WO2007142596A1 - Use of selected lactic acid bacteria for reducing infantile colic - Google Patents
Use of selected lactic acid bacteria for reducing infantile colic Download PDFInfo
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- WO2007142596A1 WO2007142596A1 PCT/SE2007/050371 SE2007050371W WO2007142596A1 WO 2007142596 A1 WO2007142596 A1 WO 2007142596A1 SE 2007050371 W SE2007050371 W SE 2007050371W WO 2007142596 A1 WO2007142596 A1 WO 2007142596A1
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/225—Lactobacillus
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/853—Lactobacillus
Definitions
- the invention herein provides certain strains of lactic acid bacteria selected for their ability of increasing cytokine IL-IO levels, for prophylaxis and/or treatment of colic, a method of selecting such strains, and products containing such strains.
- infantile colic Despite its salience in terms of both prevalence and distress the nature and causes of infantile colic have remained poorly understood. A mother's description of this condition is a baby who has been happy during the day, begins to frown, his face becomes red, he draws up his legs, screams and continues to cry for about 2-20 min after which the attack ends suddenly. Controversy arises even in the terms used to describe the condition. These terms include, “infantile colic", “evening colic” because the pain is mainly confined to evening, and "three months colic” under the pretext that it disappears after about three months from birth (Illingworth RS. Difficulties in breastfeeding. In Ronald S. Illingworth, ed. The Normal Child. 10th edn.
- Psychosocial factors include: variant of normal crying, behavioral effects of atypical parenting, and manifestation of problems in parent-infant interaction.
- Gastrointestinal disorders have been implicated in colic because of the infant's leg position and grimacing during a crying spell.
- the gastrointestinal factors are briefly reviewed below:
- Lactose malabsorption has been reported by authors based on breath hydrogen tests (Hyams J, Geerstama M, Etienne N, Treem W. Colonic hydrogen production in infants with colic. J Pediatr 1989; 115: 592). No differences have been found in stool hydrogen concentrations between infants with or without infantile colic. However, infants producing higher methane levels have been found to have decreased colic suggesting a role of methane production in its alleviation (Belson A, Shetty AK, Yorgin PD, Bujanover Y, Peled Y, Dar MH, Riaf S. Colonic hydrogen elimination and methane production in infants with and without infantile colic syndrome. Dig Dis Sci 2003; 48(9): 1762-1766).
- Gastrointestinal (GIT) hormones such as motilin, vasoactive intestinal peptide have been shown to be abnormally high in babies with colic. Lothe et al. have shown elevated levels from first day of life in babies who later developed colic suggesting an abnormal GIT physiology in infantile colic (Lothe L, Ivassson SA, Ekman R, Lindberg T. Motilin and infantile colic: A prospective study. Acta Pediatr Scand 1990; 79(4): 410-416). Neuro-developmental disorders that have been put forward suggest that abdominal cramping and colic may be a result of hyperperistalsis. The theory is supported by evidence that the use of anticholinergic agents decreases colic symptoms (Gupta SK.
- a probiotic by the generally accepted definition, is a live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance. Although originally referring to the supplementation of animal feeds for farm animals, the definition is easily applied to the human situation.
- the major consumption of probiotics by humans is in the form of dairy-based foods containing intestinal species of lactobacilli and bifidobacteria. It is implicit in the definition that consumption of the probiotic affects the composition of the intestinal microflora. It is proposed that this effect of the probiotic on the intestinal ecosystem impacts in some beneficial way on the consumer.
- reuteri might be a potential fine-targeted treatment effective for downregulating production of IL- 12 and TNF- ⁇ (and IL-6) while inducing the antiinflammatory IL-IO, thus representing an alternative therapeutic approach to counterbalance the pro-inflammatory intestinal cytokine milieu," and thus "the potential exists for Thl/Th2/Th3 driving capacities of the gut to be modulated according to composition of gut microflora, including ingested probiotics.”
- TR T regulatory
- TLRs Toll like receptors
- TLRs Toll like receptors
- motifs recognized by TLRs are not unique to pathogens but are general motifs shared by entire classes of microorganisms, and it is not fully understood how the immune system differentiates between commensal and pathogenic bacteria via the TLRs.
- L. reuteri is one of the naturally occurring inhabitants of the gastrointestinal tract of animals, and is routinely found in the intestines of healthy animals, including humans. It is known to have antimicrobial activity. See, for example U.S. Patent Nos. 5,439,678, 5,458,875, 5,534,253, 5,837,238, and 5,849,289.
- L. reuteri cells are grown under anaerobic conditions in the presence of glycerol, they produce the antimicrobial substance known as B- hydroxy-propionaldehyde (3 -HPA).
- cytokines can initiate a hyper-reflex response of the enteric neuromusculature through neuro- and myo-immune interactions (Milla PJ. Inflammatory cells and the regulation of gut motility. J Pediatr Gastroenterol Nutr 2004; 39: S750.).
- reuteri colonizes the human gastrointestinal tract and is able to exert immunomodulatory activity, including recruitment of CD4+ T-helper cells at the human ileum epithelium (Valeur N, Engel P, Carbajal N, Connolly E, Ladefoged K. Colonization and immunomodulation by Lactobacillus reuteri ATCC 55730 in the human gastrointestinal tract. Appl Environ Microbiol 2004; 70: 1176-81). Maturation of DCs is the process that converts immature DCs to mature antigen presenting cells that migrate to lymph nodes.
- MCM is generated in vitro by culturing monocytes and then using the culture supernatant fluid as a source of maturation factors.
- the major components in MCM responsible for maturation are the pro-inflammatory cytokines interleukin-1 beta (IL-I ⁇ ), IL-6 and TNF- ⁇ (Reddy A, Sapp M, Feldman M, Subklewe M, Bhardwaj N: A monocyte conditioned medium is more effective than defined cytokines in mediating the terminal maturation of human dendritic cells. Blood 1997, 90:3640-6.).
- Mature DCs produce a variety of cytokines, which stimulate and direct the T cell response. Two of these cytokines are IL-IO and IL- 12.
- IL- 12 induces a ThI type response whereas IL-IO inhibits such response.
- APCs antigen presenting cells
- Resting APCs may promote the development of CD4 + CD25 + TR cells.
- recognition of microbial molecules by TLRs results in activation of APCs.
- the APCs then produce IL-6 and additional soluble factors that together override the suppressive effects of TR cells, allowing efficient generation of TE (T effector cells)cells against the pathogen.
- the dynamic equilibrium between resting and activated APCs will also be influenced by the actions of both TR and TE cells ( Figure 1).
- TR cells produced increased levels of IL-10.
- the authors do not connect the IL-10 elevation to gut motility or colic. Even when it comes to strains, the authors mention two different bacterial species being efficient in increasing IL-10 levels. This is in contrast to the invention herein where it is showed that the probiotic to be most effective reducing colic has to be determined and selected at the strain level as the different strains of the same species have a different ability to be effective in increasing IL-10 levels. At present there is no cure for colic.
- the current treatment paradigm for colic consists of either pharmacological and/or non- pharmacological methods, providing at best marginal reduction of symptoms.
- Typical therapeutic interventions for colic offered to parents fall within four categories, including, dietary, physical, behavioral and pharmacological. Dietary manipulations include professional advice on various feeding techniques, or the use of hypoallergenic milk, soy or lactose free formulas, and an early introduction to solids (Lothe, L., et al. cow's milk formula as a cause of infantile colic: a double-blind study. Pediatrics 1982; 70:7-10; Forsyth B W C. Colic and the effect of changing formulas: a double- blind multiple-crossover study.
- prescription and non-prescription medications include belladonna alkaloids and opiates (paregoric), which may provide relief, but are fraught with risks including extra pyramidal symptoms, respiratory depression, and constipation.
- anticholinergic drugs similar in their effect to atropine, such as, Hyoscyamine (LEVISINE®, or GASTROSED®) and Dicyclomine dilate pupils, increase heart rate, decrease production of saliva, relieve spasms of gastrointestinal and urinary tracts, as well as bronchi.
- the anticholinergic drugs are the only prescription medications on the U.S.
- Non-prescription medications that have been reported as effective treatment for infantile colic include several sedative or sleep- inducing drugs, including supraphysiologic (high dose) diphenhydramine (BENADRYL®), phenobarbital, chloral hydrate, and even alcohol.
- BENADRYL® supraphysiologic diphenhydramine
- phenobarbital phenobarbital
- chloral hydrate phenobarbital
- alcohol alcohol
- a safer non-prescription medication for treatment of colic has largely included the administration of simethicone or dimethylpolysiloxane, a non-absorbable, over- the-counter drug, which reduces the size of intestinal gas bubbles.
- Simethicone has a veiy safe profile and is frequently recommended, despite several studies demonstrating that effectiveness of simethicone on infantile colic is no better than placebo (Metcalf, T J, et al, Pediatrics 1994 July; 94(1) :29-34. Sferra, T J, et al., Pediatr Clin North Am 1996 April; 43(2):489-510. Danielson, B. et al., Acta Paediatr Scand 1985 May; 74(3):446-50. Colon, A R, et al., Am Fam Physician 1989 December; 40(6): 122-4.).
- the most common treatment for colic today is to simply wait for the baby to grow out of the condition.
- Patent application EP1364483A10 describes probiotics for treatment of gut- neuromuscular abnormalities, such as colic in babies.
- the applicants mention several different bacterial species. This is in contrast to the invention herein where the probiotic to be most effective reducing colic is a specific lactic acid bacteria strain selected to be effective in increasing IL-10 levels and not a whole bacterial species, as the inventors of the present invention has showed that there are substantial differences in stimulation IL-10 production between strains also of the same species.
- gut motility is controlled by neurological signals, that are connected to the intestinal immune system and that colic is a consequence of increased gut motility, for example, due to bacterial overgrowth.
- hygienic measures begin as early as the birthing process, which disrupts the neonates capacity to uptake the mother's gut microflora.
- different microflora are established in the infant. Instead of harboring for example Escherichia coli and Lactobacilli the newborns are more often colonized with Staphylococcus aureus and other skin bacteria.
- the inventors of the present invention has made the unexpected finding that while over-growth of sldn bacteria over-activates the baby's immune system, leading to over-activated gut motility and colic as a consequence, a higher number of specific gut bacteria, such as L. reuteri DSM 17938, with capacity of promoting IL-IO production, leads to maturation of the TR system i.e. proliferation of CD4+CD25+TR cells. Up-regulation of CD4+CD25+ cells leads to calmed gut motility and consequently to beneficial effects on babies with colic. On account of these findings, nonpathogenic bacterial strains were selected for
- the invention consequently refers to the use of L. reuteri DSM 17938 for the manufacture of a medicament for the prophylaxis and/or treatment of colic, and other strains selected the same way. It is a further object of the invention to provide products containing said strains and for the administration to animals, including humans. Other objects and advantages will be more fully apparent from the following disclosure and appended claims.
- the invention herein provides certain strains of lactic acid bacteria selected for their capability of promoting production of IL-10 and consequently proliferation of CD4+CD25+ TR cells, for prophylaxis and/or treatment of colic, a method of selecting such strains, and products containing such strains.
- FIG. 1 ILlO production by DC cells in bar-graph form
- Figure 2b ILlO production by DC cells in a table.
- CD4+CD25+ cells leads to calmed gut motility and consequently beneficial effects on colic.
- the present invention herein comprises strains of lactic acid bacteria which have been selected for their capability of reducing colic, including L. reuteri DSM 17938.
- Products such as foods, nutritional additives and formulations, pharmaceuticals or medical devices containing whole cells or components derived from these strains may be formulated as is known in the art, and generally include an ingestible support as known plus the Lactobacillus-stmin, or its derived component.
- An in vitro study may be used as a method for selecting strains of lactobacilli for their capability of stimulating the production of ILlO is monocyte-derived DCs and thereby capacity to induce the development of CD4+CD25+TR cells (Example
- I)- Data disclose an indication of a powerful stimulation of IL- 10 by the specific strains L. reuteri ATCC 55730 and L. reuteri DSM 17938, and that this regulation is mediated by a substance released into the growth medium by these two specific strains during late log/stationary growth phase. On the contrary, the two other strains of L. reuteri were unable to stimulate relevant IL-10 production. To confirm the clinical relevance of the selected strains for preventing or treating colic further studies are performed in breast-fed infants with a diagnosis of infantile colic.
- Immature DCs are generated from peripheral blood monocytes (Hilkens, C. M. U., P. Kalinski, M. de Boer, and Kapsenberg. 1997. Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T- helper cells toward the ThI phenotype.
- Strains to be tested in this example are Lactobacillus reuteri ATCC 55730, Lactobacillus reuteri DSM 17938, Lactobacillus reuteri ATCC PTA 4660 and
- Lactobacillus reuteri ATCC PTA 4964 obtainable from ATCC (Manassas, VA, USA and DSMZ, Braunschweig, Germany). Strains are cultured on Columbia agar (Oxoid, Basingstoke, United Kingdom) containing 6.25% sheep blood. Lactobacilli are incubated at 37 0 C in a 5% CO 2 atmosphere. After 3 days, the number of bacteria is determined by measuring the optical density at 620 nm (OD620). Typically, an
- OD620 of 0.35 corresponded to IxIO 8 colony-forming units (cfu) for all test strains.
- EL- 12, IL-IO, and IL-6 cytokine production by mature DCs is determined by means of a 24-hour stimulation with CD40 ligand-expressing mouse plasmacytoma cells (J558), as described by Vieira PL, et. al. (Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P. Development of ThI -inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 2000;164:4507-12). Supernatants are harvested after 24 h, and the concentrations of IL-IO are measured by ELISA. For results see Figure 2. As can be seen from the results, there is a substantial difference in influence by different Lactobacillus strains in their ability to promote IL-IO production by the DCs.
- MCT-oil medium chain tri-glyceride oil
- MCT oils occur naturally, and the most abundant source is coconut oil. Most MCT oil is refined from coconut oil. MCT oil is a clear light colored liquid with no flavor and low viscosity. This oil suspension is stable for 21 months at 2-8 0 C (as documented by the manufacturer, BioGaia AB, Sweden) (alternative source of MCT oil is Akomed R, by Karlshamns AB, Karlshamn, Sweden). During the study, parents are instructed to keep the product in the refrigerator when not in use.
- Simethicone (S) was given at a dose of 60 mg/day in 3mL of a commercially available solution (Mylicon Infants Gas Relief Drops, J&J, 7050 Camp Hill Rd., Fort Washington, Pennsylvania, 19034-2210, USA) after feeding, twice a day for 28 days.
- a commercially available solution Mylicon Infants Gas Relief Drops, J&J, 7050 Camp Hill Rd., Fort Washington, Pennsylvania, 19034-2210, USA
- the day on which the pediatrician saw the infant for the first time is defined as Day -1.
- each infant underwent a medical examination and the parents were interviewed in order to obtain background data concerning type of delivery, birth weight and gestational age, family history of gastrointestinal disease and atopy.
- the last one is considered positive if the infants had one or more family members (mother, father and /or older sibling) with atopic eczema, allergic rhinitis or asthma.
- any signs and symptoms of atopic disease during the study period were recorded.
- Parents were also invited to record data concerning daily average crying time and number of colic episodes on the day after the recruitment (Day 0). The doctor randomly assigned the child to any of the study groups. Administration of study products began on Day 1.
- Parents are given written information about the study and are asked to record daily number of inconsolable crying episodes and their duration, stool consistency and frequency as well as any observed side effects (constipation, vomiting, cutaneous reactions, etc) starting from Day 0 up to Day 28, using a structured diary, hi order to ensure that all the parents noted crying time in a uniform way and to ensure that the infants are given the medication correctly, one of the researchers is always available by phone to help parents.
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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JP2009514239A JP4520531B2 (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria to reduce infant colic |
KR1020107012584A KR101308865B1 (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
KR1020087026182A KR101030661B1 (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
MX2008014869A MX2008014869A (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic. |
CA2650546A CA2650546C (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
EP07748532.4A EP2040722B1 (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
BRPI0710944A BRPI0710944B8 (en) | 2006-06-05 | 2007-05-30 | biologically pure culture, and, composition and method to reduce infantile colic |
CN2007800012187A CN101374533B (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
NZ572359A NZ572359A (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
SI200731741T SI2040722T1 (en) | 2006-06-05 | 2007-05-30 | Use of selected lactic acid bacteria for reducing infantile colic |
DK07748532.4T DK2040722T3 (en) | 2006-06-05 | 2007-05-30 | USE OF SELECTED Lactic Acid Bacteria For Reducing Infant Colic |
IL194779A IL194779A0 (en) | 2006-06-05 | 2008-10-22 | Use of selected lactic acid bacteria for reducing infantile colic |
HK09104187.6A HK1125840A1 (en) | 2006-06-05 | 2009-05-06 | Use of selected lactic acid bacteria for reducing infantile colic |
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US11/446,628 | 2006-06-05 | ||
US11/446,628 US7374924B2 (en) | 2006-06-05 | 2006-06-05 | Use of selected lactic acid bacteria for reducing infantile colic |
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US (3) | US7374924B2 (en) |
EP (1) | EP2040722B1 (en) |
JP (3) | JP4520531B2 (en) |
KR (2) | KR101030661B1 (en) |
CN (2) | CN101374533B (en) |
AU (2) | AU2007200434B2 (en) |
BR (1) | BRPI0710944B8 (en) |
CA (1) | CA2650546C (en) |
DK (1) | DK2040722T3 (en) |
GE (1) | GEP20125480B (en) |
HK (1) | HK1125840A1 (en) |
HU (1) | HUE026416T2 (en) |
IL (1) | IL194779A0 (en) |
MX (1) | MX2008014869A (en) |
MY (1) | MY162708A (en) |
NZ (2) | NZ596788A (en) |
RU (1) | RU2435844C2 (en) |
SI (1) | SI2040722T1 (en) |
UA (1) | UA93911C2 (en) |
WO (1) | WO2007142596A1 (en) |
ZA (1) | ZA200809531B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010060722A1 (en) * | 2008-11-03 | 2010-06-03 | Nestec S.A. | A nutritional composition comprising probiotics and improving sleep patterns |
WO2011012655A1 (en) | 2009-07-31 | 2011-02-03 | Nestec S.A. | Nutritional composition for breast-fed infants or pets with probiotics and selected nutrients |
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