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    • 专利摘要:
    The present invention relates to the use of nutritional compositions enriched in glutamine to improve structural and functional brain development in preterm and/or low birth weight infants.
    公开号:AU2013208359A1
    申请号:U2013208359
    申请日:2013-01-09
    公开日:2014-07-10
    发明作者:Gunther Boehm；Roelof Matthijs van Elburg
    申请人:Nutricia NV；
    IPC主号:A23L1-305
    专利说明:
    WO 2013/105851 PCT/NL2013/050007 1 GLUTAMINE ENRICHED NUTRITIONAL COMPOSITION FOR PRETERM INFANTS FIELD OF THE INVENTION 5 The present invention relates to nutritional compositions for preterm and/or low birth weight infants and the long term health effects of such compositions. BACKGROUND OF THE INVENTION With advances in neonatal intensive care, the survival of very preterm (born <32 weeks of 10 gestation) and very low birth weight (VLBW; weighing <1500 grams) children has improved considerably. However, a variety of risk factors associated with preterm and low birth weight birth, including neonatal infections and inflammatory responses, adversely affect normal brain maturation processes in these children. As a consequence, widespread differences in brain development compared to term peers are found, as indicated by an 15 overall reduction in grey and white matter volumes as measured by magnetic resonance imaging (MRI) as well as reduced white matter integrity as measured by diffusion tensor imaging (DTI). Unfortunately, these unfavourable differences in brain development appear to pertain into childhood and adolescence, and increase the risks for poor motor, cognitive, and behavioural development in very preterm/VLBW children. 20 Many infant formulae for term infants are available on the market. However, these are not optimal for administration to preterm infants or infants with a low birth weight, since the complete nutritional needs of a rapidly growing preterm infant are not met. Likewise, the composition of human milk does not fully meet the nutritional requirements. The major goal 25 of enteral nutrient supply to these infants is to achieve growth similar to fetal growth coupled with satisfactory functional development. The preferred food for infants with a low birth weight is therefore fortified human milk, or, alternatively, formula specially designed for these infants. Human milk fortifiers (HMF) and preterm infant formulae are commercially available. Typically, HMIF comprises besides protein, also carbohydrates or 30 fat, minerals and vitamins. Typically, preterm infant formulae have an increased protein concentration. Enteral feeding of very low birth weight (VLBW) infants is a challenge, WO 2013/105851 PCT/NL2013/050007 2 since metabolic demands are high and administration of enteral nutrition is limited by immaturity of the gastrointestinal tract. The amino acid glutamine has been used in nutritional compositions for preterm infants. 5 Van den Berg et al, 2005, Am J Clin Nutr 81:1397-1404 disclose that supplementation with glutamine lowers infectious morbidity in VLBL infants. Van den Berg et al, 2007, Arch. Pediatrics & Adolescent Medicine, 161:1095-1101 disclose that supplementation with glutamine decreases risk for atopic dermatitis in the first year of life and at the age of 6. Van Zwol et al, 2008, Acta Paediatrica, 97:562-567 report that there is no effect of glutamine 10 supplementation in VLBW infants on neurodevelopment outcome at age of 2 years. WO 2011/047107 discloses the use of an arginine-glutamine dipeptide to support retinal, intestinal and/or nervous system development in a neonate. Effects on structural brain development and long term functional brain development have not been reported so far. 15 SUMMARY OF THE INVENTION The inventors found that glutamine enriched feeding in the first month after birth in very preterm and/or VLBW infants has a long term effect on measures of brain development. In total 52 very preterm and/or VLBW children, who originally took part in a randomized 20 controlled trial on enteral glutamine supplementation between day 3 and 30 of life, participated in this follow up study at school age, with a mean age of 8.6 years (SD = 0.3 years). Measures of brain development included volumetric outcomes of various brain structures as well as fractional anisotropy (FA) values of major white matter tracts, using Magnetic Resonance Imaging (MRI) including Diffusion Tensor Imaging (DTI) techniques, 25 respectively. In term infants followed up at school age an increased cortical and subcortical volume was observed compared to the preterm born group. Advantageously an increased cortical brain volume and subcortical brain volume was also observed in children who were born preterm 30 and were supplemented in the first month after birth with L-glutamine when compared to the control group of preterm infants not having received L-glutamine. In particular a WO 2013/105851 PCT/NL2013/050007 3 significant increased white matter volume, brain stem volume, and hippocampus volume was observed DETAILED DESCRIPTION OF THE INVENTION 5 The present invention thus concerns a method for - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or 10 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth in a low birth weight and/or preterm infant, comprising administering a glutamine enriched nutritional composition to said low birth weight and/or preterm infant. 15 In one embodiment, the present invention is considered to be a non-medical method for - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or 20 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth. Preferably the glutamine enriched nutritional composition is administered during the first six, preferably the first four, more preferably the first two and most preferably at least the 25 first month after birth of the low birth weight and/or preterm infant. Preferably the increase in volume and/or mass and the improvement in growth of volume and/or mass is established in the infant at the age from 4 to 12 years. 30 The invention can also be worded as a nutritional composition comprising glutamine for use in increasing brain volume and/or mass in a low birth weight and/or preterm infant.
    WO 2013/105851 PCT/NL2013/050007 4 In one embodiment, increasing brain volume and/or mass preferably is increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass. 5 The invention also concerns a nutritional composition comprising glutamine for use in improving growth of brain volume and/or mass, in a low birth weight and/or preterm infant. In one embodiment, improving growth of brain volume and/or mass preferably is improving 10 growth of white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass. The invention also concerns a nutritional composition comprising glutamine for use in increasing white matter volume and/or mass, brain stem volume and/or mass, and/or 15 hippocampus volume and/or mass, in a low birth weight and/or preterm infant. The invention also concerns a nutritional composition comprising glutamine for use in improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth, in a low birth weight and/or 20 preterm infant. Preferably the nutritional composition comprising glutamine is for use in providing nutrition to a low birth weight and/or preterm infant. 25 More in particular the invention concerns a nutritional composition comprising glutamine for use in providing nutrition to a low birth weight and/or preterm infant for use in - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or 30 hippocampus volume and/or mass and/or WO 2013/105851 PCT/NL2013/050007 5 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth. The invention can also be worded as the use of a composition comprising glutamine, for the 5 manufacture of a glutamine enriched nutritional composition for use in - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or 10 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth in a low birth weight and/or preterm infant. The invention can also be worded as the use of a composition comprising glutamine, for the 15 manufacture of a glutamine enriched nutritional composition for use in providing nutrition to a low birth weight and/or preterm infant for use in - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or 2o hippocampus volume and/or mass and/or - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth. The invention can also be worded as the use of glutamine, for the manufacture of a 25 glutamine enriched nutritional composition for use in - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or 30 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth WO 2013/105851 PCT/NL2013/050007 6 in a low birth weight and/or preterm infant. The invention can also be worded as the use of glutamine, for the manufacture of a glutamine enriched nutritional composition for use in providing nutrition to a low birth 5 weight and/or preterm infant for use in - increasing brain volume and/or brain mass - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or 10 - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth. The invention can also be worded as glutamine for use - in increasing brain volume and/or mass in a low birth weight and/or preterm infant. 15 - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth 20 in a low birth weight and/or preterm infant. The invention can also be worded as glutamine for use in providing nutrition to a low birth weight and/or preterm infant for use in - in increasing brain volume and/or mass in a low birth weight and/or preterm infant. 25 - improving growth of brain volume and/or mass - increasing white matter volume and/or mass, brain stem volume and/or mass, and/or hippocampus volume and/or mass and/or - improving white matter volume and/or mass growth, brain stem volume and/or mass growth, and/or hippocampus volume and/or mass growth. 30 WO 2013/105851 PCT/NL2013/050007 7 According to the invention, increasing volume and/or mass and/or improving growth of volume and/or mass in a low birth weight and/or preterm infant is with respect to volume and/or mass in low birth weight and/or preterm infants not having been administered the glutamine enriched nutritional composition. 5 Preterm and LBW infants The present invention relates to a method for feeding an infant selected from the group consisting of low birth weight infants (LBW infants), very low birth weight infant (VLBW infants), extremely low birth weight infants (ELBW), preterm (=premature) infants and very 10 premature infants. LBW infants have a weight of less than 2500 grams at birth. VLBW infants have a weight below 1500 grams at birth. ELBW infants have a birth weight below 1000 grams at birth. Preterm infants are born before the end of the 37th week of pregnancy. Very preterm infants are born before the end of the 32th week of pregnancy. Preferably the infants are selected from the group of ELBW, VLBW, and very preterm infants. 15 Glutamine The nutritional composition of the present invention comprises glutamine. Throughout this description this is also referred to as nutritional composition comprising glutamine or glutamine enriched nutritional composition. Glutamine in the present invention refers to L 20 glutamine. Glutamine is one of the most abundant amino acids in plasma and human milk and is considered conditionally essential in preterm infants. Glutamine is utilized as a source of energy and for nucleotide synthesis in all rapidly dividing cells, such as the intestinal lining and certain immune cells. In the brain, glutamine is a substrate for neurotransmitters and an important source of energy for the nervous system. LBW or preterm, in particular 25 VLBW and/or very preterm infants, may be especially susceptible to glutamine depletion as nutritional supply of glutamine is limited in the first weeks after birth. Furthermore the endogenous capacity to synthesize glutamine from glutamate is not fully developed in these infants. 30 Glutamine is preferably present in an easily absorbable form. Because of the immaturity of the intestinal tract of the LBW and/or preterm infant, glutamine present in intact protein is WO 2013/105851 PCT/NL2013/050007 8 less easily absorbed. Therefore the glutamine is preferably present in the form of free amino acids and/or di- and/or tripeptides, most preferably glutamine dipeptide and/or free glutamine. Free glutamine and glutamine dipeptide are commercially available, for example at Ajinomoto, USA. In one embodiment glutamine dipeptide is in the form of a dipeptide of 5 2 glutamine residues. In one embodiment, glutamine dipeptide is in the form of a dipeptide of one glutamine and one amino acid other than glutamine. For example glutamine dipeptide can also be in the form of alanine-glutamine dipeptide. The term free glutamine in the context of this invnetion means in the form of a single amino acid. This includes glutamine as a single amino acid in the form of a salt. 10 The nutritional composition of the present invention comprises glutamine levels higher then normally present in human milk protein or standard preterm formula based on cow's milk derived protein. Preferably the nutritional composition of the present invention comprises at least 12 wt.%, more preferably at least 15 wt.%, more preferably at least 20 wt.%, even 15 more preferably at least 30 wt.% glutamine based on total protein. Preferably the nutritional composition of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine based on dry weight of the nutritional composition. Preferably the nutritional composition of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine based 20 on 100 kcal. Preferably the nutritional composition of the present invention comprises at least 12 wt.%, more preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein. Preferably the nutritional composition of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 25 wt.% glutamine in the form of free amino acid and/or dipeptide based on dry weight of the nutritional composition. Preferably the nutritional composition of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine in the form of free amino acid and/or dipeptide based on 100 kcal.
    WO 2013/105851 PCT/NL2013/050007 9 The daily dose of glutamine, preferably free glutamine, based on kg body weight, is preferably of 0.01 to 0.5 g, more preferably 0.03 to 0.4 g, even more preferably 0.07 to 0.35 g. 5 Nutritional composition In one embodiment the glutamine enriched composition of the present invention is a nutritional composition. In one embodiment, the present invention relates to nutritional compositions for use in feeding LBW and/or preterm infants, more preferably VLBW and/or very preterm infants. 10 In one embodiment the glutamine enriched nutritional composition of the present invention is a preterm formula. The preterm formula comprises all macro- and micronutrients needed for preterm infants so as to achieve a growth similar to fetal growth coupled with satisfactory functional development. 15 In one embodiment, the invention concerns a nutritional composition comprising between 1.5 wt.% and 20 wt.% glutamine based on dry weight of the nutritional composition, and comprising protein in such an amount that glutamine is present between 12 wt.% and 80 wt% based on total protein. Preferably the nutritional composition is a preterm formula. 20 Preferably the glutamine is in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide. In a preferred embodiment the preterm formula comprises from 5 to 25 wt.% protein, preferably 9 to 20 wt.%, more preferably 13 to 18 wt.% protein based on the dry weight of 25 the preterm formula. In a preferred embodiment the preterm formula comprises from 1.8 to 3.0 g protein, preferably, preferably 2.0 to 3.0 g, preferably 2.5 g to 2.6 g protein, per 100 ml. In a preferred embodiment the preterm formula comprises from 6 to 30 % protein, more 30 preferably 10 to 20, even more preferably 12 to 15 % protein, based on total calories. The wording "% protein based on total calories" refers to the energy of 1 g protein being 4.0 WO 2013/105851 PCT/NL2013/050007 10 kcal. For determining the amount of protein, the sum of proteins, peptides and free amino acids, including the glutamine, should be taken into account. Preferably, the protein content is determined according to the Kjeldahl method using a conversion factor of 6.25 and preferably using a conversion factor of 6.38 in case of casein dominant formula. 5 Whey protein is highly suitable as a protein source for preterm infants with a low body weight. However, since sweet whey protein generally has a high threonine content, which can result in hyperthreoninemia, preferably the present preterm formula, comprises acid whey protein or sweet whey protein from which at least part of the glycomacropeptide 10 (GMP) is removed. The present preterm formula, preferably contains from 4.7 to 7.5 g threonine per 100 g amino acids, preferably from 3.9 to 4.6 g threonine per 100 g amino acids. Preferably, the present preterm formula, contains non-hydrolysed protein, in order to decrease the osmolarity of the reconstituted preterm formula, which is beneficial in LBW and/or preterm infants, especially in VLBW and ELBW and/or very preterm infants. 15 Advantageously, the protein of the present preterm formula is hydrolysed in order to increase digestibility and gastro-intestinal tolerance. This is particularly preferred in LBW and/or preterm infants and in particular in VLBW and ELBW and/or very preterm infants since they have an immature intestinal tract which impaired digestion and absorption capacity. Advantageously and preferably, the protein is present in the preterm formula in 20 partially hydrolyzed form, thereby enabling a better solubility and digestion than intact protein, without increasing the osmolarity too much, as is the case with extensively hydrolysed protein or free amino acids. Partially hydrolyzed protein in this invention refers to protein with a degree of hydrolysis from 3 to 20 %. In a preferred embodiment of the invention the preterm formula comprises a protein with a degree of hydrolysis from 3 to 20 25 %, preferably 5 to 18 %, most preferably 5 to 15 %. In a preferred embodiment of the invention the preterm formula comprises casein and/or whey protein. In a preferred embodiment of the invention the preterm formula comprises casein. In a preferred embodiment of the invention the preterm formula comprises whey 30 protein. Preferably, the preterm formula comprises whey protein and casein derived from WO 2013/105851 PCT/NL2013/050007 11 non-human milk, preferably cow's milk. Preferably, the weight ratio (based on dry weight) of casein to whey protein is from 80/20 to 20/80, more preferably from 40/60 to 50/50. Preferably the preterm formula of the present invention comprises at least 12 wt.%, more 5 preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine based on total protein. Preferably the preterm formula of the present invention comprises no more than 80 wt.%, more preferably no more than 50 wt.% glutamine based on total protein. Preferably the preterm formula of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 10 wt.% glutamine based on dry weight of the preterm formula. Preferably the preterm formula of the present invention comprises no more than 20 wt.%, more preferably no more than 10 wt.% glutamine based on dry weight of the preterm formula. Preferably the nutritional composition of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine based on 100 kcal of the preterm formula. 15 Preferably the preterm formula of the present invention comprises no more than 5 g, even more preferably no more than 2 g glutamine based on 100 kcal of the preterm formula. Preferably the preterm formula of the present invention comprises at least 12 wt.%, more preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 20 30 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein. Preferably the preterm formula of the present invention comprises no more than 80 wt.%, more preferably no more than 50 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein. Preferably the preterm formula of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 25 wt.% glutamine in the form of free amino acid and/or dipeptide based on dry weight of the preterm formula. Preferably the preterm formula of the present invention comprises no more than 20 wt.%, more preferably no more than 10 wt% glutamine in the form of free amino acid and/or dipeptide based on dry weight of the preterm formula. Preferably the nutritional composition of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, 30 even more preferably at least 1 g glutamine in the form of free amino acid and/or dipeptide based on 100 kcal of the preterm formula. Preferably the preterm formula of the present WO 2013/105851 PCT/NL2013/050007 12 invention comprises no more than 5 g, even more preferably no more than 2 g glutamine in the form of free amino acid and/or dipeptide based on 100 kcal of the preterm formula. The preterm formula of the present invention in ready to drink form has in a preferred 5 embodiment about 70 to 90 kcal, preferably 75 to 85 kcal per 100 ml. Preferably the preterm formula has an osmolarity below 450 mOsmol/l, more preferably below 400, even more preferably below 350. Particularly in preterm infants, a too high osmloartiy is a disadvantage. 10 Preferably, the preterm formula comprises about 3.5 to 5.5 g, preferably 3.9 to 5.0 g, fat per 100 ml. Preferably the preterm formula comprises about 20 to 50 wt.%, preferably 26 to 35 wt.% fat based on dry weight of the preterm formula. Preferably the preterm formula comprises about 3.5 to 7.0 g, more preferably 5.0 to 6.5 g, more preferably 5.3 to 5.8 g fat, 15 based on 100 kcal of the preterm formula. Fat is preferably vegetable fat. Preferably the fat component comprises long chain poly-unsaturated fatty acids such as docosahexaenoic acid and arachidonic acid. These fatty acids are beneficial for brain and visual development in preterm and/or LBW infants. Preferably the fat component comprises medium chain fatty acids, preferably at least 10 wt/o and at most 40 wt/o based on total fatty acids. Medium 20 chain fatty acids are more easily absorbed by preterm and/or LBW infants. Preferably, the preterm formula comprises 6 to 10 g, preferably 7 to 8 g, digestible carbohydrates per 100 ml. Preferably the preterm formula comprises 40 to 80 wt.% preferably 40 to 50 wt.% digestible carbohydrates based on dry weight of the preterm 25 formula. Preferably the preterm formula comprises about 5 to 20 g, more preferably 6 to 15 g, more preferably 7 to 10 g digestible carbohydrates, based on 100 kcal of the preterm formula. Suitable digestible carbohydrates are lactose and maltodextin. Preferably, the preterm formula according to the present invention comprises at least one 30 non-digestible oligosaccharide. Advantageously and most preferred, the non-digestible oligosaccharide is water-soluble (according to the method disclosed in L. Prosky et al, J.
    WO 2013/105851 PCT/NL2013/050007 13 Assoc. Anal. Chem 71: 1017-1023, 1988). Non-digestible oligosaccharides, also called prebiotics, are not digested in the intestine by the action of digestive enzymes present in the human upper digestive tract (small intestine and stomach) but instead are fermented by the human intestinal microbiota. For example, glucose, fructose, galactose, sucrose, lactose, 5 maltose and the maltodextrins are considered digestible. Non-digestible oligosaccharides advantageously further improve the effect of the present glutamine on structural brain volume or growth. Non-digestible oligosaccharides stimulate a healthy gut environment, thereby aiding the uptake of glutamine. 10 Preferably the non-digestible oligosaccharide has a degree of polymerisation (DP) of 2 to 200. The average DP of the non-digestible oligosaccharide is preferably below 200, more preferably below 100, even more preferably below 60, most preferably below 40. The non digestible oligosaccharide is preferably selected from the group consisting of fructo oligosaccharide, such as inulin, non-digestible dextrin, galacto-oligosaccharide, such as 15 transgalacto-oligosaccharide, xylo-oligosaccharide, arabino-oligosaccharide, arabinogalacto-oligosaccharide, gluco-oligosaccharide, such as gentio-oligosaccharide and cyclodextrin, glucomanno-oligosaccharide, galactomanno-oligosaccharide, mannan oligosaccharide, chito-oligosaccharide, sialyloligosaccharide, such as 3-SL, 6-SL, LSTa,b,c, DSLNT, S-LNH, DS-LNH, and fuco-oligosaccharide, such as (un)sulphated fucoidan OS, 20 2-FL, 3-FL, LNFP I, II, III, V, LNnFPI, LNDH, and mixtures thereof, more preferably fructo-oligosaccharide, such as inulin, galacto-oligosaccharide, such as transgalacto oligosaccharide, which is -linked, and fuco-oligosaccharide and mixtures thereof, even more preferably transgalacto-oligosaccharide. When the non-digestible oligosaccharide is a mixture, the averages of the respective parameters are used for defining the present 25 invention. The present invention preferably provides a composition with two different non-digestible oligosaccharides, with a different type of glycosidic linkage, a different degree of polymerisation and/or a different monosaccharide composition. Here below the two 30 different non-digestible oligosaccharides are also referred to as non-digestible oligosaccharide A and B.
    WO 2013/105851 PCT/NL2013/050007 14 Preferably, at least 60%, more preferably at least 75% even more preferably 90%, most preferably 98% of the total monosaccharide units of the non-digestible oligosaccharide, are monosaccharides selected from the group consisting of galactose (gal), fructose (fru) and 5 glucose (glu) monosaccharides. Preferably the non-digestible oligosaccharide is an oligosaccharide selected from the group consisting of 0-galacto-oligosaccharide, a-galacto-oligosaccharide, and galactan. According to a more preferred embodiment non-digestible oligosaccharide A is 0-galacto 10 oligosaccharide. p-galacto-oligosaccharide is also sometimes referred to as transgalacto oligosaccharide. Preferably non-digestible oligosaccharide A comprises galacto oligosaccharides with p(1,4), p(1,3) and/or p(1,6) glycosidic bonds and a terminal glucose. Transgalacto-oligosaccharide is for example available under the trade name Vivinal@GOS (Borculo Domo Ingredients, Zwolle, Netherlands), Bi2muno (Clasado), Cup-oligo (Nissin 15 Sugar) and Oligomate55 (Yakult). Preferably non-digestible oligosaccharide is a fructo-oligosaccharide. A fructo oligosaccharide may in other context have names like fructopolysaccharides, oligofructose, polyfructose, polyfructan, inulin, levan and fructan and may refer to oligosaccharides 20 comprising -linked fructose units, which are preferably linked by p(2,1) and/or p(2,6) glycosidic linkages, and a preferable DP between 2 and 200. Preferably, the fructo oligosaccharide contains a terminal p(2,1) glycosidic linked glucose. Preferably, the fructo oligosaccharide contains at least 7 p-linked fructose units. In a further preferred embodiment inulin is used as non-digestible oligosaccharide B. Inulin is a type of fructo-oligosaccharide 25 wherein at least 75% of the glycosidic linkages are p(2,1) linkages. Typically, inulin has an average chain length between 8 and 60 monosaccharide units. A suitable fructo oligosaccharide for use in the compositions of the present invention is commercially available under the trade name Raftiline@HP (Orafti). Other suitable sources are raftilose (Orafti), fibrulose and fibruline (Cosucra) and Frutafit and frutalose (Sensus). 30 WO 2013/105851 PCT/NL2013/050007 15 Most preferred is a mixture of transgalacto-oligosaccharide with an average DP below 10, preferably below 6 and a fructo-oligosaccharide with an average DP above 7, preferably above 11, even more preferably above 20. 5 If the present preterm formula comprises galacto- and fructo-oligosaccharides the weight ratio is preferably from 1/99 to 99/1, more preferably from 1/19 to 19/1, even more preferably from I to 19/1. Preferably, the present preterm formula comprises the non-digestible oligosaccharides 10 transgalacto-oligosaccharide and fructo-oligosaccharide. Preferably, the present invention relates to a preterm formula, wherein the non-digestible oligosaccharide is selected from the group consisting of fructo-oligosaccharide and galacto oligosaccharide. 15 The present nutritional composition preferably comprises 0.05 to 20 wt.% total non digestible oligosaccharide, more preferably 0.5 to 15 wt.%, even more preferably 1 to 10 wt.%, most preferably 2.0 to 10 wt.%, based on dry weight of the present composition. Based on 100 ml the present nutritional composition preferably comprises 0.01 to 2.5 wt.
    0 % total non-digestible oligosaccharide, more preferably 0.05 to 1.5 wt.%, even more preferably 20 0.25 to 1.5 wt.%, based on 100 ml of the present composition. In one embodiment the present invention concerns a glutamine-based supplement, suitable to fortify human milk, to fortify human milk fortified with a standard human milk fortifier or to fortify a standard preterm formula. In the context of this invention, a supplement does 25 not comprise all macro- and micronutrients needed for preterm infants so as to achieve a growth similar to fetal growth coupled with satisfactory functional development. Standard preterm formula, and human milk fortified with standard human milk fortifier comprises all macro- and micronutrients needed for preterm infants so as to achieve a 30 growth similar to fetal growth coupled with satisfactory functional development. In standard preterm formula, standard human milk fortifier, human milk and human milk fortified with WO 2013/105851 PCT/NL2013/050007 16 standard human milk fortifier the amount of glutamine, more preferably free glutamine or glutamine in the form of a dipeptide, is below 12 wt.% based on total protein, also the amount of glutamine is below 1.5 wt.% based on dry weight, and also the amount of glutamine is below 0.3 g per 100 kcal. The composition of a standard preterm formula is 5 similar as described above, except for the glutamine amounts, which are lower. The glutamine based supplement according to the present invention is preferably packed in unit dose form. Preferably, the glutamine based supplement is present in a container. The container may contain more than one unit dose, preferably the container contains one single 10 unit dose. Preferably the container is a sachet. Also preferably the container is a capsule or an ampoule. In a preferred embodiment of the invention the glutamine-based supplement is present in a container, in unit dose form, and in dry form, preferably in the form of a powder, and is present in an amount of from 0.05 to 10 g, preferably 0.05 g to about 8 g powder, preferably 0.1 to 4 g even more preferable 0.2 to 1 g powder per container. 15 Preferably the container is provided with instructions for adding at least a portion of said glutamine-based supplement to human milk, to standard preterm formula, or to human milk fortified with standard HMF. Preferably, the nutritional supplement is a reconstitutable powder. Powdered nutritional supplements have the advantage that they minimize the volume displacement of preterm formula or human milk. 20 In one embodiment, the invention concerns a glutamine-based supplement in the form of a powder in a unit dose comprising at least 15 wt.% glutamine in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide on dry weight of the powder. 25 Preferably the glutamine-based supplement of the present invention comprises at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine based on total protein, even more preferably more than 50 wt.%, most preferably more than 75 wt.% glutamine based on total protein. Preferably the glutamine-based supplement of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, more 30 preferably at least 4 wt.% glutamine, even more preferably at least 15 wt.%, even more preferably at least 40 wt.%, most preferably at least 75 wt.% glutamine based on dry weight WO 2013/105851 PCT/NL2013/050007 17 of the supplement. Preferably the glutamine-based supplement of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, more preferably at least 1 g glutamine, even more preferably at least 5, more preferably at least 10, most preferably at least 20 g glutamine based on 100 kcal. 5 Preferably the glutamine-based supplement of the present invention comprises at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein, even more preferably more than 50 wt.%, most preferably more than 75 wt.% glutamine in the form of free amino 10 acid and/or dipeptide based on total protein. Preferably the glutamine-based supplement of the present invention comprises at least 1.5 wt.%, more preferably at least 2 wt.%, more preferably at least 4 wt.%, even more preferably at least 15 wt.%, even more preferably at least 40 wt.%, most preferably at least 75 wt.% glutamine in the form of free amino acid and/or dipeptide based on dry weight of the supplement. Preferably the glutamine-based 15 supplement of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, more preferably at least 1 g glutamine, even more preferably at least 5, more preferably at least 10, most preferably at least 20 g glutamine in the form of free amino acids and/or dipeptide based on 100 kcal. 20 In one embodiment, the glutamine-based supplement comprises further components such as proteins other than free glutamine, carbohydrates, fats, minerals like calcium and-or vitamins. In one embodiment, the glutamine-based supplement comprises non digestible oligosaccharides as discussed above. 25 Preferably the glutamine-based supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 12 wt.%, more preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine based on total protein. Preferably the nutritional supplement is added to 30 human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition WO 2013/105851 PCT/NL2013/050007 18 comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine based on dry weight of the nutritional composition. Preferably the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine 5 enriched nutritional composition comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine based on 100 kcal. Preferably the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final 10 glutamine enriched nutritional composition comprises at least 12 wt.%, more preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein. Preferably the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine 15 enriched nutritional composition comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine in the form of amino acid and/or dipeptide based on dry weight of the nutritional composition. Preferably the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional 20 composition comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine in the form of free amino acid and/or dipeptide based on 100 kcal. Preferably the glutamine-based supplement comprises at least 10 wt.% non digestible oligosaccharides based on dry weight of the glutamine-based supplement, preferably at least 25 15 wt.%, more preferably at least 20 wt.%, more preferably at least 25 wt.%, or at least 30 wt.% or at least 40 wt.% up to at most 50 wt.% non digestible oligosaccharides based on dry weight of the glutamine-based supplement. Preferably, the non digestible oligosaccharides in the glutamine-based supplement invention 30 are selected from the group consisting of fructo-oligosaccharide and galacto oligosaccharide.
    WO 2013/105851 PCT/NL2013/050007 19 Preferably, the glutamine-based supplement comprises the non-digestible oligosaccharides transgalacto-oligosaccharide and fructo-oligosaccharide. 5 Preferably the present nutritional composition comprising glutamine is in dry form, preferably a powder. This powder is suitable for reconstitution with water or another aqueous phase. When glutamine is in powder form it advantageously has a better shelf life. Glutamine, in particular free glutamine and glutamine dipeptide, is more stable when stored in dry form. 10 In one embodiment, the present invention concerns a method for preparing a glutamine enriched nutritional composition comprising adding glutamine to a nutritional composition. Preferably the glutamine that is added is in the form of glutamine free amino acid, glutamine dipeptide, and/or glutamine tripeptide, preferably in the form of free glutamine and/or 15 glutamine dipeptide. Preferably the nutritional composition to which glutamine is added is human milk, standard preterm formula or human milk fortified with standard human milk fortifier. Application 20 Administration of the present nutritional composition to the preterm and/or LBW infant is enterally or parenterally, more preferably enterally, more preferably orally via a bottle, even more preferably enterally by naso-gastric tube feeding. Enteral feeding has the advantage that the glutamine will provide a beneficial effect in the intestinal tract as well regarding intestinal infections and improving barrier function. 25 Administration of the nutritional composition comprising glutamine is preferably during the first month after birth, more preferably until a body weight of 2500 is reached. Preferably the administration is daily. Preferably the administration is daily for at least a period of a week, more preferably 30 days. 30 WO 2013/105851 PCT/NL2013/050007 20 The inventors found that glutamine enriched feeding in the first month after birth in very preterm and/or VLBW infants has a long term effect on measures of brain development. Advantageously an increased cortical brain volume and subcortical brain volume was also observed in children who were born preterm and were supplemented in the first month after 5 birth with glutamine when compared to the control group of preterm infants not having received glutamine. In particular a statistically significant increased white matter volume, brain stem volume, and hippocampus volume was observed. The present invention preferably relates to a nutritional composition comprising glutamine 10 for use in increasing brain volume and/or brain mass in preterm and/or LBW infants. With increase brain volume and/or brain mass is meant an increase to a value more similar to a term infant control group. Alternatively, with increase brain volume and/or brain mass is meant an increase compared to a preterm control group not having received the nutritional composition comprising glutamine of the present invention. Alternatively,with increase of 15 brain mass and/or brain volume also increase in brain size or brain tissue is meant. In particular an increase in brain volume and/or mass refers to an increase of volume and/or mass in brain structure selected from the group consisting of cortical brain, intracranial volume, grey matter, white matter and cerebellum, subcortical brain, brain stem, thalamus, 20 putamen, caudate nucleus, hippocampus, globus pallidum, amygdale, nucleus accumbens and the corpus callosum, more particular white matter, brain stem, and hippocampus. The present invention preferably relates to a nutritional composition comprising glutamine for use in improving growth of brain volume and/or mass in preterm and/or LBW infants. 25 With improving growth of brain volume and/or brain mass is meant an increased growth to a value more similar to a term infant control group, thus preferably an increased growth compared to the growth in a term control group to arrive at a value of brain volume and/or brain mass more similar to that in the term control group. Alternatively, with improving growth of brain volume and/or mass in preterm and/or LBW infants is meant an increased 30 growth compared to a preterm control group not having received the nutritional composition comprising glutamine of the present invention. With improving growth of brain mass and/or WO 2013/105851 PCT/NL2013/050007 21 brain volume also improving of structural brain development is meant. With improving growth of brain mass and/or brain volume also stimulating growth of brain mass and/or brain volume and stimulating of structural brain development is meant. With improving growth of brain mass and/or brain volume also increased growth of brain mass and/or brain 5 volume and increased structural brain development is meant. In particular an improvement of growth of brain volume and/or mass refers to an improvement of growth of volume and/or mass of brain structure selected from the group consisting of cortical brain, intracranial volume, grey matter, white matter and cerebellum, 10 subcortical brain, brain stem, thalamus, putamen, caudate nucleus, hippocampus, globus pallidum, amygdale, nucleus accumbens and the corpus callosum, more particular white matter, brain stem, and hippocampus. Smaller total brain volumes, white and grey matter volumes, as well as smaller volumes of 15 the cerebellum, hippocampus, and corpus callosum have been found associated with lower outcomes in terms of IQ by at least one study, see Allin et al., Brain 2001, 1: 60-6; Taylor et al., Dev Neuropsychol 2011, 1: 96-117; Parker et al., Brain 2008, 5: 1344-51; Allin et al., Arch Pediatr Adolesc Med 2007, 12: 1183-9; Martinussen et al., J Pediatr 2009, 6: 848-53; Narberhaus et al., Neuropsychologia 2008, 1: 111-6; Reiss et al., J Pediatr 2004, 2:242-9; 20 Yung et al., Pediatr Res 2007, 6: 732-6; Northam et al., Ann Neurol 2011, 4: 702-11. In one embodiment the nutritional composition comprising glutamine according to the present invention is for improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial 25 working memory task, improvement of visuomotor skills later in life in infants born preterm and/or with low birth weight. In a preferred embodiment the nutritional composition comprising glutamine according to the present invention is for improving neurocognitive functioning, later in life in infants born preterm and/or with low birth weight. 30 The effects on the brain structure and/or functioning as described above are preferably established later in life. The effects on the brain as described above are preferably WO 2013/105851 PCT/NL2013/050007 22 established during school age. With school age an age between 4 and 12 years is meant. It is particularly relevant that the observed effects of the nutritional composition comprising glutamine on the brain are established during school age, since then the neurocognitive function is more evident. 5 In a preferred embodiment the invention concerns a method for improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, improvement of visuomotor skills (caterpillar-task) in a subject at an age from 4 to 12 years, comprising adminstering a 10 nutritional composition comprising glutamine according to the present invention, or a glutamine-based supplement according to the present invention, to low birth weight and/or preterm infants. In one embodiment the method for improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, improvement of visuomotor skills 15 (caterpillar-task) is a non-medical method. Preferably the method or non-medical method for improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, improvement of visuomotor skills (caterpillar-task) is for providing nutrition to a low birth weight and/or preterm infant. Preferably the nutrition to a low birth weight 20 and/or preterm infant is provided in the first month after birth, preferably during the first month after birth. In a preferred embodiment the method according to the invention is for improving neurocognitive functioning, later in life in infants born preterm and/or with low birth weight. 25 The invention can also be worded as a nutritional composition according to the present invention, or a glutamine-based supplement according to the present invention, for use in providing nutrition to a low birth weight and/or preterm infant, for use in improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, 30 improvement of visuomotor skills (caterpillar-task) at an age from 4 to 12 years. Preferably the nutritional composition comprises between 1.5 wt.% and 20 wt.% glutamine based on WO 2013/105851 PCT/NL2013/050007 23 dry weight of the nutritional composition, and comprising protein in such an amount that glutamine is present between 12 wt.% and 80 wt% based on total protein. Preferably the nutritional composition is a preterm formula. Preferably the glutamine in the nutritional composition is in the form of free glutamine, glutamine dipeptide and/or glutamine 5 tripeptide, preferably free glutamine and/or glutamine dipeptide. Preferably the nutritional composition or glutamine-based supplement further comprises non-digestible oligosaccharides selected from the group consisting of galacto-oligosaccharides and fructo oligosaccharides, preferably in an amount as defined above. Preferably the nutrition to a low birth weight and/or preterm infant is provided in the first month after birth, preferably 10 during the first month after birth. Preferably the nutritional composition according to the present invention, or a glutamine-based supplement according to the present invention, is for use in providing nutrition to a low birth weight and/or preterm infant, for use in improving neurocognitive functioning, at an age from 4 to 12 years. 15 The invention can also be worded as the use of glutamine, or a composition comprising glutamine, for the manufacture of a glutamine enriched nutritional composition for use in providing nutrition to a low birth weight and/or preterm infant for use in improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, 20 improvement of visuomotor skills (caterpillar-task) at an age from 4 to 12 years. Preferably the nutritional composition comprises between 1.5 wt.% and 20 wt.% glutamine based on dry weight of the nutritional composition, and comprising protein in such an amount that glutamine is present between 12 wt.% and 80 wt% based on total protein. Preferably the nutritional composition is a preterm formula. Preferably the glutamine in the nutritional 25 composition is in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide, preferably free glutamine and/or glutamine dipeptide. Preferably the nutritional composition or glutamine-based supplement further comprises non-digestible oligosaccharides selected from the group consisting of galacto-oligosaccharides and fructo oligosaccharides, preferably in an amount as defined above. Preferably the nutrition to a low 30 birth weight and/or preterm infant is provided in the first month after birth, preferably during the first month after birth. Preferably the use according to the present invention is for WO 2013/105851 PCT/NL2013/050007 24 use in providing nutrition to a low birth weight and/or preterm infant for use in improving neurocognitive functioning at an age from 4 to 12 years. In one embodiment the low birth weight or preterm infant is a very low birth weight infant 5 or a very premature infant. In one embodiment, the daily dose of glutamine provided to the infant is at least 0.01 to 0.5 g/kg body weight, preferably 0.03 to 0.4, even more preferably 0.07 to 0.35 g/kg body weight. In one embodiment the nutritional composition comprises galacto-oligosaccharides. In one embodiment, the nutritional composition is a glutamine based supplement in the form of a powder in a unit dose comprising at least 15 wt.% 10 glutamine in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide on dry weight of the powder. In one embodiment, the glutamine-based supplement comprises at least 10 wt.% non digestible oligosaccharides based on dry weight of the glutamine-based supplement. 15 EXAMPLES Example 1: Effect of glutamine supplementation in VLBW and or very preterm infants on brain volume later in life A randomized, placebo controlled clinical trial was performed. For a detailed protocol of the 20 study, see van den Berg et al, 2004, Glutamine-enriched enteral nutrition in very low birth weight infants. Design of a double-blind randomised controlled trial [ISRCTN73254583], BMC Pediatrics 4:17. In short: Infants with a gestational age <32 weeks and/or birth weight <1500 g were 25 enrolled. In total 52 very preterm and/or VLBW children, which had taken part in a randomized controlled trial on enteral glutamine supplementation between day 3 and 30 of life, participated in this follow up study at the mean age of 8.6 years (SD = 0.3 years). 30 infants were in the control group and 22 in the glutamine supplementation group. Also comparisons were made with a control group (n=52) of term born infants. 30 WO 2013/105851 PCT/NL2013/050007 25 The glutamine nutritional supplement was in powder form and contained 82 wt.% L glutamine in total and 18 wt.% glucose (nitrogen 15.5 wt/wt%; 371 kcal/100 g), whereas the isonitrogenous control powder contained 100 wt.% L-alanine (nitrogen 15.7 wt/wt%, 435 kcal/100 g). The two powders were indistinguishable by appearance, colour and smell. 5 Between days 3 and 30 of life, supplementation was administered in increasing doses to a maximum of 0.3 g/kg glutamine per day in the glutamine group. Initially, the supplementation dose was based on birth weight. After 2 weeks the dose was adjusted to actual body weight. Two members of the nursing staff daily added supplementation to breast milk or to preterm formula (Nenatal@, Nutricia Nederland B.V., Zoetermeer, The 10 Netherlands), according to the parents' choice. Per 100 ml, Nenatal@ provides 78 kcal, 2.1 g protein (casein-whey protein weight ratio 40:60), 4.4 g fat and 7.5 g carbohydrate. Nenatal® does not contain free glutamine and alanine or glutamine and alanine in the form of dipeptide. Protocol guidelines for the introduction of parenteral and enteral nutrition are disclosed in van den Berg et al., 2004. 15 All statistical analyses are performed on an intention to treat basis. In addition, alternative per protocol analyses are performed, excluding all patients who are not treated according to protocol, defined as more than 3 consecutive days or more than a total of 5 days on minimal enteral feeding or without supplementation. A p value <0.05 is considered significant (two 20 tailed). SPSS 9.0 (SPSS Inc., Chicago, IL, USA) and STAT 7.0 (Stat-Corp LP, College Station, TX, USA) are used for data analysis. A p value of 0.1 or below is considered to represent a realistic effect, a trend. Due to the small size of the groups also the effect size is taken into account. An effect size above 0.4 is considered to represent a trend. 25 Results: No statistically significant difference of the control preterm group and glutamine supplemented preterm group for follow up was present regarding base line characteristics, such as age, social economic status, ethnicity, birth weight, gestational age, head circumference, HELLP syndrome, BPD (bronchopulmonary dysplasia), IVH 30 (intraventricular hemorrhage) grade I/II, IVH grade III/IV, ROP (retinopathy of prematurity) grade II/IV, Apgar score after 5 min., mode of delivery, gender and drop outs. The control WO 2013/105851 PCT/NL2013/050007 26 group had more infections and a higher use of prenatal corticosteroids. Mean birth weight was 1186 (sd 336) gram in the control group, and 1252 (sd 380) in the glutamine group. Gestational age was 28.9 (sd 1.7) weeks in the control group and 29.4 (sd 1.7) in the glutamine group. 5 Brain cortical volumes were determined by MRI and calculated using FSL software "FAST" and corrected for age at MRI scan, gender and body weight for gestational age. Brain cortical volumes were significantly higher in the term control group than in the preterm group. This was the case for intracranial volume, grey matter, white matter and 10 cerebellum volume. In the preterm group, the glutamine supplemented group had a significantly higher white matter volume. A tendency for an increase in intracranial volume, and cerebellum volume was also observed, see Table 1. The cortical brain volumes in the glutamine group were higher than in the control group, and were more comparable to the term control group. 15 Table 1: Cortical volumes in children born preterm and being supplemented with L glutamine or with control during the first month of life. Brain structures Control Glutamine Term Effect size* P-value* (in cm 3 ) infants Intracranial 1574.1 1649.8 1654.1 0.48 0.07 volume (sd) (134.4) (179.3) (132.7) Grey matter (sd) 705.4 (63.3) 727.4 735.8 (53.6) 0.29 0.39 (85.60) White matter (sd) 466.5 (49.2) 496.5 (60.4) 494.5 (49.6) 0.54 0.03 Cerebellum (sd) 105.7 (9.5) 110.89 113.2 (11.1) 0.41 0.13 (15.3) * For control versus glutamine group 20 Brain subcortical volumes were determined by MRI and calculated using FSL software "FAST" and corrected for age at MRI scan, gender and body weight for gestational age.
    WO 2013/105851 PCT/NL2013/050007 27 Brain subcortical volumes were significantly higher in the term controls than in preterm group. This was the case for the brain stem, thalamus, putamen, caudate nucleus, hippocampus, globus pallidum, amygdale, nucleus accumbens and the corpus callosum volume. In the preterm group, the glutamine supplemented group had higher subcortical 5 volume, and significantly higher brain stem volume and hippocampus volume, and a tendency for an increase in other subcortical brain structures volume, see Table 2. The subcortical brain volumes in the glutamine group were higher than in the control group, and were more comparable to the term control group. 10 Table 2: Subcortical volumes in children born preterm and being supplemented with L glutamine or with control during the first month of life. Brain structures (in cm') Control Glutamine Term Effect P-value* infants size* Subcortical structures 62.9 (5.81) 66.5 (8.2) 68.5 (4.9) 0.50 0.06 - Brain stem 17.6(2.2) 18.9(2.5) 19.2(1.8) 0.54 0.04 - Thalamus 14.6 (1.5) 15.3 (2.1) 16.0 (1.1) 0.39 0.14 - Putamen 10.1 (1.1) 10.9(1.6) 10.9(1.0) 0.55 0.06 - Caudate Nucleus 7.3 (1.1) 7.4(1.4) 8.0(1.0) 0.10 0.86 - Hippocampus 6.9 (0.6) 7.2 (0.8) 7.4 (0.8) 0.47 0.04 - Globus Pallidum 3.3 (0.3) 3.5 (0.4) 3.5 (0.3) 0.48 0.10 - Amygdala 2.2 (0.39) 2.3 (0.4) 2.3 (0.4) 0.46 0.08 - Nucleus 1.0 (0.18) 1.0 (0.3) 1.1 (0.2) 0.04 0.82 accumbens Corpus callosum (in 521.0 535.7 558.4 0.18 0.40 mm 2 ) (72.0) (90.0) (80.7) * For control versus glutamine group The improved brain development established at school age is indicative for improvement in 15 neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, improvement of visuomotor skills (caterpillar-task). In particular these data are indicative of WO 2013/105851 PCT/NL2013/050007 28 improved neurocognitive functioning. fMRI (functional MRI data) indicate a neuronal activation more similar to term infants, in the glutamine fed preterm group later in life. Example 2: Effect of glutamine supplementation in VLBW and or very preterm infants on 5 brain volume later in life Intellectual development was measured in the same group of infants as example 1 by a short form of the Wechsler Intelligence Scale for Children-Ill (WISC-III), including the subtests Vocabulary and Block Design. 68 infants completed the tests. Both subtests correlate strongly (r 0-90) with full-scale intelligence quotient (FSIQ). Scores on this test were 10 normalised with a mean of 100 (SD 15). There was a trend (p=0.12 when adjusted for gestational age and socioeconomic status) in improved IQ (WISC-III FSIQ being 102, sd 17.7, n=30) in the glutamine group compared to the control group (WISC-III FSIQ 93.6 sd 17.2 n=34). 15 Example 3: Preterm formula enriched in glutamine Preterm formula in powder form comprising per 100 g about 486 kcal, 15.1 g protein, 46.1 g digestible carbohydrates, 26.7 g fat and 4.8 g non-digestible oligosaccharides. Furthermore the composition comprises minerals, trace elements, vitamins, L-carnitine, choline, myo inositol and taurine as known in the art and according to guidelines for preterm infants. For 20 a ready to drink form, about 16.5 g powder is reconstituted with water until a final volume of 100 ml. The protein comprises about 85 wt.% casein and whey protein from cow's milk based on total protein in a weight ratio of 1:1.5. About 15 wt.% of the protein is free glutamine. The non-digestible oligosaccharides are galacto-oligosaccharides (Vivinal GOS) and 25 fructopolysaccharides (RaftilinHP) in a weight ratio of 9:1. Example 4: Nutritional supplement enriched in glutamine. Human milk fortifier in powder form packed in sachets comprising about 2 g. Based on 100 g powder the composition comprises 361 kcal, 19 g protein, 71.5 g digestible 30 carbohydrates, the rest being minerals, trace elements and vitamins. The protein consists of free glutamine.
    权利要求:
    Claims (13)
    [1] 1. Use of glutamine, or a composition comprising glutamine, for the manufacture of a glutamine enriched nutritional composition for use in providing nutrition to a low birth 5 weight and/or preterm infant for use in improving neurocognitive functioning, behavioral and/or motional development, improving neuronal activation during interference task or during visuo-spatial working memory task, improvement of visuomotor skills (caterpillar-task) at an age from 4 to 12 years. 10
    [2] 2. Use according to claim 1 for use in providing nutrition to a low birth weight and/or preterm infant for use in improving neurocognitive functioning at an age from 4 to 12 years.
    [3] 3. The use according to claim 1 or 2 wherein the low birth weight or preterm infant is a 15 very low birth weight infant or a very premature infant.
    [4] 4. The use according to any one of claims 1 to 3 wherein the daily dose of glutamine provided to the infant is at least 0.01 to 0.5 g/kg body weight, preferably 0.03 to 0.4, even more preferably 0.07 to 0.35 g/kg body weight. 20
    [5] 5. The use according to any one of claims 1 to 4, wherein the nutritional composition is administered to the infant during the first month after birth.
    [6] 6. The use according to any one of claims 1 to 5, wherein the nutritional composition is a 25 preterm formula.
    [7] 7. The use according to any one of claims 1 to 6, wherein the nutritional composition comprises between 1.5 wt.% and 20 wt.% glutamine based on dry weight of the nutritional composition, and comprises protein in such an amount that glutamine is 30 present between 12 wt.% and 80 wt% based on total protein. WO 2013/105851 PCT/NL2013/050007 30
    [8] 8. The use according to any one of claims 1 to 7, wherein the glutamine in the nutritional composition is in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide, preferably free glutamine and/or glutamine dipeptide. 5
    [9] 9. The use according to any one of claims 1 to 8, wherein the nutritional composition further comprises non-digestible oligosaccharides selected from the group consisting of galacto-oligosaccharides and fructo-oligosaccharides.
    [10] 10. The use according to claim 9, wherein the nutritional composition comprises at least 0.5 10 wt.% non digestible oligosaccharides based on dry weight of the composition.
    [11] 11. The use according to any one of claims 9 or 10, wherein the nutritional composition comprises galacto-oligosaccharides. 15
    [12] 12. The use according to any one of claims I to 11 wherein the nutritional composition is a glutamine-based supplement in the form of a powder in a unit dose comprising at least 15 wt.% glutamine in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide on dry weight of the powder. 20
    [13] 13. The use according to claim 12 wherein the glutamine-based supplement comprises at least 10 wt.% non digestible oligosaccharides based on dry weight of the glutamine based supplement.
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    同族专利:
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    CN104039174B|2016-11-16|
    CN104039174A|2014-09-10|
    WO2013105851A1|2013-07-18|
    AU2013208359B2|2016-08-25|
    BR112014016346A8|2017-07-04|
    BR112014016346A2|2017-06-13|
    EP2802223B1|2017-05-03|
    PL2802223T3|2017-10-31|
    RU2014132846A|2016-02-27|
    ES2633787T3|2017-09-25|
    EP2802223A1|2014-11-19|
    US20140357571A1|2014-12-04|
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    法律状态:
    2016-12-22| FGA| Letters patent sealed or granted (standard patent)|
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