 5.0 seconds and then cold exposure to 4°C for 10 minutes. Using this protocol, 70-80% of animals develop abdominal necrosis by the 3rd to 4th day of life as described in
• Treatment Groups There were 2 treatment groups: preterm formula
• LCPUFAs added to Formula B were arachidonic acid and docosahexanoic acid.
• the LCPUFAs were added in the following amounts: 20 mg/lOOkcal docosahexanoic acid and 30 mg/100 kcal arachidonic acid.
• the first component of the study examined gut damage which was confirmed at time of necropsy by gross examination and histopathology. Gross examination and histopathology characterized changes in gut damage, maturity and integrity.
• the second component of the study investigated the mechanisms underlying changes in gut damage, maturity and integrity. The following outcome variables were measured: endotoxemia and PLA 2 .
• Plasma endotoxin was assessed using a spectrophotometric method provided in a Limulus Amebocyte Lysate (LAL) assay commercially available from Biowhittaker, Walkersville, MD.
• LAL Limulus Amebocyte Lysate
• Phospholipase A mRNA expression.
• PLA Limulus Amebocyte Lysate
• Animals developed symptoms of intestinal injury typically between 48 and 72 hours of life, and included abdominal distention, discoloration of the anterior abdominal wall, bloody stools, and respiratory distress.
• LCPUFA supplementation reduces gut injury in an established neonatal rat model of ischemic gut damage. Furthermore, the data demonstrate that the beneficial effect of LCPUFA supplementation includes reduced gut permeability.
• the reduced gut permeability was associated with a reduction in endotoxemia. Endotoxemia is a result of bacterial and/or endotoxin translocation across the gut into the systemic circulation. Concurrent lower expressions of intestinal PLA 2 mRNA and PAF receptor mRNA were indicative of a reduced endotoxin induced inflammatory response.

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• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Polymers & Plastics (AREA)
• Food Science & Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Nutrition Science (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Mycology (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Pediatric Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)

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Cited By (6)

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Citations (7)

• 1999
  • 1999-12-13 EA EA200100662A patent/EA200100662A1/ru unknown
  • 1999-12-13 CN CN99814534A patent/CN1330542A/zh active Pending
  • 1999-12-13 JP JP2000587763A patent/JP2002532420A/ja active Pending
  • 1999-12-13 WO PCT/US1999/029478 patent/WO2000035443A1/en not_active Application Discontinuation
  • 1999-12-13 KR KR1020017007472A patent/KR20020002361A/ko not_active Application Discontinuation
  • 1999-12-13 IL IL14332299A patent/IL143322A0/xx unknown
  • 1999-12-13 CA CA002351469A patent/CA2351469A1/en not_active Abandoned
  • 1999-12-13 HU HU0104760A patent/HUP0104760A2/hu unknown
  • 1999-12-13 EP EP99965234A patent/EP1140063A1/en not_active Withdrawn
  • 1999-12-13 BR BR9916156-7A patent/BR9916156A/pt not_active Application Discontinuation
  • 1999-12-13 AU AU31196/00A patent/AU3119600A/en not_active Abandoned
  • 1999-12-13 PL PL99348810A patent/PL348810A1/xx not_active Application Discontinuation
  • 1999-12-14 AR ARP990106370A patent/AR021669A1/es unknown
• 2001
  • 2001-06-14 NO NO20012947A patent/NO20012947D0/no not_active Application Discontinuation

Patent Citations (7)

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