WO1996035440A1 - Pharmaceutical composition comprising lactobacillus plantarum and arginine - Google Patents
Pharmaceutical composition comprising lactobacillus plantarum and arginine Download PDFInfo
- Publication number
- WO1996035440A1 WO1996035440A1 PCT/SE1996/000603 SE9600603W WO9635440A1 WO 1996035440 A1 WO1996035440 A1 WO 1996035440A1 SE 9600603 W SE9600603 W SE 9600603W WO 9635440 A1 WO9635440 A1 WO 9635440A1
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- WIPO (PCT)
- Prior art keywords
- lactobacillus plantarum
- pharmaceutical composition
- arginine
- strain
- composition according
- Prior art date
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Classifications
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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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Definitions
- composition comprising Lactobacillus plantarum and arginine
- the present invention refers to a pharmaceutical composition
- a pharmaceutical composition comprising a Lactobacillus plantarum strain having the ability to colonize or adhere to the human intestinal mucosa in combination with arginine.
- Said composition can be used for the prophylactic or curative treatment of acute liver injury and failure as well as associated conditions in which there is a defective mucosal membrane barrier and increased bacterial translocation.
- Bacterial translocation that is the escape of microorganisms and toxic compounds from the gut lumen by crossing the intestinal mucosal barrier or by traversing the bowel wall, is of essential importance in the development of many disorders. Bacterial translocation can for instance occur in immunocompromised patients, in critically ill and multiple organ failure patients, multiple trauma patients and burn cases, in liver diseases and inflammatory bowel diseases, and in patients suffering from malnutrition. Viral hepatitis, fulminant hepatic failure, cirrhosis, alcoholic hepatitis, cholangitis and autoimmune diseases such as chronic active hepatitis are liver diseases in which bacterial translocation can take place.
- Acute liver failure has a high mortality rate and a significant proportion of the mortality can be attributed to the high incidence of sepsis.
- most infections are caused by the patients own microflora and many patients dying of sepsis or multiple system organ failure have enteric bacteremi for which no septic focus is identified, indicating that these infections may have originated from the gut. Because of the high frequency of clinically significant bacterial sepsis during fulminant hepatic failure there is also a need of prophylactic treatment.
- Bacterial translocation can lead to sepsis and septise ia, which potentiate the liver failure and can lead to multiple organ failure.
- the treatment of the increased bacterial infection is by using antibiotics, which has many side effects and can affect the intestinal mucosal barrier and microflora.
- the amino acid arginine has a potent effect on body immune system, particularly after trauma. Furthermore arginine is a known precursor of polyamines which are considered important mediators of cell growth and differentiation. It is also known that arginine stimulates the local and systemic immune system.
- SE 9501056-7 refers to the use of certain Lactobacillus strains having an adhesin conferring adherence to a receptor in human intestinal epithelial cells for the preparation of a pharmaceutical composition triggering the immune response, and also for treatment of translocation of pathogenic or potentially pathogenic bacteria over intact intestinal epithelium.
- Said application especially refers to the use of Lactobacillus plan ⁇ tarum 299, DSM 6595, and Lactobacillus plantarum 299v, DSM 9843, as well as other Lactobacillus plantarum strains belonging to a cluster as specified.
- the invention refers to a pharmaceutical composition compri ⁇ sing
- Lactobacillus plantarum strain having the ability to colonize human intestinal mucosa in vivo;
- the invention especially refers to a pharmaceutical composi ⁇ tion wherein the Lactobacillus strain has an adhesin conferring adherence to a receptor on human intestinal epithelial cells.
- the adhesion between the glycoprotein receptor and the adhesin is inhibited by the sugar ⁇ -methyl mannoside, which implies that the receptor is mannose-containing.
- This receptor is, however, different from the mannose-containing receptor for E. coli type 1 fimbriae, which can be shown by means of hemagglutination tests. It is believed that the receptor contains the Man ⁇ l-2Man sequence.
- the invention especially refers to a pharmaceutical composi ⁇ tion wherein the Lactobacillus plantarum strain belongs to a cluster having a restriction endonuclease analysis similarity of more than 70 % to strain Lactobacillus plantarum 299, deposition number DSM 6595, by using the Pearson product moment correlation coefficient and the unweighed pair group algorithm with arit- methic averages (UPGMA; GelCompare 3.0, Applied Maths, Kortrijk, Belgium) .
- REA Restriction endonuclease analysis
- Lactobacillus plantarum strains are described in our copending application SE 9501056-7, which is incorporated as a reference.
- Arginine in the composition preferably is L-arginine. It is however also possible to use a protein rich in arginine, such as cottonseed protein, or a protein from soybeens or peas.
- the pharmaceutical composition of the invention comprises in addition to the Lactobacillus strain and arginine also a carrier which is pharmaceutically acceptable.
- Conventional carriers are for example physiologically acceptable substrates fermented by the bacterium in question, as well as foodstuffs of various kinds, especially based on starch or milk, but also inert solid or liquid substances, such as saline or water.
- a suitable sub ⁇ strate should contain liquid or solid fibres which are not resorbed in the gastro-intestinal tract and which when fermented with Lactobacillus form short fatty acids.
- starchcontaining substrates can be mentioned cereals, such as oats and wheat, corn, root vegetables such as potatoes and certain fruits such as green bananas.
- composition according to the invention can be adminis ⁇ tered in any suitable way, preferably orally or rectally, for example in the form of enema. It can also be administered ente- rally through a catheter inserted in the intestines via the stomach or directly in the intestines. Tests have shown that the effect is improved if dietary fibres in the form of for example oatmeal gruel or of 0-glucans are supplied. The treatment should take place once or several times daily for a period of 1 - 2 weeks.
- liver failure for instance in connection with liver surgery and liver inflammation, the liver does not fulfill its normal functions, but ammonia, nitrogen compounds, endotoxins and other bacterial products will pass through the liver without being metabolized and effect the whole body.
- One way to reduce the load on the liver during these circumstances is to give the patient an enema or to provoke a diarrhea in order to rinse the intestines. In doing this many products which are needed for the intestines to function are removed.
- a composition of the invention could preferably be administrated as an enema in a situation like this.
- the Lactobacillus strain can preferably be used in a con ⁇ centration of 10 7 -10 9 CFU/ml in the pharmaceutical composition.
- the preferred dose of arginine to a human is 25-30 g/d.
- a preferred carrier for oral administration is a lactic acid fermented food product, such as a nutrient solution based on oatmeal, for instance as described in WO 89/08405, or based on milk, for instance cheese.
- Another preferred carrier is a diet fibre product, such as beta-glucans, pectin, oligosaccharides, which in turn can be included in the lactic acid fermented food product.
- the preferred amount to be given 1-5 times a day, is 100-200 ml.
- a preferred composition for oral administration comprises the arginine component protected from being digested in the small intestine, for instance by means of preaggregation of arginine with a gelforming polysaccharide which, when swelling in the gastrointestinal tract will provide a protective gel coating up to the fermentation in the colon.
- This type of gel coating can be performed with pectins, guar seed powder and glucomannane from the Konjac plant, such as the commercial product Propal (Shimizu Co. , Japan) .
- the carrier is preferably a physio ⁇ logical solution in which the arginine and Lactobacillus are suspended, optionally together with a diet fibre as beta-glucan or pectin.
- the preferred amount given, 1-2 times a day, is then 20-50 ml.
- Figure 1 is a dendrogram showing the similarity in % between different tested strains of Lactobacillus which have been cha- - racterized by the REA-method, based on the Pearson product moment correlation coefficient and UPGMA.
- strains 299 and 299v which were both isolated from healthy human intestinal mucosa, have been deposited at the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH on July 2, 1991 and March 16, 1995, respectively, and have been given the deposition numbers DSM 6595 (299) and DSM 9843 (299v) .
- the strains 299, 299v, 79, 105 and 107 are Gram positive, catalase-negative rods growing on Rogosa agar at pH 5.5 and capable of producing lactic acid from glucose anaerobically.
- the ability of the strains to ferment different carbohydrates is shown in Table 1. The tests have been carried out by means of the API 50 CH in accordance with the instructions of the manufacturer.
- each DNA was separately digested at 37°C for 4 h with 10 units of Hindlll, Clal and EcoRI; each endonuclease was used separately.
- Stahl et al, above used Asp718 instead of Hind III, but digestion with Asp718 resulted in too many large bands to be optimal for the present methodology.
- the cleaved DNA fragments are separated as to size by gel electrophoresis using submerged horizontal agarose slab gels.
- the gels consisted of 150 ml of 0.9 % agaroses (ultrapure DNA grade; low electro-endo osmosis; BioRad Laboratories, Richmond, USA) and were cast as slab gels (150 by 235 mm).
- the data set was analyzed by using the Pearson product moment correlation coefficient (r) and the unweighed pair group algorithm with arithmetic averages (UPGMA) (Ro ersburg, H.C. 1984, Cluster analysis for research. Lifetime Learning Publica ⁇ tions, Belmont, California, USA) .
- the Pearson correlation coef ⁇ ficients and the UPGMA values were calculated for the complete data set and the GelCompar 3.0 program was used.
- Fig. 1 the cluster having a similarity >70 % to L. plantarum 299 has been marked out.
- Lactobacillus plantarum 299, 299v, 79 and 105 had identical plasmid profiles, i.e. five plasmids of 4, 9, 15, 21 and >30 MDa. Lactobacillus plantarum 107 had three plasmids of 4, 15 and 21 MDa.
- the aim of this experiment is to study the effect of rectal supplementation of different strains of Lactobacillus with and without arginine on the extent of liver injury and bacterial translocation in an acute liver injury model.
- L. reuteri R2LC isolated from rat intestinal mucosa
- L. rhamnosus DSM 6594 isolate 271 isolated from human colon
- L. fermentum 8704:3 isolate 245 isolated from human jejunum
- L. reuteri 108 isolated from human jejunum
- L. plantarum DSM 9843 strain 299v isolated from human jejunum and rectum. All bacterial strains were obtained from the Laboratory of Food Hygiene, Dept. of Food Technology, Lund University, Lund, Sweden.
- mice Male Sprague-Dawley rats with a weight range of 200-300 g were divided into 13 groups of six animals: normal, control acute liver injury (ALI) , supplemented arginine (SA) , supplemented Lactobacillus reuteri R2CL (SR) , supplemented Lactobacillus reuteri R2CL + arginine (SRA) , supplemented Lactobacillus rhamnosus 271 (SS) , supplemented Lactobacillus rha nosus 271 + arginine (SSA) , supplemented Lactobacillus plantarum 299v (SP) , supplemented Lactobacillus plantarum 299v + arginine (SPA), supplemented Lactobacillus fermentum 8704:3 (SF) , supplemented Lactobacillus fermentum 8704:3 + arginine (SFA) , supplemented Lactobacillus reuteri 108 (ST) and supplemented
- liver enzymes in the blood were measured after centrifugation of the blood (lOOOxg, 10 min) on a Kodak, Echa che 700 XRC, in accordance to the recommendations of the Committee on the Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physio ⁇ logy (Scan J Clin Lab Inves 1974; 33:291-306).
- the serum amino- transferases are sensitive indicators of liver cell injury and most helpful in recognizing acute hepatocellular diseases and they are the most frequently measured indicators of liver dis ⁇ eases. Hepatobiliary diseases lead to the elevation of serum alkaline phosphatase. In hepatocellular damage the serum bilirubin values are higher. The combination of an increased serum bilirubin, an elevated ASAT or ALAT, and an elevated alkaline phosphatase has a predictive accuracy for the presence of liver dieases.
- liver enzymes decreased in all the groups supplemented with Lactobacillus with and without arginine, and that said decrease was most significant in the group supplemented with the combination of arginine and Lactobacillus plantarum.
- Liver histology Samples from the lobe of the liver were placed in 4 % phosphate buffered formaldehyde. Paraffin-embedded samples were sliced and studied under light microscopy after staining with hematoxylin and eosin. At least three slides were studied from each specimen. Liver histological scoring was done according to Chojkier, M. et al., Gastroenterology 1985; 88:115- 21 and Shiratori, Y. et al., Hepatology 1988;8(4): 815-21 with slight modification. The degree av hepatocellular necrosis and inflammatory cell infiltration was quantitatively assessed blindly at the Department of Pathology at Lund University as follows:
- liver histological score showed a significant difference in the supplemented L. plantarum + arginine group compared to the acute liver injury control group.
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Abstract
The invention refers to a pharmaceutical composition comprising a Lactobacillus plantarum strain having the ability to colonize human intestinal mucosa in vivo, in combination with arginine and a pharmaceutically acceptable carrier. The composition can be used for curative and/or prophylactic treatment of liver injury and failure and associated bacterial translocation in mammals inclusive man.
Description
Pharmaceutical composition comprising Lactobacillus plantarum and arginine
The present invention refers to a pharmaceutical composition comprising a Lactobacillus plantarum strain having the ability to colonize or adhere to the human intestinal mucosa in combination with arginine. Said composition can be used for the prophylactic or curative treatment of acute liver injury and failure as well as associated conditions in which there is a defective mucosal membrane barrier and increased bacterial translocation.
Background of the invention
Bacterial translocation, that is the escape of microorganisms and toxic compounds from the gut lumen by crossing the intestinal mucosal barrier or by traversing the bowel wall, is of essential importance in the development of many disorders. Bacterial translocation can for instance occur in immunocompromised patients, in critically ill and multiple organ failure patients, multiple trauma patients and burn cases, in liver diseases and inflammatory bowel diseases, and in patients suffering from malnutrition. Viral hepatitis, fulminant hepatic failure, cirrhosis, alcoholic hepatitis, cholangitis and autoimmune diseases such as chronic active hepatitis are liver diseases in which bacterial translocation can take place.
In acute liver failure following hepatitis, toxic insults or after major liver surgery, there is an increased bacterial translocation from the gut. This may explain some of the infec¬ tious complications seen in these conditions. Acute liver failure has a high mortality rate and a significant proportion of the mortality can be attributed to the high incidence of sepsis. In critically ill or immunocompromised patients most infections are caused by the patients own microflora and many patients dying of sepsis or multiple system organ failure have enteric bacteremi for which no septic focus is identified, indicating that these infections may have originated from the gut. Because of the high frequency of clinically significant bacterial sepsis during fulminant hepatic failure there is also a need of prophylactic treatment.
Bacterial translocation can lead to sepsis and septise ia, which potentiate the liver failure and can lead to multiple organ
failure. The treatment of the increased bacterial infection is by using antibiotics, which has many side effects and can affect the intestinal mucosal barrier and microflora.
These findings have led to an increased interest for microbi¬ al species which can beneficially affect the microbial balance of the host, e.g. by producing antimicrobial components or by competitive growing. Lactobacillus has been among the most studied species, and have in certain instances been shown to counteract the proliferation of pathogens. Lactobacilli consti¬ tute an integral part of the normal gastrointestinal microeco-lo- gy and are involved in host metabolism. Bacteriotherapy with lactobacilli has been reported to be effective in both pseudo- membraneous and ulcerative colitis.
The amino acid arginine has a potent effect on body immune system, particularly after trauma. Furthermore arginine is a known precursor of polyamines which are considered important mediators of cell growth and differentiation. It is also known that arginine stimulates the local and systemic immune system.
Prior art
SE 9501056-7 refers to the use of certain Lactobacillus strains having an adhesin conferring adherence to a receptor in human intestinal epithelial cells for the preparation of a pharmaceutical composition triggering the immune response, and also for treatment of translocation of pathogenic or potentially pathogenic bacteria over intact intestinal epithelium. Said application especially refers to the use of Lactobacillus plan¬ tarum 299, DSM 6595, and Lactobacillus plantarum 299v, DSM 9843, as well as other Lactobacillus plantarum strains belonging to a cluster as specified.
Gianotti, Luca et al., Annals of surgery, Vol 217, No. 6, 644-654, investigate the effect of dietary arginine on bacterial translocation. An increased survival could be observed in animals fed with an arginine-supplemented diet. Quantitative colony counts and the calculated percentage of remaining viable bacteria showed that the ability to kill translocated organisms was significantly enhanced in animals receiving arginine.
Daly, John E., et al., Surgery 112:55-67, 1992 show that enteral nutrition with supplemental arginine, RNA and omega-3-
fatty acids in patients after operation improves the immune defence through different mechanisms.
Description of the invention
It has now surprisingly been found that a combination of certain strains of Lactobacillus and arginine significantly reduces the degree of liver injury and failure associated with bacterial translocation.
The invention refers to a pharmaceutical composition compri¬ sing
- a Lactobacillus plantarum strain having the ability to colonize human intestinal mucosa in vivo;
- arginine; and
- a pharmaceutically acceptable carrier.
The invention especially refers to a pharmaceutical composi¬ tion wherein the Lactobacillus strain has an adhesin conferring adherence to a receptor on human intestinal epithelial cells. The adhesion between the glycoprotein receptor and the adhesin is inhibited by the sugar α-methyl mannoside, which implies that the receptor is mannose-containing. This receptor is, however, different from the mannose-containing receptor for E. coli type 1 fimbriae, which can be shown by means of hemagglutination tests. It is believed that the receptor contains the Manαl-2Man sequence.
The invention especially refers to a pharmaceutical composi¬ tion wherein the Lactobacillus plantarum strain belongs to a cluster having a restriction endonuclease analysis similarity of more than 70 % to strain Lactobacillus plantarum 299, deposition number DSM 6595, by using the Pearson product moment correlation coefficient and the unweighed pair group algorithm with arit- methic averages (UPGMA; GelCompare 3.0, Applied Maths, Kortrijk, Belgium) .
Restriction endonuclease analysis, REA, refers to analysis of the cleavage pattern formed in electrophoresis on agar gel of the bacterial chromosomal DNA which has been decomposed with restric¬ tion enzymes according to the method described below under Genotype identification. By characterization of the strains by means of their REA-pattern the identity of the used isolates can be established.
In particular the invention refers to a composition compri¬ sing any of the strains
Lactobacillus plantarum 299 DSM 6595
Lactobacillus plantarum 299v DSM 9843
Lactobacillus plantarum 79
Lactobacillus plantarum 105
Lactobacillus plantarum 107 or other strains with more than 70 % similarity to L. plantarum 299 in terms of REA.
The preferred Lactobacillus plantarum strains are described in our copending application SE 9501056-7, which is incorporated as a reference.
Arginine in the composition preferably is L-arginine. It is however also possible to use a protein rich in arginine, such as cottonseed protein, or a protein from soybeens or peas.
The pharmaceutical composition of the invention comprises in addition to the Lactobacillus strain and arginine also a carrier which is pharmaceutically acceptable. Conventional carriers are for example physiologically acceptable substrates fermented by the bacterium in question, as well as foodstuffs of various kinds, especially based on starch or milk, but also inert solid or liquid substances, such as saline or water. A suitable sub¬ strate should contain liquid or solid fibres which are not resorbed in the gastro-intestinal tract and which when fermented with Lactobacillus form short fatty acids. As an example of suitable, starchcontaining substrates can be mentioned cereals, such as oats and wheat, corn, root vegetables such as potatoes and certain fruits such as green bananas.
The composition according to the invention can be adminis¬ tered in any suitable way, preferably orally or rectally, for example in the form of enema. It can also be administered ente- rally through a catheter inserted in the intestines via the stomach or directly in the intestines. Tests have shown that the effect is improved if dietary fibres in the form of for example oatmeal gruel or of 0-glucans are supplied. The treatment should take place once or several times daily for a period of 1 - 2 weeks.
In liver failure, for instance in connection with liver surgery and liver inflammation, the liver does not fulfill its
normal functions, but ammonia, nitrogen compounds, endotoxins and other bacterial products will pass through the liver without being metabolized and effect the whole body. One way to reduce the load on the liver during these circumstances is to give the patient an enema or to provoke a diarrhea in order to rinse the intestines. In doing this many products which are needed for the intestines to function are removed. A composition of the invention could preferably be administrated as an enema in a situation like this.
The Lactobacillus strain can preferably be used in a con¬ centration of 107-109 CFU/ml in the pharmaceutical composition. The preferred dose of arginine to a human is 25-30 g/d.
A preferred carrier for oral administration is a lactic acid fermented food product, such as a nutrient solution based on oatmeal, for instance as described in WO 89/08405, or based on milk, for instance cheese. Another preferred carrier is a diet fibre product, such as beta-glucans, pectin, oligosaccharides, which in turn can be included in the lactic acid fermented food product. In oral administration the preferred amount to be given, 1-5 times a day, is 100-200 ml.
A preferred composition for oral administration comprises the arginine component protected from being digested in the small intestine, for instance by means of preaggregation of arginine with a gelforming polysaccharide which, when swelling in the gastrointestinal tract will provide a protective gel coating up to the fermentation in the colon. This type of gel coating can be performed with pectins, guar seed powder and glucomannane from the Konjac plant, such as the commercial product Propal (Shimizu Co. , Japan) .
In rectal administration the carrier is preferably a physio¬ logical solution in which the arginine and Lactobacillus are suspended, optionally together with a diet fibre as beta-glucan or pectin. The preferred amount given, 1-2 times a day, is then 20-50 ml.
Brief description of the drawings
Figure 1 is a dendrogram showing the similarity in % between different tested strains of Lactobacillus which have been cha- - racterized by the REA-method, based on the Pearson product moment
correlation coefficient and UPGMA.
Identification of strains
The strains 299 and 299v, which were both isolated from healthy human intestinal mucosa, have been deposited at the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH on July 2, 1991 and March 16, 1995, respectively, and have been given the deposition numbers DSM 6595 (299) and DSM 9843 (299v) .
Phenotypic identification The strains 299, 299v, 79, 105 and 107 are Gram positive, catalase-negative rods growing on Rogosa agar at pH 5.5 and capable of producing lactic acid from glucose anaerobically. The ability of the strains to ferment different carbohydrates is shown in Table 1. The tests have been carried out by means of the API 50 CH in accordance with the instructions of the manufacturer.
Table 1
Fermentation patterns of strains L. plantarum 299, L. plantarum 299v, L. plantarum 107, L. plantarum 105 and . plantarum 275 on API 50CH at 30°C and 37°C.
CarJ o- L .pli 3Λt- L . plant¬ L . plant¬ L . plant¬ L . plant- hydrate arum arum arum arum arum
299 299v 107 105 79
30 °C 37 °C 30 °C 37 °C 30 °C 37°C 30°C 37 °C 30 °C 37 °C
Glycerol - - - - - - - - - -
Erythritol - - - - - - - - - -
D-arabinose — — — - - - - - —
L-arabinose + + + + + + + + ++
Ribose + + + + + + + + + +
D-xylose - - - - - - - - —
L-xylose — — — - - — —
Adonitol - - - - - - - — - -
0-methyl- - - - - - - - - - - xyloside
Galactose + + + + + + + + + +
D-glucose + + + + + + + + + +
D-fructose + + + + + + + + + +
D-mannose + + + + + + + + + + -sorbose - - - - - - - - - -
Rhamnose - - - - - - - - - -
Dulcitol - - - - - - - - - -
Inositol - - - - - - - - - -
Mannitol + + + + + + + + + +
Sorbitol + + + + + + + + + + α-methyl-D- + + + + + + + + ++ mannoside o-methyl-D- - - - - - - - - — glucoside
N-acetyl- + + + + + + + + + + glucoseamine
Amygdaline + + + + + + + + + +
Arbutin + + + + + + + + + +
Aesculin + + + + + + + + + +
Salicine + + + + + + + + + +
Cellobiose + + + + + + + + + +
Maltose + + + + + + + + + +
Lactose + + + + + + + + + +
Melibiose + + + + + + + + + +
Saccharose + + + + + + + + + +
Trehalose + + + + + + + + + +
Inulin - - - - - - - - - -
Melezitose + + + + + + + + + +
D-raffinose - - + - + - - - —
Starch - - - - - - - - - -
Glycogen - - - - - - - - - -
Xylitol - - - - - - - - - - β-gentio- + + + + + + + + + + biose
D-turanose + + + + + + + + + +
D-lyxose - - - - - - - - - -
D-tagarose - - - - - - - - - -
D-fucose - - - - - - - - - -
L-fucose - - - - - - - - - -
D-arabitol - - + - + - + - + -
L-arabitol - - - - - - - - - -
Gluconate + + + + + + + + + +
2-ceto- - - - - - - - - - - gluconate
5-ceto- - - - - - - - - - - gluconate
Phenotypically the strains can be identified as Lacto¬ bacillus plantarum.
Genotypic identification
REA
The strains have been examined as to the cleavage pattern of the chromosomal DNA, through restriction-endonuclease analysis - REA - method according to Stahl M, Molin G, Persson A, Ahrne S & Stlihl S, International Journal of Systematic Bacteriology, 40:189-193, 1990, and further developed by Johansson, M-L, et al., International Journal of Systematic Bacteriology 45:670-675, 1995. Schematically REA can be described as follows: Chromosomal DNA from the strains involved in the study were prepared and cleaved by restriction endonucleases. 0.75 μg of each DNA was separately digested at 37°C for 4 h with 10 units of Hindlll, Clal and EcoRI; each endonuclease was used separately. Stahl et al, above, used Asp718 instead of Hind III, but digestion with Asp718 resulted in too many large bands to be optimal for the present methodology. The cleaved DNA fragments are separated as to size by gel electrophoresis using submerged horizontal agarose slab gels. The gels consisted of 150 ml of 0.9 % agaroses (ultrapure DNA grade; low electro-endo osmosis; BioRad Laboratories, Richmond, USA) and were cast as slab gels (150 by 235 mm). 0.2 μg of a High Molecular Weight DNA marker (Bethesda Research Laboratories, BRL) together with 0.5 μg of a DNA molecular weight marker VI (Boehringer Mannheim, Germany) were used as standards. Additionally pHC 79 digested with EcoRI (molecular weight 4.2 x 106; Boehringer Mannheim) was added to each well as an internal standard. Minimal band distortion and maximal sharpness were achieved by applying the sample DNA in Ficoll loading buffer (2g of Ficoll, 8 ml of water, 0.25% brom- phenol) .
Gels were run at a constant voltage of 40V for 18h at 8.5°C. The buffer (89 mM Tris, 23 mM H3P04, 2 mM sodium EDTA, pH 8.3) was recirculated during the running period. Thereafter, the gels were stained for 20 minutes in ethidium bromide (2 μg/ml) and destained in distilled water, visualized at 302 nm with a UV transilluminator (UVP Inc., San Gabriel, USA) and photographed. This way of running the gel electrophoresis gave well distributed
and relatively well-separated band down to a molecular weight of 1.2 x 106.
Band patterns on photo negatives were scanned with a laser densitometer (UltroScan XL; LKB-Produkter AB, Bromma, Swe¬ den) . The resolution was 1000 points per lane, and each lane was about 50 mm long. Data were obtained by using the LKB 2400 GelScan XL software package (LKB-Produkter AB) . The band patterns were normalized and background noise was subtracted using the rolling-disc algorithm of the GelCo par 3.0 program (Applied Maths, Kortrijk, Belgium) . The data from the three cleavages (by Hindlll, Clal and EcoRI) were combined for each strain (using Gel Compar 3.0).
The data set was analyzed by using the Pearson product moment correlation coefficient (r) and the unweighed pair group algorithm with arithmetic averages (UPGMA) (Ro ersburg, H.C. 1984, Cluster analysis for research. Lifetime Learning Publica¬ tions, Belmont, California, USA) . The Pearson correlation coef¬ ficients and the UPGMA values were calculated for the complete data set and the GelCompar 3.0 program was used. In Fig. 1 the cluster having a similarity >70 % to L. plantarum 299 has been marked out.
Plasmid profiling
The strains were tested according to the method described by Chassy et al (1976) as to the contents of plasmids. Lactobacillus plantarum 299, 299v, 79 and 105 had identical plasmid profiles, i.e. five plasmids of 4, 9, 15, 21 and >30 MDa. Lactobacillus plantarum 107 had three plasmids of 4, 15 and 21 MDa.
Biological tests in rats
The aim of this experiment is to study the effect of rectal supplementation of different strains of Lactobacillus with and without arginine on the extent of liver injury and bacterial translocation in an acute liver injury model.
Five different Lactobacillus strains were used in the experiment: L. reuteri R2LC isolated from rat intestinal mucosa, L. rhamnosus DSM 6594 (strain 271) isolated from human colon, L. fermentum 8704:3 (strain 245) isolated from human jejunum, L. reuteri 108 isolated from human jejunum and L. plantarum DSM
9843 (strain 299v) isolated from human jejunum and rectum. All bacterial strains were obtained from the Laboratory of Food Hygiene, Dept. of Food Technology, Lund University, Lund, Sweden.
Male Sprague-Dawley rats with a weight range of 200-300 g were divided into 13 groups of six animals: normal, control acute liver injury (ALI) , supplemented arginine (SA) , supplemented Lactobacillus reuteri R2CL (SR) , supplemented Lactobacillus reuteri R2CL + arginine (SRA) , supplemented Lactobacillus rhamnosus 271 (SS) , supplemented Lactobacillus rha nosus 271 + arginine (SSA) , supplemented Lactobacillus plantarum 299v (SP) , supplemented Lactobacillus plantarum 299v + arginine (SPA), supplemented Lactobacillus fermentum 8704:3 (SF) , supplemented Lactobacillus fermentum 8704:3 + arginine (SFA) , supplemented Lactobacillus reuteri 108 (ST) and supplemented Lactobacillus reuteri 108 + arginine (STA) . All animals received normal rat chow (R3, Lactamin AB, Stockholm) and water ad libitum throughout the experiment and were kept at 12 hours light/dark cycle and 22°C room temperature. The different Lactobacillus strains were administered rectally once daily for 8 days with and without 2 % arginine through a rectal tube. The daily supplementation of the Lactobacillus strains was about 3xl09 CFU per animal in 3 ml. Acute liver injury was induced on the 8th day by intraperitoneal injection of D-galactoseamine (Sigma Chemical Co., St Louis, USA), 1.1 g/kg body weight, which brings about an increased leakage of bacteria from the intestinal lumen to distant organs. In the acute liver control group, normal saline was supplemented daily for 8 days and the liver injury induced on the 8th day. Samples were collected 24 and 48 hours after the evocation of the liver injury. Under ether anesthesia a laparotomy was performed through a midline incision under aseptic technique. Portal blood was collected for bacteriological tests and arterial blood was collected for bacteriological and liver enzymes tests. Samples from the caudate lobe of the liver and mesenteric lymph nodes (MLN) were obtained for bacteriological and liver histology studies.
Incidence of translocated bacteria. In the bacteriolo¬ gical analysis blood samples were immediately placed in EDTA containing sterile tubes. Tissue samples were placed in 5 ml of sterile transport medium. The samples were placed in ultrasonic
bath for 5 minutes and swirled on Chiltern (Terma-Glas, Sweden) for 2 minutes. Total aerobic plate count was made by placing 1.0 ml of the sample on brain heart infusion agar BHI (Oxoid) and incubated at 37°C for 3 days. Total anaerobic plate count was made by placing the samples on BHI and incubating under anaerobic condition at 37°C. After 3 days the number of colonies formed on each plate were counted and corrected for the weight of the original tissue. The incidence of bacterial translocation in different parts of each rat of the respective group of six rats is stated in Table 1 below.
Table 1 Incidence of bacterial translocation after 24 h
Group Portal Arterial Liver MLN blood blood
Normal 0/6 0/6 0/6 0/6
ALI 5/6 6/6 6/6 6/6
SA 5/6 3/6 6/6 4/6
SRA 1/6* 1/6** 4/6 2/6*
SR 2/6 1/6** 5/6 3/6
SSA 5/6 4/6 6/6 6/6
SS 3/6 3/6 6/6 6/6
SPA 2/6 1/6** 5/6 5/6
SP 3/6 2/6* 4/6 2/6*
SFA 1/6* 2/6* 5/6 5/6
SF 5/6 2/6* 5/6 5/6
STA 1/6* 1/6** 4/6 4/6
ST 2/6 1/6** 4/6 4/6
* denotes p < 0.05, ** denotes p < 0.01 in comparison to the acute liver control group
In the scoring of the incidence of bacterial translocation above the presence or absence of bacteria in the blood or tissue of the rat is stated; that is as a positive value
is given to a rat if at least one bacterium is found. The incidence of bacterial translocation was evaluated using Fisher's exact test. A probability level less than 0.05 was considered to be significant.
As can be seen from Table 1 the incidence of bacterial translocation to the blood increased significantly in the acute liver injury control group compared to the normal control. The incidence of bacterial translocation was, however, significantly reduced in the groups supplemented with L. plantarum 299v, L. reuteri R2LC and 108, and L. fermentum 8704:3 with and without arginine. The incidence of translocated bacteria in the liver and mesenteric lymph nodes decreased slightly in all groups compared to the acute liver injury control group.
Liver enzymes in the blood. The liver enzymes serum bilirubin (Bil) , alkaline phosphatase (ALP) , aspartate amino- transferase (ASAT) and alanine aminotransferase (ALAT) levels in arterial blood were measured after centrifugation of the blood (lOOOxg, 10 min) on a Kodak, Echa che 700 XRC, in accordance to the recommendations of the Committee on the Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physio¬ logy (Scan J Clin Lab Inves 1974; 33:291-306). The serum amino- transferases are sensitive indicators of liver cell injury and most helpful in recognizing acute hepatocellular diseases and they are the most frequently measured indicators of liver dis¬ eases. Hepatobiliary diseases lead to the elevation of serum alkaline phosphatase. In hepatocellular damage the serum bilirubin values are higher. The combination of an increased serum bilirubin, an elevated ASAT or ALAT, and an elevated alkaline phosphatase has a predictive accuracy for the presence of liver dieases.
All values are presented as mean ± SEM. The results have been statistically evaluated using all pairwise multiple comparison methods.
Table 2 Level of liver enzymes in the arterial blood
Groups ALP Bil ASAT ALAT (μKat/1) (μmol/1) (μKat/1) (μKat/1)
ALI 16.4311.41 16,1713,36 97.83115.90 86.17116.44
SA 14,8611.12 14.5712.20 59.83112.54 50.5018.89
SRA 14.5511.48 14.5014.15 60.42112.92 48.87112.04
SR 14.8310.60 15.0011.46 62.6713.76 58.8319.64
SSA 15.6011.69 15.8014.72 65.17121.13 60.50117.99
SS 16.2012.58 15.6214.20 65.57123.35 64.03113.97
SPA 12.8310.83 6.5811.56 23.0014.57* 25.3215.16
SP 13.6711.38 10.8512.40 45.18110.23 44.67110.84
SFA 14.6711.43 13.8312.98 55.50116.67 56.55117.03
SF 14.9210.84 14.8315.69 57.35113.53 57.67+13.20
STA 13.6711.33 12.0015.14 46.17111.63 41.83110.68
ST 14.1711.19 14.0011.98 59.67112.93 58.33111.57
* p < 0.05 compared to the ALI group using Neuman-Keuls all pairwise multiple comparison method
From the above table can be seen that the liver enzymes decreased in all the groups supplemented with Lactobacillus with and without arginine, and that said decrease was most significant in the group supplemented with the combination of arginine and Lactobacillus plantarum.
Liver histology. Samples from the lobe of the liver were placed in 4 % phosphate buffered formaldehyde. Paraffin-embedded samples were sliced and studied under light microscopy after staining with hematoxylin and eosin. At least three slides were studied from each specimen. Liver histological scoring was done according to Chojkier, M. et al., Gastroenterology 1985; 88:115- 21 and Shiratori, Y. et al., Hepatology 1988;8(4): 815-21 with slight modification. The degree av hepatocellular necrosis and inflammatory cell infiltration was quantitatively assessed blindly at the Department of Pathology at Lund University as
follows:
1 minimal
2 moderate
3 submassive
4 massive
The results of the test are given in Table 3 below.
Table 3 Total histoloqical score of the liver
24 hours 48 hours
Groups Total score Groups Total Score
ALI 4.810.3 ALI 5.310.5
SA 4.310.2 SA 3.310.2*
SRA 3.510.6 SPA 3.010.6*
SR 4.010.3 SP 3.710.2
SSA 4.310.2
SS 4.210.4
SPA 2.810.2*
SP 4.010.0
SFA 4.210.5
SF 4.010.5
STA 4.010.0
ST 4.310.3
* p < 0.05 compared to the ALI group using Dunn's all pairwise multiple comparison method
Twenty four hours, as well as 48 hours, after the liver injury, the liver histological score showed a significant difference in the supplemented L. plantarum + arginine group compared to the acute liver injury control group.
Summary
The incidence of infections with intestinal bacteria in patients with acute liver failure of different etiology is very high, about 30-40 %. Translocation of the bacteria to the extraintestinal sites potentiate the liver failure and can lead
to septicemia and multiple organ failure. From the above tests can be concluded that a composition of the invention comprising arginine and Lactobacillus plantarum strains seemed to be superior to the other tested strains in preventing liver injury and failure and associated bacterial translocation, as can be judged by the significant decrease in the release of liver enzymes and bilirubin, decrease in bacterial translocation as well as from the liver histology scores.
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis)
A. The indications made below relate to the microorganism referred to in the description on page 2 , 3 , 4 , 6 , 18 - line
B. IDENTIFICATTON OF DEPOSIT Further deposits are identified on an additional sheet j
Name of depositary institution
DSM - Deutsche Sammlung von Mikroorganismen von Zellkulturen GmbH
Address of depositary institution (including postal code and country)
Mascheroder Weg 1 B D-3300 BRAUNSCHWEIG Germany
Date of deposit Accession Number
2 July 1991 DSM 6595
C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indications are not for all designated States)
E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable)
The indications listed below will be submitted to the International Bureau later (specify the general nature of th indications e.g., 'Accession Number of Deposit")
For International Bureau use only
I I This sheet was received by the International Bureau on:
Authorized officer
Form PCr/RO/134 (July 1992)
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis)
A. The indications made below relate to the microorganism referred to in the description on page 2 , 4 , 6 , 18 . line
B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet |
Name of depositary institution
DSM - Deutsche Sammlung von Mikroorganismen von Zellkulturen GmbH
Address of depositary institution (including postal code and country) Mascheroder Weg 1 B D-3300 BRAUNSCHWEIZ Germany
Date of deposit Accession Number
16 March 1995 DSM 9843
C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indications are not for all designated States)
E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable)
The indications listed below will be submitted to the International Bureau later (specify the general nature of the indications eg., "Accessio Number of Deposit*)
For receiving Office use only For International Bureau use only
[ ] This sheet was received with the international application I I This sheet was received by the International Bureau on:
Authorized officer Authorized officer
Form PCT/RO/134 (July 1992)
Claims
1. A pharmaceutical composition comprising
- a Lactobacillus plantarum strain having the ability to colonize human intestinal mucosa in vivo;
- arginine; and
- a pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to claim 1, wherein the Lactobacillus plantarum strain has an adhesin conferring adherence to a receptor on human intestinal epithelial cells.
3. A pharmaceutical composition according to claim 1 or 2, wherein the Lactobacillus strain is a strain of Lactobacillus plantarum belonging to a cluster having a restriction endonuclease analysis similarity of more than 70 % to a strain Lactobacillus plantarum 299, deposition number DSM 6595, by using the Pearson product moment correlation coefficient and the unweighed pair group algorithm with aritmethic averages (UPGMA; GelCompare 3.0, Applied Maths, Kortrijk, Belgium).
4. A pharmaceutical composition according to any of claims 1-3, wherein the Lactobacillus plantarum strain is selected from the group consisting of Lactobacillus plantarum 299, DSM 6595, and Lactobacillus plantarum 299v, DSM 9843.
5. A pharmaceutical composition according to any of claims 1-4, wherein the arginine is L-arginine.
6. A pharmaceutical composition according to any of claims 1-5 for oral or rectal administration.
7. A pharmaceutical composition according to any of claims 1-6 for the treatment of acute liver injury and failure and associated bacterial translocation in mammals including man.
8. A method of curative and/or prophylactic treatment of liver injury and failure and associated bacterial translocation in mammals including man comprising administration of a therapeutically effective dose of a pharmaceutical composition according to any of claims 1-6.
9. A composition comprising a combination of a strain of Lactobacillus plantarum and arginine for use in therapy.
10. The use of a composition according to any of claims 1-6 and 9 in the manufacture of a medicament for the curative and/or prophylactic treatment of liver injury and failure and associated bacterial translocation in mammals including man.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR9608284A BR9608284A (en) | 1995-05-09 | 1996-05-08 | Pharmaceutical composition comprising lactobacillus plantarum and arginine |
| EP96914505A EP0825869B1 (en) | 1995-05-09 | 1996-05-08 | Pharmaceutical composition comprising lactobacillus plantarum and arginine |
| DE69622855T DE69622855T2 (en) | 1995-05-09 | 1996-05-08 | PHARMACEUTICAL COMPOSITIONS WHICH CONTAIN LACTOBACILLUS PLANTARUM AND ARGININE |
| JP53399796A JP4058560B2 (en) | 1995-05-09 | 1996-05-08 | Pharmaceutical composition comprising Lactobacillus plantarum and arginine |
| PL96323320A PL184603B1 (en) | 1995-05-09 | 1996-05-08 | Pharmaceutic agent containing lactobacillus plantarum and arginin |
| EE9700269A EE03597B1 (en) | 1995-05-09 | 1996-05-08 | A pharmaceutical composition comprising Lactobacillus plantarum and arginine |
| AT96914505T ATE221783T1 (en) | 1995-05-09 | 1996-05-08 | PHARMACEUTICAL COMPOSITIONS CONTAINING LACTOBACILLUS PLANTARUM AND ARGININE |
| AU57846/96A AU704886B2 (en) | 1995-05-09 | 1996-05-08 | Pharmaceutical composition comprising lactobacillus plantarum and arginine |
| DE0825869T DE825869T1 (en) | 1995-05-09 | 1996-05-08 | PHARMACEUTICAL COMPOSITIONS WHICH CONTAIN LACTOBACILLUS PLANTARUM AND ARGININE |
| NO19975136A NO317668B1 (en) | 1995-05-09 | 1997-11-07 | Pharmaceutical composition comprising Lactobacillus plantarum and arginine, and use thereof |
| GR980300028T GR980300028T1 (en) | 1995-05-09 | 1998-04-30 | Pharmaceutical composition comprising lactobacillus plantarum and arginine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9501719-0 | 1995-05-09 | ||
| SE9501719A SE9501719D0 (en) | 1995-05-09 | 1995-05-09 | Pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996035440A1 true WO1996035440A1 (en) | 1996-11-14 |
Family
ID=20398250
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1996/000603 WO1996035440A1 (en) | 1995-05-09 | 1996-05-08 | Pharmaceutical composition comprising lactobacillus plantarum and arginine |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0825869B1 (en) |
| JP (1) | JP4058560B2 (en) |
| KR (1) | KR19990008403A (en) |
| CN (1) | CN1152678C (en) |
| AT (1) | ATE221783T1 (en) |
| AU (1) | AU704886B2 (en) |
| BR (1) | BR9608284A (en) |
| CA (1) | CA2220498A1 (en) |
| DE (2) | DE825869T1 (en) |
| EE (1) | EE03597B1 (en) |
| ES (1) | ES2112818T3 (en) |
| GR (1) | GR980300028T1 (en) |
| NO (1) | NO317668B1 (en) |
| PL (1) | PL184603B1 (en) |
| SE (1) | SE9501719D0 (en) |
| WO (1) | WO1996035440A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100585391B1 (en) * | 2002-01-24 | 2006-06-01 | 주식회사 프로바이오닉 | Acid tolerant probiotic Lactobacillus plantarum Probio-38 that can suppresses the growth of pathogenic microorganisms and TGE coronavirus |
| US7217414B2 (en) | 2000-03-24 | 2007-05-15 | Nestec S.A. | Methods of preventing peritonitis by administering lactic acid bacterium |
| WO2010064777A1 (en) * | 2008-12-03 | 2010-06-10 | 씨제이 제일제당(주) | Novel lactobacillus plantarum and composition containing the same |
| WO2010064778A1 (en) * | 2008-12-03 | 2010-06-10 | 씨제이 제일제당(주) | Novel lactobacillus plantarum and composition containing the same |
| US10286026B2 (en) | 2005-09-28 | 2019-05-14 | Nordic Rebalance A/S | Probiotic fermented cereal compositions and methods for treatment of gastrointestinal diseases caused by pro-inflammatory bacteria |
| US11633486B2 (en) | 2017-04-17 | 2023-04-25 | The University Of Chicago | Polymer materials for delivery of short-chain fatty acids to the intestine for applications in human health and treatment of disease |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100376954B1 (en) * | 1995-07-31 | 2003-07-18 | 프로비 에이비 | Lactobacillus colonized in the intestine |
| SE527555C2 (en) * | 2003-04-04 | 2006-04-11 | Probi Ab | Composition for treating cardiovascular disease, diabetes, cancer, Alzheimer's disease, has tannase-producing strains of Lactobacillus plantarum or Lactobacillus species that adhere to human intestinal mucosa in combination with tannin |
| JP4947636B2 (en) | 2004-03-31 | 2012-06-06 | カルピス株式会社 | Preventive or suppressive of liver damage |
| KR100592717B1 (en) * | 2004-11-20 | 2006-06-26 | 주식회사 알엔에이 | Composition having preventive and therapeutic effects of liver damage |
| CN1322111C (en) * | 2004-12-17 | 2007-06-20 | 上海交大昂立股份有限公司 | Plant lactobacillaceae and use thereof |
| CN100337653C (en) * | 2004-12-21 | 2007-09-19 | 上海交大昂立股份有限公司 | Combination of containing Lactobobacillus plantarum |
| JP5413819B2 (en) * | 2008-02-08 | 2014-02-12 | 国立大学法人広島大学 | Liver function improving agent and its production tool, and use thereof |
| JP5823695B2 (en) * | 2008-12-03 | 2015-11-25 | 国立大学法人広島大学 | Liver dysfunction preventive |
| KR101255050B1 (en) | 2009-07-14 | 2013-04-16 | 씨제이제일제당 (주) | Novel lactobacillus plantarum and compositions comprising the same |
| KR101486999B1 (en) | 2009-07-22 | 2015-01-28 | 씨제이제일제당 주식회사 | Novel lactobacillus plantarum and compositions comprising the same |
| CN102618456B (en) * | 2012-02-28 | 2013-08-21 | 江南大学 | Lactobacillus rhamnosus capable of relieving chronic alcohol liver injury and application thereof |
| TWI463986B (en) * | 2012-08-29 | 2014-12-11 | Univ China Medical | New use of lactobacillus plantarum cmu995 strain |
| EP4444332A1 (en) * | 2021-12-09 | 2024-10-16 | Société des Produits Nestlé S.A. | Lactobacillus acidophilus to increase agmatine production by microbiota |
-
1995
- 1995-05-09 SE SE9501719A patent/SE9501719D0/en unknown
-
1996
- 1996-05-08 ES ES96914505T patent/ES2112818T3/en not_active Expired - Lifetime
- 1996-05-08 WO PCT/SE1996/000603 patent/WO1996035440A1/en active IP Right Grant
- 1996-05-08 CN CNB961953993A patent/CN1152678C/en not_active Expired - Fee Related
- 1996-05-08 KR KR1019970707930A patent/KR19990008403A/en not_active Application Discontinuation
- 1996-05-08 AT AT96914505T patent/ATE221783T1/en not_active IP Right Cessation
- 1996-05-08 AU AU57846/96A patent/AU704886B2/en not_active Ceased
- 1996-05-08 DE DE0825869T patent/DE825869T1/en active Pending
- 1996-05-08 DE DE69622855T patent/DE69622855T2/en not_active Expired - Fee Related
- 1996-05-08 JP JP53399796A patent/JP4058560B2/en not_active Expired - Fee Related
- 1996-05-08 EE EE9700269A patent/EE03597B1/en not_active IP Right Cessation
- 1996-05-08 PL PL96323320A patent/PL184603B1/en not_active IP Right Cessation
- 1996-05-08 BR BR9608284A patent/BR9608284A/en not_active IP Right Cessation
- 1996-05-08 EP EP96914505A patent/EP0825869B1/en not_active Expired - Lifetime
- 1996-05-08 CA CA002220498A patent/CA2220498A1/en not_active Abandoned
-
1997
- 1997-11-07 NO NO19975136A patent/NO317668B1/en not_active Application Discontinuation
-
1998
- 1998-04-30 GR GR980300028T patent/GR980300028T1/en unknown
Non-Patent Citations (5)
| Title |
|---|
| AACN CLINICAL ISSUES, Volume 5, No. 4, 1994, LINDA M. LORD et al., "The Role of the Gut in Critical Illness", pages 450-458. * |
| ANN. INST. PASTEUR/MICROBIOL., Volume 137A, 1986, E.N. MOYEN et al., "Modification Par L'Erythromycine et un Extrait de Lactobacillus Acidophilus de La Colonisation De L'Instestin et de La Translocation de Campylobacter Jejuni Chez La Souris Axenique", pages 199-207. * |
| ANNALS OF SURGERY, Volume 217, No. 6, 1993, LUCA GIANOTTI et al., "Arginine-Supplemented Diets Improve Survival in Gut-Derived Sepsis and Peritonitis by Modulating Bacterial Clearance", pages 644-653. * |
| DIALOG INFORMATION SERVICES, File 155, Medline, Dialog Accession No. 08912145, Medline Accession No. 94227145, DE OCA J., "Bacterial Translocation from the Nutritional Perspective la Translocation Bacteriana Desde la Perspectiva Nutricional"; & NUTR. HOSP. (SPAIN), Jan-Feb. 1994, 9(1), p2-11. * |
| DIALOG INFORMATION SERVICES, File 350, Dialog Accession No. 000531012, WPI Accession No. 66-31586/F/00, AJINOMOTO CO LTD, "Lactic Acid Bacteria Prepns. Contng. Amino Acids as Stabilisers"; & JP,B,43 008 009, 6800, (BASIC). * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7217414B2 (en) | 2000-03-24 | 2007-05-15 | Nestec S.A. | Methods of preventing peritonitis by administering lactic acid bacterium |
| US7678370B2 (en) | 2000-03-24 | 2010-03-16 | Nestec S.A. | Methods of preventing peritonitis by administering lactic acid bacterium |
| KR100585391B1 (en) * | 2002-01-24 | 2006-06-01 | 주식회사 프로바이오닉 | Acid tolerant probiotic Lactobacillus plantarum Probio-38 that can suppresses the growth of pathogenic microorganisms and TGE coronavirus |
| US10286026B2 (en) | 2005-09-28 | 2019-05-14 | Nordic Rebalance A/S | Probiotic fermented cereal compositions and methods for treatment of gastrointestinal diseases caused by pro-inflammatory bacteria |
| WO2010064777A1 (en) * | 2008-12-03 | 2010-06-10 | 씨제이 제일제당(주) | Novel lactobacillus plantarum and composition containing the same |
| WO2010064778A1 (en) * | 2008-12-03 | 2010-06-10 | 씨제이 제일제당(주) | Novel lactobacillus plantarum and composition containing the same |
| US9572845B2 (en) | 2008-12-03 | 2017-02-21 | Cj Cheiljedang Corp. | Lactobacillus plantarum and composition containing the same |
| US9962418B2 (en) | 2008-12-03 | 2018-05-08 | Cj Cheiljedang Corp. | Lactobacillus plantarum and composition containing the same |
| US11633486B2 (en) | 2017-04-17 | 2023-04-25 | The University Of Chicago | Polymer materials for delivery of short-chain fatty acids to the intestine for applications in human health and treatment of disease |
Also Published As
| Publication number | Publication date |
|---|---|
| PL323320A1 (en) | 1998-03-16 |
| NO975136L (en) | 1997-11-07 |
| GR980300028T1 (en) | 1998-04-30 |
| NO975136D0 (en) | 1997-11-07 |
| BR9608284A (en) | 1999-06-08 |
| SE9501719D0 (en) | 1995-05-09 |
| KR19990008403A (en) | 1999-01-25 |
| EE03597B1 (en) | 2002-02-15 |
| CN1190346A (en) | 1998-08-12 |
| ES2112818T1 (en) | 1998-04-16 |
| NO317668B1 (en) | 2004-11-29 |
| EE9700269A (en) | 1998-04-15 |
| EP0825869B1 (en) | 2002-08-07 |
| JPH11504936A (en) | 1999-05-11 |
| CA2220498A1 (en) | 1996-11-14 |
| ES2112818T3 (en) | 2003-02-16 |
| PL184603B1 (en) | 2002-11-29 |
| CN1152678C (en) | 2004-06-09 |
| DE69622855D1 (en) | 2002-09-12 |
| JP4058560B2 (en) | 2008-03-12 |
| ATE221783T1 (en) | 2002-08-15 |
| AU704886B2 (en) | 1999-05-06 |
| EP0825869A1 (en) | 1998-03-04 |
| DE825869T1 (en) | 1998-07-16 |
| DE69622855T2 (en) | 2003-04-10 |
| AU5784696A (en) | 1996-11-29 |
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