CA2351469A1 - Method and composition for the maintenance and restitution of gut integrity - Google Patents
Method and composition for the maintenance and restitution of gut integrity Download PDFInfo
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- CA2351469A1 CA2351469A1 CA002351469A CA2351469A CA2351469A1 CA 2351469 A1 CA2351469 A1 CA 2351469A1 CA 002351469 A CA002351469 A CA 002351469A CA 2351469 A CA2351469 A CA 2351469A CA 2351469 A1 CA2351469 A1 CA 2351469A1
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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Abstract
A method, and formulation for use in the method, for maintaining and enhancing the restitution of gut integrity in an individual in need thereof comprising administering to the individual a formulation comprising an effective amount at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid.
Description
METHOD AND COMPOSITION FOR THE MAINTENANCE AND
FIELD OF THE INVENTION
The present invention is directed to emteral formulations that contain lang-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.
BACKGROUND OF THE INVENTION
Several disease states are characterized by an increase in gut permeability.
Examples of such disease states include colitis, Crohn's disease, irritable bowel syndrome, celiac disease, starvation, cystic fibrosis, necrotizing enterocolitis and gut damage resulting from chemotherapy and radiation treatment. Moreover, food allergies in the premature infant andlor an immature gut is associated with a higher permeability predisposing the infant to aberrant nutrient absorption and translocation of endotoxins and bacteria into the circulation.
Long chain PUFAs in enteral formulations or compositions are well known.
U.S. Patent No. 4,670,2$5 discloses a specific fat blend suitable for use in infant formulations. The fat blend contains at least onE: CZO or C22 n-6 fatty acid and one Czo or CZ~ n-3 fatty acid. The CZa or CZ~ n-6 fatty acid is present in a total amount of about 0.13 to 5.6% by weight of all fatty acids in the composition. The CZO or C~~ n-3 fatty acid is included in a total amount of about 0.013 to about 4.44% by weight of alI fatty acids in the composition. This patent disclose;> the use of egg lipids to supply the fatty acids.
U.S. Patent No. 4,91$,063 discloses formulations containing mixtures of phospholipids and neutral lipids for the prevention or treatment of ulcers and inf~Iammatory 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.
WO 00!35443 PCT/US99I294~8 PCT International Publication No. W096110922 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 B 1 discloses an all vegetable oil fat blend which utilizes randomized palm oil or randomized palm olefin oil as the sole palmitic acid oii source. It is disclosed that the ~~ompositions are particularly useful in infant formulas particularly for preterm or low birth weight infants.
SUMMARY OF THE INVENTION
The present invention is directed to methods for maintaining gut integrity arid 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 poly-unsaturated 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 wiith 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-:~ 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.
BRIEF DESCRIPTION OF THE DRAWINGS
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 PLAZ
mRNA expression levels.
Figure 3 shows the effect of the present formula on intestinal PAF-receptor levels in RNA.
DETAILED DESCRIPTION OF THE INVEN'CION
The polyunsaturated fatty acids useful in the present invention include fatty acids of twenty carbons or more having at leasht two carbon-carbon double bonds.
The number and position of double bonds in the fatty acids are designated by the nomenclature conventionally used. For example, 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 rc;ferred to as C,o:4 n-6.
Similarly, 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":6 n-3.
Preferably, 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 6I mg and preferably 10 to 51 mglkg body weight. Similarly, 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.
In order to achieve the effective amounts of n-6 and n-3 polyunsaturated fatty acid indicated above, the formulations used in the present method should comprise about 4 to about 50, and preferably about 8 to about 41 mg/I00 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 th.e n-3 polyunsaturated fatty acid. Again, 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. Disease states which compromise gut integrity in this manner include colitis, Crohn's disease, irritable bowel syndrome, celiac disease, starvation, cystic fibrosis, damage resulting from chemotherapy and radiation treatment and food allergies. In the premature infant, the immature gut is also associated with higher permeability which predisposes the infant to aberrant nutrition absorption and translocation of endotoxin and bacteria into the circulation. The present formulation is administered enterally to both adults and infants.
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.
The term 'infant formula' will be readily recognizable to those skilled in the art. When .diluted or reconstituted, if initially in concentration or powder form, to the ready to feed state, a typical infant formula will comprise about 60-110 grams of carbohydrates per liter, 10-35 grams of protein per liter, and 20-50 grams of Iipid per liter, as well as vitamins, minerals, fibers, emulsifiers, etc. To such an infant formula is added the appropriate amounts of n-6 and n-3 polyunsaturated fatty acid to maintain and enhance the restitution of gut integrity in the infant in need of treatment.
Examples of suitable, commercially available infarct formula to which the n-6 and n-3 polyunsaturated fatty acid may be added include S--26, S-26 LBW and SMA
available from Wyeth Nutritionals International.
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:
WO 00135443 PCTIUS99/294~8 Fat Blend 1l Fatty Fat, tv Ac:id C6:0 Caproic --C8:0 Caprylic; 9.1 C 10:0 Capric 6.1 C 12:0 Lauric 10.3 C 14:0 Myristic 4.6 1 () C 14:1 Myristolieic --C 16:0 Palmitic 13.5 CI6: 0 at sh-2 % of Palmitic C 16:1 w7 Palmitol.eic 0.1 C 18:0 Stearic 4.8 C 18: l w9 Oleic 32.3 C 18:2w6 Linoleic 15.9 C18:3w3 Linolenic 1.7 C20:0 Arachid:~ic 0.3 C20:2w6 --C20:3w6 --C20:4w6 Arachidonic 0.6 C22:0 Docosanoic 0.3 C22:6w3 Docosahenxaenoic 0.4 C24:0 Total 100 _6_ Fat Blend 2 Fatty Acid Fatty Aci~~ X70 C6:0 Caproic 0.35 C8:0 Caprylic 9.87 C 10:0 Cupric 4.63 C 12:0 Lauric 6.4 C 14:0 Myristic 2.46 C 14:1 Myristoleic 0.02 C 16:0 Palmitic 13.43 C16: 0 at sh-2 % of Palr~2itic 39.0 C 16:1 w7 Palmitole:ic 0.03 C 18:0 Stearic 2.61 C 18:1 w9 Oleic 39.39 C 18:2w6 Linoleic 13.94 C 18:3w3 Linolenic 1.29 C20:0 Arachidic 0.01 C20:2w6 0.01 C20:3w6 0.02 C20:4w6 Arachidonic 0.61 C22:0 Docosanoic 0.3 C22:6w3 Docosahenxaenoic 0.38 C24:0 0.02 Total 100 WO 00!35443 PCT/US99l29478 _7_ Specific examples of infant formula suitable for use in the present invention are set forth below:
Infant Formula A
Ingredients Water 84.30 Lactose 1.20 Nonfat Dry Milk :2.83 Whey Powder 2.83 Maltodextrin 4.45 Fat Blend .4.11 Vitamins i,).02 Minerals 0.25 Taurine 0.01 100.00 Infant Formula B
ingredients Water 5'7.77 Skim Milk (liquid) 2'9.49 Whey Protein Concentrate 2.?6 Lactose 1.16 Maltodextrin 4.35 Fat Blend 4.15 Vitamins 0.03 Minerals X0.28 Taurine X1.01 10x0.00 The present invention will now be illustrated with reference to the following specific example.
_g_ EXAMPLES
The method of the present invention was l:ested in a neonatal rat model of hypoxia induced gut injury. Reduced gut permeability is associated with reduced endotoxemia and a lowered intestinal phospholipase-2 (PLAz) gene expression.
Lower PLAZ expression levels is indicative of a down-regulation of the inflammatory cascade.
Animal Model. Rat pups were delivered via abdominal incision from time-dated pregnant Sprague-Dawley rats on the 21 st day of gestation. The newborn rats were fed via the orogastric route 0.1 ml of formula (S2b-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. In addition, 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 minuaes. Using this protocol, 70-80%
of animals develop abdominal necrosis by the 3rd to 4th day of life as described in Caplan, M.S.; Hedlund, E.; Adler, L.; and Hsueh, W., "Role of Asphyxia and Feeding in a Neonatal Rat Model of Necrotizin g Enterocolitis," Pedatr.
Pathol., 14:1017-1028 ( 1994).
Treatment Groups. There were 2 treatment groups: preterm formula (Formula A) and preterm formula with LCPUFA.s {Formula B). The LCPUFAs added to Formula B were arachidonic acid and docosahexanoic acid. The LCPUFAs were added in the following amounts: 20 mg/100kcal 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 grass examination and histopathology. Gross examination and histopatho:logy 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 PLA2.
Gut Damage. Following euthanasia, the intestines were evaluated by gross inspection and histologic evaluation for confirmation of gut damage and maturation.
Endotoxemia. Plasma endotoxin was assessed using a spectrophotometric method provided in a Limulus Amebocyte Lysate (LAL) assay commercially available from Biowhittaker, Walkersville, MD.
_y_ Phospholipase A, mRNA expression. To quantitate PLA.' mRNA expression, competitive PCR was performed using mRNA recovered from intestinal homogenate.
Serial dilutions of eRNA were added to intestinal. RNA and the PCR reaction was performed using standard conditions previously described. Products were run on an agarose gel and then quantified using phosphorimaging density.
Statistics. Differences between groups of ordinate data were compared using Chi-square analysis using Yates' correction. Differences between continuous l0 variables were compared using the Student-t test or analysis or variance where appropriate. P < 0.05 was considered significant.
Supplementation with LCPUFAs reduced the incidence of ischemic gut damage (ischemic gut damage: 17/24 control vs. 81'24 LCPUFA, p = 0.031 using 3x2 chi-square) compared to the formula without LCPUFAs in neonatal rats (see Table 1). Animals developed symptoms of intestinal injury typically between 48 and hours of life, and included abdominal distention, discoloration of the anterior abdominal wall, bloody stools, and respiratory distress.
Table 1 Effect of formula supplementation on reducing ischemic gut damage's Formula Ischemic Gut No Ischemic Gut LD. Dannage Damage *P = .031 As seen in Figure l, plasma endotoxin levels measured between 48-72 hours showed that LCPUFA supplemented rats had lower plasma endotoxemia (25 ~ 4 EU/mI) than the unsupplemented rats (276 ~ 39 EC.1/ml). Figure 2 demonstrates that Intestinal PLAZ mRNA expression was significantly lower among LCPUFA
supplemented rats {0.41 + 0.09 molecules/gm tissue:) as compared to unsupplemented rats (0.68 ~ 0.11 molecules/gm tissue}. Moreover, intestinal PAF receptor mRNA
expression was also lower among LCPUFA supplemented rats, 1.5 ~ 0.3 vs. 2.1 ~
0.2 (Figure 3).
The results demonstrate that LCPUFA supplementation reduces gut injury in an established neonatal rat model of ischemic gut damage. Furthermore, the data demonstrate that the -beneficial effect of LCPUF'A 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, mRNA and PAF receptor mRNA were indicative of a reduced endotoxin induced inflammatory response. .
The present invention maybe embodied iin other specific forms without departing from the spirit or essential attributes thereof and., accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.
FIELD OF THE INVENTION
The present invention is directed to emteral formulations that contain lang-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.
BACKGROUND OF THE INVENTION
Several disease states are characterized by an increase in gut permeability.
Examples of such disease states include colitis, Crohn's disease, irritable bowel syndrome, celiac disease, starvation, cystic fibrosis, necrotizing enterocolitis and gut damage resulting from chemotherapy and radiation treatment. Moreover, food allergies in the premature infant andlor an immature gut is associated with a higher permeability predisposing the infant to aberrant nutrient absorption and translocation of endotoxins and bacteria into the circulation.
Long chain PUFAs in enteral formulations or compositions are well known.
U.S. Patent No. 4,670,2$5 discloses a specific fat blend suitable for use in infant formulations. The fat blend contains at least onE: CZO or C22 n-6 fatty acid and one Czo or CZ~ n-3 fatty acid. The CZa or CZ~ n-6 fatty acid is present in a total amount of about 0.13 to 5.6% by weight of all fatty acids in the composition. The CZO or C~~ n-3 fatty acid is included in a total amount of about 0.013 to about 4.44% by weight of alI fatty acids in the composition. This patent disclose;> the use of egg lipids to supply the fatty acids.
U.S. Patent No. 4,91$,063 discloses formulations containing mixtures of phospholipids and neutral lipids for the prevention or treatment of ulcers and inf~Iammatory 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.
WO 00!35443 PCT/US99I294~8 PCT International Publication No. W096110922 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 B 1 discloses an all vegetable oil fat blend which utilizes randomized palm oil or randomized palm olefin oil as the sole palmitic acid oii source. It is disclosed that the ~~ompositions are particularly useful in infant formulas particularly for preterm or low birth weight infants.
SUMMARY OF THE INVENTION
The present invention is directed to methods for maintaining gut integrity arid 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 poly-unsaturated 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 wiith 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-:~ 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.
BRIEF DESCRIPTION OF THE DRAWINGS
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 PLAZ
mRNA expression levels.
Figure 3 shows the effect of the present formula on intestinal PAF-receptor levels in RNA.
DETAILED DESCRIPTION OF THE INVEN'CION
The polyunsaturated fatty acids useful in the present invention include fatty acids of twenty carbons or more having at leasht two carbon-carbon double bonds.
The number and position of double bonds in the fatty acids are designated by the nomenclature conventionally used. For example, 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 rc;ferred to as C,o:4 n-6.
Similarly, 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":6 n-3.
Preferably, 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 6I mg and preferably 10 to 51 mglkg body weight. Similarly, 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.
In order to achieve the effective amounts of n-6 and n-3 polyunsaturated fatty acid indicated above, the formulations used in the present method should comprise about 4 to about 50, and preferably about 8 to about 41 mg/I00 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 th.e n-3 polyunsaturated fatty acid. Again, 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. Disease states which compromise gut integrity in this manner include colitis, Crohn's disease, irritable bowel syndrome, celiac disease, starvation, cystic fibrosis, damage resulting from chemotherapy and radiation treatment and food allergies. In the premature infant, the immature gut is also associated with higher permeability which predisposes the infant to aberrant nutrition absorption and translocation of endotoxin and bacteria into the circulation. The present formulation is administered enterally to both adults and infants.
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.
The term 'infant formula' will be readily recognizable to those skilled in the art. When .diluted or reconstituted, if initially in concentration or powder form, to the ready to feed state, a typical infant formula will comprise about 60-110 grams of carbohydrates per liter, 10-35 grams of protein per liter, and 20-50 grams of Iipid per liter, as well as vitamins, minerals, fibers, emulsifiers, etc. To such an infant formula is added the appropriate amounts of n-6 and n-3 polyunsaturated fatty acid to maintain and enhance the restitution of gut integrity in the infant in need of treatment.
Examples of suitable, commercially available infarct formula to which the n-6 and n-3 polyunsaturated fatty acid may be added include S--26, S-26 LBW and SMA
available from Wyeth Nutritionals International.
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:
WO 00135443 PCTIUS99/294~8 Fat Blend 1l Fatty Fat, tv Ac:id C6:0 Caproic --C8:0 Caprylic; 9.1 C 10:0 Capric 6.1 C 12:0 Lauric 10.3 C 14:0 Myristic 4.6 1 () C 14:1 Myristolieic --C 16:0 Palmitic 13.5 CI6: 0 at sh-2 % of Palmitic C 16:1 w7 Palmitol.eic 0.1 C 18:0 Stearic 4.8 C 18: l w9 Oleic 32.3 C 18:2w6 Linoleic 15.9 C18:3w3 Linolenic 1.7 C20:0 Arachid:~ic 0.3 C20:2w6 --C20:3w6 --C20:4w6 Arachidonic 0.6 C22:0 Docosanoic 0.3 C22:6w3 Docosahenxaenoic 0.4 C24:0 Total 100 _6_ Fat Blend 2 Fatty Acid Fatty Aci~~ X70 C6:0 Caproic 0.35 C8:0 Caprylic 9.87 C 10:0 Cupric 4.63 C 12:0 Lauric 6.4 C 14:0 Myristic 2.46 C 14:1 Myristoleic 0.02 C 16:0 Palmitic 13.43 C16: 0 at sh-2 % of Palr~2itic 39.0 C 16:1 w7 Palmitole:ic 0.03 C 18:0 Stearic 2.61 C 18:1 w9 Oleic 39.39 C 18:2w6 Linoleic 13.94 C 18:3w3 Linolenic 1.29 C20:0 Arachidic 0.01 C20:2w6 0.01 C20:3w6 0.02 C20:4w6 Arachidonic 0.61 C22:0 Docosanoic 0.3 C22:6w3 Docosahenxaenoic 0.38 C24:0 0.02 Total 100 WO 00!35443 PCT/US99l29478 _7_ Specific examples of infant formula suitable for use in the present invention are set forth below:
Infant Formula A
Ingredients Water 84.30 Lactose 1.20 Nonfat Dry Milk :2.83 Whey Powder 2.83 Maltodextrin 4.45 Fat Blend .4.11 Vitamins i,).02 Minerals 0.25 Taurine 0.01 100.00 Infant Formula B
ingredients Water 5'7.77 Skim Milk (liquid) 2'9.49 Whey Protein Concentrate 2.?6 Lactose 1.16 Maltodextrin 4.35 Fat Blend 4.15 Vitamins 0.03 Minerals X0.28 Taurine X1.01 10x0.00 The present invention will now be illustrated with reference to the following specific example.
_g_ EXAMPLES
The method of the present invention was l:ested in a neonatal rat model of hypoxia induced gut injury. Reduced gut permeability is associated with reduced endotoxemia and a lowered intestinal phospholipase-2 (PLAz) gene expression.
Lower PLAZ expression levels is indicative of a down-regulation of the inflammatory cascade.
Animal Model. Rat pups were delivered via abdominal incision from time-dated pregnant Sprague-Dawley rats on the 21 st day of gestation. The newborn rats were fed via the orogastric route 0.1 ml of formula (S2b-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. In addition, 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 minuaes. Using this protocol, 70-80%
of animals develop abdominal necrosis by the 3rd to 4th day of life as described in Caplan, M.S.; Hedlund, E.; Adler, L.; and Hsueh, W., "Role of Asphyxia and Feeding in a Neonatal Rat Model of Necrotizin g Enterocolitis," Pedatr.
Pathol., 14:1017-1028 ( 1994).
Treatment Groups. There were 2 treatment groups: preterm formula (Formula A) and preterm formula with LCPUFA.s {Formula B). The LCPUFAs added to Formula B were arachidonic acid and docosahexanoic acid. The LCPUFAs were added in the following amounts: 20 mg/100kcal 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 grass examination and histopathology. Gross examination and histopatho:logy 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 PLA2.
Gut Damage. Following euthanasia, the intestines were evaluated by gross inspection and histologic evaluation for confirmation of gut damage and maturation.
Endotoxemia. Plasma endotoxin was assessed using a spectrophotometric method provided in a Limulus Amebocyte Lysate (LAL) assay commercially available from Biowhittaker, Walkersville, MD.
_y_ Phospholipase A, mRNA expression. To quantitate PLA.' mRNA expression, competitive PCR was performed using mRNA recovered from intestinal homogenate.
Serial dilutions of eRNA were added to intestinal. RNA and the PCR reaction was performed using standard conditions previously described. Products were run on an agarose gel and then quantified using phosphorimaging density.
Statistics. Differences between groups of ordinate data were compared using Chi-square analysis using Yates' correction. Differences between continuous l0 variables were compared using the Student-t test or analysis or variance where appropriate. P < 0.05 was considered significant.
Supplementation with LCPUFAs reduced the incidence of ischemic gut damage (ischemic gut damage: 17/24 control vs. 81'24 LCPUFA, p = 0.031 using 3x2 chi-square) compared to the formula without LCPUFAs in neonatal rats (see Table 1). Animals developed symptoms of intestinal injury typically between 48 and hours of life, and included abdominal distention, discoloration of the anterior abdominal wall, bloody stools, and respiratory distress.
Table 1 Effect of formula supplementation on reducing ischemic gut damage's Formula Ischemic Gut No Ischemic Gut LD. Dannage Damage *P = .031 As seen in Figure l, plasma endotoxin levels measured between 48-72 hours showed that LCPUFA supplemented rats had lower plasma endotoxemia (25 ~ 4 EU/mI) than the unsupplemented rats (276 ~ 39 EC.1/ml). Figure 2 demonstrates that Intestinal PLAZ mRNA expression was significantly lower among LCPUFA
supplemented rats {0.41 + 0.09 molecules/gm tissue:) as compared to unsupplemented rats (0.68 ~ 0.11 molecules/gm tissue}. Moreover, intestinal PAF receptor mRNA
expression was also lower among LCPUFA supplemented rats, 1.5 ~ 0.3 vs. 2.1 ~
0.2 (Figure 3).
The results demonstrate that LCPUFA supplementation reduces gut injury in an established neonatal rat model of ischemic gut damage. Furthermore, the data demonstrate that the -beneficial effect of LCPUF'A 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, mRNA and PAF receptor mRNA were indicative of a reduced endotoxin induced inflammatory response. .
The present invention maybe embodied iin other specific forms without departing from the spirit or essential attributes thereof and., accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.
Claims (21)
1. A method for maintaining and enhancing the restitution of gut integrity in an individual in need thereof comprising administering to the individual a formulation comprising an effective amount at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid.
2. A method according to claim 1, where said n-6 polyunsaturated fatty acid is arachidonic acid and said n-3 polyunsaturated fatty acid is docosahexanoic acid.
3. A method according to claim 1 or 2, where said formulation is an infant formula.
4. A method according to any of claims 1 to 3, wherein said formulation comprises 4 to 50 mg/100 ml of said polyunsaturated n-6 fatty acid and 4 to 50 mg/100 ml of said polyunsaturated n-3 fatty acid.
5. A method according to claim 4, wherein said formulation comprises 8 to 41 mg/100 ml of said n-6 polyunsaturated fatty acid and 4 to 41 mg/100 ml of said n-3 polyunsaturated fatty acid.
6. A method according to any preceding claims, wherein said formulation comprises said n-6 polyunsaturated fatty acid and. said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2.5:1.
7. A method according to claim 6, wherein said formulation comprises said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2:1.
8. A formulation comprising an effective amount at least one n-6 polyunsaturated fatty acid in combination with at least one n-3 polyunsaturated fatty acid for use in maintaining and enhancing the restitution of gut integrity in an individual in need thereof.
9. A formulation according to claim 8, where said n-6 polyunsaturated fatty acid is arachidonic acid and said n-3 polyunsaturated fatty acid is docosahexanoic acid.
10. A formulation according to claim 8 or 9 where said formulation is an infant formula.
11. A formulation according to claim any of claims 8 to 10 wherein said formulation comprises 4 to 50 mg/100 ml of said polyunsaturated n-6 fatty acid and 4 to 50 mg/100 ml of said polyunsaturated n-3 fatty acid.
12. A formulation according to claim 11 wherein said formulation comprises 8 to 41 mg/100 ml of said n-6 polyunsaturated fatty acid and 4 to 41 mg/100 ml of said n-3 polyunsaturated fatty acid.
13. A formulation according to any of claims 8 to 12, wherein said formulation comprises said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2.5:1.
14. A formulation according to claim 13, wherein said formulation comprises said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2:1.
15. 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 maintaining and enhancing the restitution of gut integrity in an individual in need thereof.
16. Use according to claim 15, where said n-6 polyunsaturated fatty acid is arachidonic acid and said n-3 polyunsaturated fatty acid is docosahexanoic acid.
17. Use according to claim 15 or 16 where said formulation is an infant formula.
18. Use according to any of claims 15 to 17 wherein said formulation comprises to 50 mg/100 ml of said polyunsaturated n-6 fatty acid and 4 to 50 mg/100 ml of said polyunsaturated n-3 fatty acid.
19. Use according to claim 18, wherein said formulation comprises 8 to 41 mg/100 ml of said n-6 polyunsaturated fatty acid and 4 to 41 mg/100 ml of said n-3 polyunsaturated fatty acid.
20. Use according to claim 19, wherein said formulation comprises said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2.5:1.
21. Use according to claim 20, wherein said formulation comprises said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid in a ratio of 1:1 to 2:1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11237498P | 1998-12-15 | 1998-12-15 | |
| US60/112,374 | 1998-12-15 | ||
| PCT/US1999/029478 WO2000035443A1 (en) | 1998-12-15 | 1999-12-13 | Method and composition for the maintenance and restitution of gut integrity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2351469A1 true CA2351469A1 (en) | 2000-06-22 |
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ID=22343574
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|---|---|---|---|
| CA002351469A Abandoned CA2351469A1 (en) | 1998-12-15 | 1999-12-13 | Method and composition for the maintenance and restitution of gut integrity |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1140063A1 (en) |
| JP (1) | JP2002532420A (en) |
| KR (1) | KR20020002361A (en) |
| CN (1) | CN1330542A (en) |
| AR (1) | AR021669A1 (en) |
| AU (1) | AU3119600A (en) |
| BR (1) | BR9916156A (en) |
| CA (1) | CA2351469A1 (en) |
| EA (1) | EA200100662A1 (en) |
| HU (1) | HUP0104760A2 (en) |
| IL (1) | IL143322A0 (en) |
| NO (1) | NO20012947L (en) |
| PL (1) | PL348810A1 (en) |
| WO (1) | WO2000035443A1 (en) |
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| ES2416287T3 (en) | 2003-06-23 | 2013-07-31 | Nestec S.A. | Use of a nutritional formula for the optimal function of the intestinal barrier |
| US7862808B2 (en) | 2004-07-01 | 2011-01-04 | Mead Johnson Nutrition Company | Method for preventing or treating respiratory infections and acute otitis media in infants using Lactobacillus rhamnosus LGG and Bifidobacterium lactis Bb-12 |
| US7303745B2 (en) | 2005-04-15 | 2007-12-04 | Bristol-Myers Squibb Company | Method for preventing or treating the development of respiratory allergies |
| US20060233762A1 (en) * | 2005-04-15 | 2006-10-19 | Mcmahon Robert J | Method for treating or preventing systemic inflammation in formula-fed infants |
| JP2007063219A (en) * | 2005-09-01 | 2007-03-15 | Juntendo | Agent for preventing neonatal necrotizing enterocolitis |
| SG191784A1 (en) * | 2010-12-29 | 2013-08-30 | Abbott Lab | Nutritional products including a novel fat system including monoglycerides |
| MX2017003660A (en) * | 2014-09-30 | 2017-06-26 | Nestec Sa | Nutritional composition for use in promoting gut and/or liver maturation and/or repair. |
| WO2023245470A1 (en) * | 2022-06-22 | 2023-12-28 | 南方医科大学珠江医院 | Use of mdp analog in preparing medicament for treating inflammatory bowel disease |
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|---|---|---|---|---|
| US4670285A (en) * | 1982-08-06 | 1987-06-02 | The University Of Toronto Innovations Foundation | Infant formula |
| DE3603000A1 (en) * | 1986-01-31 | 1987-08-06 | Milupa Ag | NEW FATTY MIXTURE OF POLYENIC ACID AND THEIR USE IN THE PRODUCTION OF INFANT FOODS |
| GB9224809D0 (en) * | 1992-11-26 | 1993-01-13 | Scotia Holdings Plc | Schizophrenia |
| US5444054A (en) * | 1994-04-01 | 1995-08-22 | Abbott Labatories | Method of treating ulcerative colitis |
| DE4417851C1 (en) * | 1994-05-20 | 1995-10-05 | Horst Heirler | Dietary food with medium-chain fatty acids and its use |
| EP0711503A3 (en) * | 1994-11-14 | 1997-11-26 | Scotia Holdings Plc | Milk fortified with GLA and/or DGLA |
| US5993221A (en) * | 1997-05-01 | 1999-11-30 | Beth Israel Deaconess Medical Center, Inc. | Dietary formulation comprising arachidonic acid and methods of use |
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1999
- 1999-12-13 EA EA200100662A patent/EA200100662A1/en unknown
- 1999-12-13 HU HU0104760A patent/HUP0104760A2/en unknown
- 1999-12-13 JP JP2000587763A patent/JP2002532420A/en active Pending
- 1999-12-13 KR KR1020017007472A patent/KR20020002361A/en not_active Application Discontinuation
- 1999-12-13 CA CA002351469A patent/CA2351469A1/en not_active Abandoned
- 1999-12-13 BR BR9916156-7A patent/BR9916156A/en not_active Application Discontinuation
- 1999-12-13 PL PL99348810A patent/PL348810A1/en not_active Application Discontinuation
- 1999-12-13 AU AU31196/00A patent/AU3119600A/en not_active Abandoned
- 1999-12-13 EP EP99965234A patent/EP1140063A1/en not_active Withdrawn
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- 1999-12-13 CN CN99814534A patent/CN1330542A/en active Pending
- 1999-12-13 WO PCT/US1999/029478 patent/WO2000035443A1/en not_active Application Discontinuation
- 1999-12-14 AR ARP990106370A patent/AR021669A1/en unknown
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Also Published As
| Publication number | Publication date |
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| AU3119600A (en) | 2000-07-03 |
| WO2000035443A1 (en) | 2000-06-22 |
| NO20012947D0 (en) | 2001-06-14 |
| JP2002532420A (en) | 2002-10-02 |
| AR021669A1 (en) | 2002-07-31 |
| EP1140063A1 (en) | 2001-10-10 |
| BR9916156A (en) | 2001-09-04 |
| EA200100662A1 (en) | 2001-12-24 |
| NO20012947L (en) | 2001-06-14 |
| PL348810A1 (en) | 2002-06-17 |
| IL143322A0 (en) | 2002-04-21 |
| WO2000035443A9 (en) | 2000-12-07 |
| HUP0104760A2 (en) | 2002-04-29 |
| KR20020002361A (en) | 2002-01-09 |
| CN1330542A (en) | 2002-01-09 |
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