WO2004022727A1 - Probiotic bacterium: lactobacillus fermentum - Google Patents
Probiotic bacterium: lactobacillus fermentum Download PDFInfo
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- WO2004022727A1 WO2004022727A1 PCT/AU2003/001176 AU0301176W WO2004022727A1 WO 2004022727 A1 WO2004022727 A1 WO 2004022727A1 AU 0301176 W AU0301176 W AU 0301176W WO 2004022727 A1 WO2004022727 A1 WO 2004022727A1
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- lactobacillus fermentum
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/04—Antibacterial agents
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- 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
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
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- 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
- A61P37/08—Antiallergic agents
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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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/143—Fermentum
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Probiotic bacterium Lactobacillus fermentum
- the present invention relates to variants of the bacterium Lactobacillus fermentum, formulations of the variant and components thereof, and their use in preventing and/or treating disease in mammals and promoting mammalian health.
- microbes play an important role in the health of the host, by producing essential vitamins and nutrients required by the colonocytes, assisting with the degradation of complex nutrients, protecting the host from invasion by pathogens and stimulating the immune system.
- the microbes in the bowel contribute to mineral absorption and lipid metabolism because of the lowered pH as a result of the short chain fatty acids produced by the microbes.
- These short chain fatty acids are regulators of colon physiology and play an important role in maintaining normal bowel function.
- the upper gastrointestinal tract contains only bacteria swallowed with the saliva and food. As a result of the high acidity of gastric juices, few organisms, mostly lactobacilli, can be cultured from the normal stomach.
- the upper small intestine contains relatively sparse numbers of lactobacilli and enterococci.
- the flora of the gastrointestinal tract gradually changes until it becomes similar to that found in the colon, predominantly Bacteroides, Bifidobacteriwn, Fusobacte ⁇ um, Lactobacillus and Eubacterium.
- This normal flora of the body is a complex ecosystem, which is regulated by the diet, microbial interactions and host factors such as the motility of the gut and intestinal secretions. External factors such as stress, dietary changes and medications can affect the normal flora and alter the types of organisms present or their metabolism. Ifthe balance is disrupted it can be detrimental to the host and can cause disease.
- the balance is lost and invading pathogens are successful in penetrating the body's defences causing infections or triggering inappropriate immune responses.
- the balance between host and indigenous flora can be compromised leading to infection by normally dormant organisms, e.g. episodes of thrush Candida lbicans infection) or Chstridium difficile infection following the use of antibiotics.
- IBS irritable bowel syndrome
- a new probiotic bacterial variant of Lactobacillus fermentum having surprising advantageous features over pre-existing strains of this bacterium as well as other probiotic microorganisms has been isolated. It is particularly useful in the prevention and/or treatment of gastrointestinal disorders due to its advantageous ability to colonise the gastrointestinal tract. Further, this variant has advantageous immunomodulatory effects, which occur both locally in the gut and at mucosal sites throughout the body via the common mucosal immune system. As a result of the commonality of the mucosal system the variant can also be used in the prevention and/or treatment of other disorders of mucosal surfaces and conditions resulting from mucosal surface disturbances or disturbances in the immune system or status of a subject.
- a novel Lactobacillus fermentum variant having the following characteristics: (a) it is gram positive, facultative rod,
- the Lactobacillus fermentum variant strain is VRI 003 (accession number NM02/31074).
- the component is a cell fragment, extract, secretion or purified component.
- composition comprising a Lactobacillus fermentum variant or a component thereof according to the first aspect and a pharmaceutically acceptable carrier.
- the composition comprises strain VRI 003 or a component thereof.
- the composition comprises live cells of the Lactobacillus fermentum variant.
- the corapostion may also contain dead cells of the Lactobacillus variant.
- the composition comprises a component that is a cell fragment, extract, secretion or a purified component. Procedures for preparing such fragments, extracts, secretions or purified components are well known.
- the cells can be sonicated or the cell wall itself can be physically disrupted and/or the cell contents collected. Whole cells can be washed to extract surface components and these extracts can then be fractionated if required.
- the Lactobacillus fermentum is combined with other compounds such as prebiotics, non-digestible dietary components, dietary fibre or pharmaceutically active compounds.
- the prebiotic comprises or consists of inulin, a resistant starch, an oligosaccharide, a gum or a beta-glucan.
- the prebiotic is an unmodified high amylose maize starch or a beta-glucan.
- the composition maybe prepared as a tablet, capsule, powder, gel, paste, liquid formulation, dietary supplement or a food product and the like.
- the composition is prepared in a tablet or capsule form
- the invention provides a method for the prevention and/or treatment of a gastrointestinal disorder or a symptom thereof, comprising the step of administering a Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect, to a subject in need of such treatment.
- Lactobacillus fermentum is the variant VRI 003.
- subject and “individual” are used interchangeably in this specification and the context of the present invention include within their scope any mammal which can develop, or already has, a gastrointestinal disorder and/or disorders of mucosal surfaces and/or conditions resulting from mucosal surface disturbances or disturbances in the immune system of whatever cause.
- the preferred subjects for adm mstration of the treatment of the present invention are humans, domestic pets and farm animals.
- the gastrointestinal disorder is irritable bowel syndrome (IBS), inflammatory bowel disease, Crohn's disease and or symptoms thereof, such as for example diarrhoea, bloating, flatulence, abdominal cramping, abdominal pain, or constipation.
- IBS irritable bowel syndrome
- the gastrointestinal disorder may be caused by pathogenic organisms that ma be bacterial, viral or protozoan. However, it may also be caused merely by colonisation of the gastrointestinal tract with inappropriate organisms or by inflammatory and/or autoimmune mechanisms.
- the disturbance or disorder is the result of colonisation of the subject's gastrointestinal tract by a pathogen.
- the disturbance or disorder is the result of a high pathogen load as herein defined.
- the pathogen is a bacteria, virus or protozoa.
- the pathogen is Salmonella, E. coli, Helicobacter, Vibrio, Pseudomonas, Closttidium, bacteroides; or a virus such as Norwaiks or rotavirus, or a protozoan such as Cryptosporidium, Entamoeba, Giardia and Dientamoeba.
- a "high pathogen load” may occur when a subject has (a) been subjected to attack by a pathogen in an amount not within the normal range of their everyday exposure; (b) been subjected to attack by a virulent pathogen; (c) been subjected to attack by a pathogen at a time when the subject's resistance is lowered, for example, at a time when the immune system is depleted and/or when the subject's other natural defence mechanisms are not functioning normally.
- the subject' s resistance may be low due to, for example, stress or antibiotic treatment.
- the invention provides a method for preventing and/or treating a disorder of a mucosal surface or a symptom thereof, comprising the step of administering a Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect to a subject requiring such treatment.
- the disorder of the mucosal surface is eczema roseaca or atopic dermatitis.
- the invention provides a method of stimulating IL-12 production in a subject, comprising the step of administering an effective amount of a Lactobacillus fermentum variant or a component therof according to the first aspect, or a composition according to the second aspect, to a subject in need of such treatment.
- the invention provides a method of up-regulating IFN- ⁇ comprising the step of administering an effective amount o Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect, to a subj ect in need of such treatment.
- the invention provides a method of inducing a Th 1-ty ⁇ e response in a subject, comprising the step of administering an effective amount of a Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect, to a subject in need of such treatment.
- the invention provides a method of inhibiting the growth of a pathogen, comprising the step of administering an effective amount of a Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect, to a subject in need of such treatment.
- the invention provides a method of modulating indigenous microbes of the gastrointestinal tract, comprising the step of administering an effective amount of a Lactobacillus fermentum variant or a component thereof according to the first aspect, or a composition according to the second aspect, to a subject in need of such treatment.
- the required dosage amount will vary according to the severity of the condition to be treated, the cause of the condition, age of the subject and other standard clinical parameters which can be easily determined by routine procedures within the skill set of those skilled in the art.
- the Lactobacillus fermentum variant, or a component thereof or the composition comprising said variant may be administered by any known means but preferably it is administered orally.
- the Lactobacillus fermentum variant, or the composition comprising said variant or a component thereof may be administered in conjunction with one or more other pharmaceutically active agents.
- the variant, or the composition comprising said variant may be administered simultaneously (co-administered) with the other treatments or it may be administered sequentially in any order.
- Lactobacillus fermentum variant or a component thereof or a composition comprising it be administered daily. It can be administered several times per day, or it may be administered infrequently (for example every second or third day), depending on the progress of treatment of the condition in question, its cause and severity. These parameters can also be easily determined by those skilled in the art.
- the term “stable” includes within its scope a loss in viability of up to 25% per six months' storage at 25 C
- component as it applies to components of the L fermentum of the invention includes but is not limited to cell fragments, extracts, secretions and purified agents derived from the bacterium.
- FIGs 4 and 5 A two-dimensional analysis of the cell wall proteins extracted from L fermentum VRI 003 cells compared to the cell walls of L fermentum LMG, previously shown not to adhere to the Peyer's patches, shows that the VRI 003 upregulates two cell wall proteins and downregulates the expression of a number of other cell wall proteins, ( Figure 4) when compared to L fermentum LMG ( Figure 5).
- Figure 6 Effect of L fermentum VRI 003 stimulation on cytokine production by macrophages.
- Figure 8 Effect of oral administration of L fermentum VRI 003 on cytokine levels in the spleen following oral dosing of L fermentum VRI 003.
- Figure 9 Stability of L fermentum VRI 003 in Size I gelatin capsules combined with low water activity resistant starch and stored in foil-foil blister packs at 4C, 25C and 30C.
- Figure 10 Changes in bacteria in faecal material from IBS subject #4 during an 8- week trial. Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure IL Changes in bacteria in faecal material from IBS subject #5 during an 8- week trial. Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure 12 Changes in bacteria in faecal material from IBS subject #9 during an 8- week trial. Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure 13 Changes in bacteria in faecal material from IBS subject #2 during an 8- week trial. Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure 14 Changes in bacteria in faecal material from IBS subject #3 during an 8- week trial, Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure 15 Changes in bacteria in faecal material from IBS subject #7 during an 8- week trial Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Figure 16 Changes in bacteria in faecal material from IBS subject #6 during an 8- week trial. Microbial profiles monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as colony forming units (cfu) per mL.
- Lactobacillus fermentum variant having the following characteristics:
- the variant is Lactobacillus fermentum VRI 003.
- the present invention also provides a method for the prevention and/or treatment of a gastrointestinal disorder comprising the administration of ' a Lactobacillus fermentum variant or a component thereof, or a composition comprising the variant to a subject.
- the variant can be combined with other agents, for example, a prebiotic, a non-digestible dietary component, dietary fibre or a pharmaceutically active compound such as aspirin and statins.
- the methods and compositions of the present invention have been developed for human and veterinary applications in the treatment of gastrointestinal disorders, but as a result of the commonaHty of the mucosal system, the treatments may be applied to other disorders of mucosal surfaces and conditions resulting from mucosal surface disturbances or disturbances in the immune system or status of a subject. Whether used for treatment of humans or domestic animals, the underlying principles are the same and advantageously the treatments of the present invention maybe used irrespective of the cause of the conditions described above.
- the effective daily dosage is in the range of about 1 8 -10 12 bacteria and frequency of administration is once or twice daily.
- the amount may, for example, be below the above-mentioned range; and in other circumstances, it can be used at an amount above the range.
- the Lactobacillus fermentum variant can be formulated by known means, using conventional pharmaceutically acceptable carriers, excipients, solvents or adjuvants. Such procedures and ingredients are well known and are amply described in standard texts and manuals, for example "Remington: The Science and Practice of Pharmacy", 1 95, Mack Publishing Co. Easton, PA 18042, USA, which is incorporated herein by reference.
- Lactobacillus fermentum variant or components thereof may also be formulated into a food product by the usual well-known means.
- composition comprising the bacterium includes viable bacteria, wet bacteria, dried bacteria or components of the bacterium including but not restricted to cell fragments, extracts, secretions and purified components.
- the food or drink product of the invention contains at least one of the bacterium, a material containing the same and a processed product thereof as the effective ingredient
- a composition can be formulated to be suitable for oral administration in a variety of ways, for example in the form of a tablet, a capsule, a liquid, a dietary supplement, a paste, a gel, a food product and the like. Other formulations will be readily apparent to one skilled in the art.
- the bacterium can be used in food or drink products or can be used in combination with other food materials and food components appropriately in conventional manners.
- the composition is prepared as a dairy or dairy-based food product with or without other components that are routinely used in the production of such dairy products.
- compositions of the present invention may also include known antioxidants, buffering agents, and other agents such as coloring agents, flavorings, vitarnins or minerals.
- Thickening agents may be added to the compositions such as corn starch, guar gum, xanthum gum and the like.
- Preferred additional components of a therapeutic composition of this invention can include prebiotics such as inulin, non-digestible dietary components, dietary fibre, pharmaceutically acceptable compounds and other nutrients. Dietary or supplementary enzymes such as lactase, a ylase, glucanase, catalase, and the like enzymes can also be included.
- Preferred prebiotics include unmodified high amylose maize starch or beta-glucan,
- the bacterium is combined with a carrier which is physiologically compatible with the gastrointestinal tissue or mucosal surface of the species to which it is administered.
- Carriers can be comprised of solid-based, dry materials for formulation into tablet, capsule or powdered form; or the carrier can be comprised of liquid or gel-based materials for formulations into liquid or gel forms.
- the specific type of carrier, as well as the final formulation depends, in part, upon the selected route(s) of administration.
- Typical carriers for dry formulations include, but are not limited to: trehalose, malto-dextrin, rice flour, micro-crystalline cellulose (MCC) magnesium sterate, inositol, FOS, GOS, dextrose, sucrose, and like carriers.
- Dry formulations e.g., powders
- Suitable liquid or gel-based carriers include but are not limited to: water and physiological salt solutions; urea; alcohols and derivatives (e.g., methanol, ethanol, propanol, butanol); glycols (e.g., ethylene glycol, propylene glycol, and the like).
- water-based carriers possess a neutral pH value (i.e., pH 7.0).
- Preservatives may also be included within the carrier including methylpa aben, propylparaben, benzyl alcohol and ethylene diamine tefraacetate salt.
- the composition of the carrier can be varied so long as it does not interfere significantly with the pharmacological activity of the active ingredients.
- the methods of the present invention comprise administration of the Lactobacillus fermentum variant or components thereof a composition comprising the variant or components thereof, to a human or animal to treat and/or prevent a gastrointestinal disorder or a disorder of a mucosal surface and conditions resulting from mucosal surface disturbances or disturbances in the immune system or status of a subject and/or the symptoms associated with such disorders, for example, irritable bowel syndrome (IBS), inflammatory bowel disease and/or symptoms thereof, such as ⁇ or example diarrhoea, bloating, flatulence, abdominal cramping, abdominal pain, or constipation, and eczema or rosacea.
- IBS irritable bowel syndrome
- This treatment can result in a modulation of the indigenous microbes of the gastrointestinal tract.
- Acr ⁇ nistration is preferably carried out using a tablet, a capsule, a gel, a liquid formulation, a powder, a paste, a dietary supplement or a food product and the like formulation, all formulated to contain a therapeutic composition of the present invention by use of methods well-known within the art.
- the VRI 003 variant was isolated from a healthy subject. In a series of laboratory experiments, the VRI 003 variant was found to adhere to the gastrointestinal epithelial tissue. It was also shown to have a demonstrable effect on human gastrointestinal pathogens, and was resistant to bile acids. The VRI 003 variant also survived in a low pH environment and was resistant to pepsin and to. nutrient limited conditions.
- the bacterial variant VRI 003 can be cultured on Rogosa agar (Oxoid) Plates were incubated at 37 C in an anaerobic chamber for 24 hours. The strain was purified by successive transfers on MRS agar (Oxoid) plates incubated at 37 C in an anaerobic chamber for 24 hours and the final culture stored at -70°C in 20% glycerol by subculruring in MRS broth at 37 C for 24 hours in anaerobic conditions prior to the addition of glycerol to the culture broth.
- Variant VRI 003 was a catalase negative, Gram positive rod which produced gas when grown anaerobically on brain heart infusion (BHI) (Oxoid) broth containing glucose. It was broadly identified therefore as an heterofe ⁇ nentative lactobacillus and confirmed to be L. fermentum strain according to the API carbohydrate kit (50 CHL kit; Biomerieux; supplier data base and database with a certainty of 99.9%. In particular, sugars 5, 10, 11, 12, 13, 25, 28, 29, 30, 31, 32 and 25 are utilized by strain VRI 003.
- BHI brain heart infusion
- the cell is a short rod, Gram positive and consistent with the description of the morphology of Lactobacillus fermentum.
- Lactobacillus fermentum strain VRI 003 was deposited under the provisions of the Budapest Treaty, at the Australian Government Analytical Laboratories, PO BOX 385
- strain VRI 003 grows in the presence of 0.5% and 0.15% bile salts when acids were added to MRS broth (Oxoid) and the strain incubated anaerobically at 37 C for 8 hours.
- VRI 002 were noted with time of incubation. After 6 hours incubation, VRI 003 was able to utilize the following sugars, as defined by medium turning yellow,
- VRI 002 was able to utilise all the above at this time, except mannose.
- VRI 002 Arabinose and Mannitol.
- VRI 003 in addition to these two started utilizing extra sugars, namely, rharnnose and N-Acetyl-Glucosamine.
- VRI-003 strain After 48 hours ' incubation, VRI-003 strain had utilised all the Gluco Na Te, while the VRI-002 strain had only very slight utilisation.
- the L fermentum cells were pretreated prior to the adhesion assay with proteinase enzymes and metraperiodate to determine whether polysaccharide of proteins were involved in the adhesion. It was shown that the treatment with metaperiodate increased adhesion and therefore without being bound by theory, one can conclude that the extracellular polysaccharides were not involved in adhesion and, in fact, reduced attachment.
- the treatment of the L fermentum cells with proteinase enzymes dramatically decreased attachment, thus implicating cell wall proteins in the attachment to the Peyer's Patches.
- cell surface extracts could significantly block binding when added to the tissue prior to the addition of the whole L fermentum cells, confirming the presence of a moiety with affinity for the Peyer's Patches on the cell wall surface of the L fermentum VRI 003.
- Adhesion index expressed as a percentage of the number of adhering bacteria per mg wet weight of Peyer's patches. Adhesion to control tissues represents 100% adhesion. Data are expressed as means ⁇ standard errors means. Either the L fermentum VRI 003 or the Peyer's patches were pre-treated with the various treatments prior to being included in the adhesion assay,.
- L fermentum VRI 003 were generated and stimulated with different concentrations of L fermentum VRI 003 for 4 hours.
- L fermentum VRI 003 were either given at a high concentration (multiplicity of infection (MOI- 260; Cone. 1) or a low concentration (MOI -26, Cone.2).
- mice were orally administered with 1 x 10 9 cfti/mouse/day of L fermentum VRI 003. The mice were sacrificed at different timepoints. Spleens and Peyer's patches were excised and immune parameters measured.
- BALB/c mice were orally administered with I x 10 9 CFU/mouse/day of L fermentum VRI 003 for 5 days.
- Control mice received PBS. The mice were sacrificed on day 6. Spleens and Peyer's patches were excised and immune parameters measured.
- oral feeding of L fermentum VRI 003 for 5 days leads to significantly enhanced IFN- ⁇ and IL-12 by the Peyer's patches compared to the control group and to the other lab strain used in the experiment (Another strain of L fermentum -LF 1).
- Figure 8 shows that feeding L fermentum VRI-003 did not seem to affect cytokine levels in the spleen.
- While the capacity to colonize the human gastrointestinal tract is not a prerequisite for the active function of a probiotic strain in the digestive tract, it is a desirable characteristic. If the probiotic strain can adhere to the gastrointestinal tract epithelium, it can colonise, i.e. establish and grow within the tract, and continually produce metabolites that may mediate the beneficial effect.
- the variant VRI 003 colonises the human digestive tract when orally administered to a range of humans. (x) Antagonistic effects.
- This inhibitory effect on growth is referred to as an antagonistic effect and the antagonistic metabolites can be classified as low or high molecular weight compounds.
- Three different methods have been used to evaluate the antagonistic capacity of strain VRI 003 against a range of human pathogens, namely a direct plate co-culture assay, broth culturing in spent culture fluid from the Lactobacillus and an animal challenge model
- the direct plate method was used for screening a large number of pathogens by using a point inocula of the Lactobacillus that are overlaid with the pathogens and the size of the zone of growth inhibition of the pathogen measured after incubation.
- the VRI 003 was co- cultured with the pathogen in liquid medium and the number of viable pathogen cells enumerated after 24 hours. The size of the zone was used to quantify the extent of inhibition.
- the inhibitory activity of strain VRI 003 was also examined to determine whether low and high molecular weight metabolites of the lactobacillus mediated the growth inhibitory effects detected.
- the bacterial spent culture fluid of VRI 003 was collected and one part dialysed to retain only compounds with a molecular weight greater than 8,000.
- the growth of selected human pathogens was studied in the absence and presence of the dialysis retentates and the non-dialysed spent culture fluids. While the non-dialysed filter sterilised spent culture fluid prevented growth of the pathogens, the dialysates exhibited bacteriostatic as well as bacteriocidal effects.
- Lactobacillus fermentum variant VRI 003 is grown in a fermentation vessel at 37°C, The vessel is then cooled and the fermentation broth concentrated, preferably by centrifugation. The collected culture is dried, preferably by freeze-drying and subsequently milled. The milled material is then blended with the major excipient to give the desired level of microbes per gram of dry material. The level to be used is dependant on the application (range up to log 11 per gram). The standardised material is then used in the formulation by mixing all ingredients in a blender (preferably a V- blender).
- the viability of VRI 003 after large-scale production and freeze-drying was determined by analysing the colony forming units per gram (CFU/ g) of dried material.
- the dried powder was examined both before and after encapsulation in the gelatin capsules.
- the number of viable cells was determined for ten individual l samples of the powder. The contents often capsules were also individually analysed.
- VRI 003 maintained high levels of viability through production and encapsulation.
- powder and capsule contents showed similar adhesion characteristics to those of laboratory grown control culture.
- Example 4 Effect of administration of Lactobacillus fermentum VRI, VRI 003, with or without a prebiotic, on symptoms of irritable bowel syndrome (D3S) and gastrointestinal flora profile fi) Experimental design Participants
- the single-blinded placebo trial extended for a duration of 8 weeks, consisting of three weeks placebo treatment followed by two weeks washout (no treatment) and concluding with 3 weeks synbiotic treatment, ie, treatment with a formulation containing VRI 003 variant and a prebiotic.
- 3 weeks synbiotic treatment ie, treatment with a formulation containing VRI 003 variant and a prebiotic.
- a smaller group of patients was treated with a formulation containing VRI 003 alone,
- Typical treatment protocol was as follows (provided for the symbiotic formulation but a similar protocol was used for a formulation with VRI 003 alone).
- Placebo capsules contained microcrystalline cellulose NF XVIII (Mingtai Chemical Company Ltd, Taiwan), while probiotic capsules consisted of Lactobacillus fermentum (VRI 003) as a freeze-dried powder
- Faecal inoculum was collected from subjects with IBS whom had not taken antibiotics for three months prior to commencement of the trial. Faeces were collected into a clean plastic container and transferred into the anaerobic chamber upon arrival. One part faeces was homogenized with three parts half-strength Wilkin-Chalgrens (WC) broth (Oxoid, CM643) in a Seward stomacher bag. Enumeration of bacteria
- Table 1 Bacteria populations enumerated in fermentation.
- VRI 003 was effective even when administered alone. However, the combination of VRI 003 with high amylose maize starch elevated the levels of VRI 003 bacteria and decreased levels of certain bacteria such as Salmonella and Clostridium when compared to the probiotic alone or the beta-glucan alone. Exa ple 5: Changes in the faecal microbial profiles using material from D3S subjects during the trial
- Results have been obtained for changes in the total aerobes, enteric bacteria, total anaerobes, Gram negative anaerobes, lactobacilli, clostridia and bifidobacteria during the trial.
- Time points displayed on the graph are representative of the faecal microbal profile at the start of the trial (baseline), end of placebo treatment, end of washout period and end of synbiotic treatment.
- subjects were separated into the subgroups, diarrhoea, constipation and alternating diarrhoea and constipation predominant, according to the symptoms they normally experience with the condition. This sub grouping allows subjects to be appropriately assessed due to the wide variability in symptoms experienced by those with the condition (Akehurst and Kaltenthaler, 2001).
- One subject did not fit into either of the three subgroups and has been placed into a separate group for flatulence, bloating and crampy abdominal pain predominant.
- Diarrhoea predominant subjects were separated into the subgroups, diarrhoea
- Lactobacilli were initially detected at IxlO 7 log cfu.mL "1 and exhibited a decrease of two log at the end of the placebo and synbiotic treatment periods, which peaked again in between, during the washout period.
- Clostridia remained undetectable throughout the whole trial, while numbers of bifidobacteria, which began at 5xl0 7 log cfu.mL "1 , increased by one log during the synbiotic treatment period.
- Subject 5 (figure 11): Total aerobes, which were initially detected at 5xl0 5 log cfu.mL "1 , increased by one log during the washout and synbiotic treatment periods. Enteric bacteria remained at levels similar to those of the total aerobes (5x10 5 log cfu. L '1 ) during all time points, except at the end of the placebo treatment period, in which numbers of enteric bacteria decreased by two log, Numbers of total anaerobes and Gram negative anaerobes continued throughout the trial at a constant level of IxlO 9 log though decreased by one to one and a half log at the end of the placebo treatment period.
- Lactobacilli which began at IxlO 6 log cfu.mL'', decreased by one log at the end of the placebo treatment period but increased by three log at the end of the washout period, only to decrease again by one log at the end of the synbiotic treatment period.
- Clostridia was detected at the beginning of the trial at IxlO 3 log cfu.mL '1 and remained undetectable throughout the rest of the trial.
- Bifidobacteria which began at 5xl0 8 log cfu.mL "1 , decreased by one log at the end of the placebo and synbiotic treatment period, but increased by one log in between during the washout period.
- Subject 9 (figure 12): Total aerobes and enteric bacteria were detected at IxlO 7 log cfu.mL "1 at the baseline and proceeded to decrease slowly by one and a half log by the end of the synbiotic treatment period. Total anaerobes and gram negative anaerobes were detected at 5x10 8 log cfu.mL' 1 at the baseline, increased by one log at the end of the placebo treatment period and remained at a steady level for the rest of the study. Lactobacilli were detected at 5xl0 5 log cfu.mL *1 at the baseline, however became undetectable during the placebo treatment period.
- Lactobacilli were detected again at 5xl0 3 log cfv mL "1 at the end of the washout period and increased by one log at the end of the symbiotic treatment period.
- Clostridia were absent for the duration of the trial.
- Bifidobacteria began at 5xl0 7 log cfu- L" 1 , decreased by one a half log at the end of the placebo treatment period, however increased again to 5x10 8 log cfu.mL "1 by the end of the washout period and remained at this level till the end of the synbiotic treatment period. Constipation predominant subjects
- Subject 2 (figure 13): Total aerobes and enteric bacteria were initially detected at I lO 7 log cfu-mL "1 and remained at similar levels throughout the trial, except at the end of the placebo treatment period, where numbers of enteric bacteria increased by one log. Numbers of total anaerobes and Gram negative anaerobes remained at similar levels of IxlO 5 log cfu.mL '1 throughout the trial, with an increase of one log at the end of the placebo treatment period, which decreased by half a log by the end of the synbiotic treatment period.
- Lactobacilli which began at IxlO 3 log cfu-mL "1 , increased by one log at the end of the placebo treatment period, but became undetectable at the end of washout period and increased again by three log by the end of the synbiotic treatment period.
- Clostridia was present only at the beginning of the trial at IxlO 3 log cfu.mL" 1 and remained undetectable throughout the rest of the trial.
- Bifidobacteria were initially detected at IxlO 7 log cfu.mL "1 and decreased by one and a half log at the end of the placebo treatment period, and then became undetectable during the rest of the trial.
- Subject 3 (figure 14): Total aerobes and enteric bacteria remained at similar levels of 5x10 4 log cfu.mL "1 for the duration of the trial and increased by two log at the end of the placebo treatment period, though decreased by one log by the end of the synbiotic treatment period.
- Total anaerobes and Gram negative anaerobes began at IxlO 7 log cr raL "1 and continued a steady increase of two log by the end of the synbiotic treatment period. Lactobacilli were detected at the beginning of the trial at IxlO 4 log cfu-mL "1 , but then became undetectable at the end of the placebo treatment period.
- lactobacilli were shown to increase by four and a half log at the end of the washout period and decrease again by half a log at the end of the synbiotic treatment period.
- Clostridia were only detected at the end of the placebo treatment period at IxlO 4 log cfu.mL "1 and remained undetectable for the rest of the trial.
- Bifidobacteria which began at IxlO 7 log cfu.mL "1 was not able to be detected at the end of the placebo treatment period, though became detectable again by the end of the washout period and increased by four and a half log by the end of the synbiotic treatment period.
- Lactobacilli were not detected for most part of the study, except by the end of the synbiotic treatment period, at 5xl0 3 log cfu.mL "1 .
- clostridia was only detected at the beginning of the trial at IxlO 3 log cn nL "1 .
- Bifidobacteria were initially detected at 5xlO ⁇ log cftunL "1 , however became undetectable during the placebo treatment period, only to be detected again during the washout period at 5 ⁇ l0 7 log cfu.mL "1 and increased by half a log at the end of the synbiotic treatment period.
- Clostridia was not detected during the study, except at the end of the synbiotic treatment period at 5x10 3 log cfu.mL "1 .
- Bifidobacteria began at IxlO 7 log cfu-mL '1 and decreased by three log by the end of the placebo treatment period, only to increase again to IxlO 7 log cfu.mL "1 during the washout period and finally decreased by three log at the end of the synbiotic treatment period.
- Example 6 Changes in the severity of symptoms of IBS subjects during the trial Results have been obtained for the changes in the severity of symptoms including diarrhoea, constipation, alternating diarrhoea and constipation, flatulence, bloating and crampy abdominal pain.
- Each symptom is graded on a scale of 0 to 10, with 0 indicating absence of the symptom and 10 indicating extreme severity of the symptom. Results are displayed on a scale of 1 to 5, with 1 indicating mild severity of the symptom and 5 indicating extreme severity of the symptom. Changes in the severity of symptoms were monitored every week in all subjects, however, the results will display only time points representing the baseline (beginning of the trial), placebo treatment period, washout period and synbiotic treatment period. Subjects were again separated into subgroups, diarrhoea-, constipation- and alternating diarrhoea and constipation predominant in accordance with the symptoms they normally experience with the condition, Diarrhoea predominant subjects
- Subject 5 (table 4): The severity of diarrhoea at the baseline was extremely high and only decreased slightly to 4 by the placebo treatment period, after which it remained at high severity. Flatulence was low at the baseline, absent during the placebo treatment period, but increased again during the washout and synbiotic treatment periods by 1 and 2 respectively. The severity of crampy abdominal pain remained at the same level of 3 throughout the trial, though decreased a little by 1 during the washout period. Symptoms of flatulence and bloating remained absent throughout the duration of the trial.
- Table 4 Changes in the severity of symptoms of subject #5 during an 8 week trial. Severity of symptoms were monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as 4- (low severity) to 4- 4- 4- 4- + (extreme severity).
- Subject 9 (table 5): Diarrhoea began at mid range (3) at the baseline and continued at this severity up until the synbiotic treatment period, where it had reduced by 2 down to low severity. Constipation was absent during the trial, apart from the placebo treatment period, in which it had increased by 1. Flatulence was also absent during the trial, however increased by 3 during the washout period. Bloating, which was at medium severity (3) at the baseline, reduced by 1 during the placebo treatment period. However, this increased again by 1 during the washout period and then dropped down to low severity (1) during the probiotic treatment period. Crampy abdcmrinal pain was absent throughout the duration of the trial
- Table 5 Changes in the severity of symptoms of subject #9 during an 8 week trial. Severity of symptoms were monitored during the baseline, placebo, washout and synbiotic treatment periods, Results expressed as 4- (low severity) to 4- 4- 4- 4- 4- (extreme severity).
- Subject 2 (table 6): Diarrhoea, which was absent at the baseline and for the most part of the trial, increased by 1 during the synbiotic treatment period. Constipation, flatulence and bloating remained at high severity (5) at the baseline and during the placebo and washout periods, though decreased by 1 during the synbiotic treatment period. Crampy abdominal pain was at high severity (4) at the baseline and during the placebo treatment period, however reduced by 3 down to low severity during the washout and synbiotic treatment period.
- Subject 3 (table 7): Constipation began at low severity (2) at the baseline and continued at this level during the placebo treatment period, however became absent during the washout and synbiotic treatment periods. Flatulence began at very high severity (5) at the baseline, reduced down to 3 during the placebo treatment period and further reduced down to low severity (2) during the washout and synbiotic treatment periods. Bloating also began at very high severity at the baseline and was also able to reduce in severity during the placebo, washout and synbiotic treatment periods to 4, 3 and 3 respectively. Crampy abdominal pain began at high severity (4) at the baseline and reduced to low severity (I) during the placebo treatment period, after which it became absent for the remainder of the trial Diarrhoea was absent for the duration of the trial. Table 7 Changes in the severity of symptoms of subject #3 during an 8 week trial. Severity of symptoms were monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as + (low severity) to + + + + + (extreme severity).
- Subject 7 (table 8): Diarrhoea started at low severity (1) at the baseline but increased to 2 during the washout and synbiotic treatment periods. Constipation, which was at low severity (2) at the baseline, decreased by 1 during the placebo and washout periods, but increased to 3 during the synbiotic treatment period. Flatulence began at low severity (1) at the baseline and remained low for the most part of the trial, however it increased to 3 during the synbiotic treatment period. Bloating began at low severity (2) and decreased to 1 during the placebo treatment period, however continued to increase during the washout and synbiotic treatment periods to 3 and 4 respectively. Crampy abdominal pain was absent during the trial, except during the synbiotic treatment period, when it had increased to medium severity (3).
- Table 8 Changes in the severity of symptoms of subject #7 during an 8-week trial. Severity of symptoms were monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as + (low severity) to + + + + + (extreme severity).
- Diarrhoea was absent for most of the trial, except during the synbiotic treatment period, in which it had increased by 1 to low severity.
- Flatulence began at medium severity (3) at the baseline and reduced to low severity (1) during the placebo and washout periods, however increased up to medium severity (3) once again during the synbiotic treatment period.
- Bloating also began at medium severity (3) at the baseline and became absent during the placebo treatment period, however it had also increased again during the washout and synbiotic treatment periods to 1 and 3 respectively, Crampy abdominal pain began at low severity (2) at the baseline, was absent during the placebo treatment period but increased by 1 and 3 during the washout and synbiotic treatment periods respectively.
- Constipation remained absent for the duration of the trial
- Table 9 Changes in the severity of symptoms of subject #6 during an 8 week trial. Severity of symptoms were monitored during the baseline, placebo, washout and synbiotic treatment periods. Results expressed as + (low severity) to + + + + + (extreme severity).
- the clinical trial lasted for a total duration of 8 weeks, the first 3 weeks involved a placebo treatment consisting of maltodextrin capsules and cellulose. This was followed by a 2 week washout period in which no treatment was taken, The last 3 weeks mvolved a symbiotic treatment consisting of VRI 003 capsules and RS. Faecal samples were collected at the beginning of the trial to establish a baseline, after which further samples were taken before and after each treatment period. In addition, weekly questionnaires were also completed by each patient to monitor changes in their severity of symptoms via a scoring system graded from 0 to 10, with 0 being the absence of the symptom and 10 being the most severe. Results were then converted to a scale of 1 to 5 for convenience and shown for the baseline, placebo, washout and symbiotic treatment periods.
- Subject 4 exhibited a general decrease in the severity of all symptoms (table 3) by the end of the synbiotic treatment period, in particular diarrhoea, which started off at high severity at the baseline and then proceeded to low severity by the end of the synbiotic treatment period.
- a possible correlation with this symptom may be seen in the slow decrease of enteric bacteria (figure 10) from 1x10 s log cfu-mL" 1 at the baseline, down to 5xl0 3 log cfu.mL "1 at the end of the synbiotic treatment period.
- Subject 5 did not appear to display an overall reduction in the severity of any symptoms (table 4) during the trial. However, it may be noted that during the placebo treatment period, absence of flatulence was observed, which may be related to a two log decrease in the numbers of enteric bacteria (figure 11). The general overview of this subject would indicate that the synbiotic treatment did not appear to promote any beneficial effects on the individual, but rather the placebo treatment may have had some beneficial effect on the severity of symptoms. Numbers of lactobacilli increased by three log during the washout period, though decreased one log by the end of the synbiotic treatment period.
- the large increase in lactobacilli during the washout period may also relate to the decrease in crampy abdominal pain exhibited by the subject during this time, which then increased in severity by the end of the synbiotic treatment period, along with a minor decrease in lactobacilli during this period.
- the observation of an increase in lactobacilli associated with a decrease in crampy abdominal pain may also relate to the finding by Nobaek et al, which observed that administration of Lactobacillus plantarum decreased pain and flatulence in patients with IBS (Nobaek, et al, 2000).
- bifidobacteria and lactobacilli may also be associated with the adhiinistration of RS, which has been shown to promote the growth bifidobacteria and thereby lactobacilli (Brown, et al, 2000).
- Constipation predominant subjects Subject 2 did not appear to display an improvement in most symptoms (table 6), apart from crampy abdominal pain, which greatly decreased in severity during the washout and synbiotic treatment period.
- Results from the faecal microbial profile show that during the synbiotic treatment period, bifidobacteria were unable to be detected and a decrease (one log) in total aerobes and enteric bacteria were observed during this time.
- Subject 3 displayed an overall general improvement in the severity of symptoms (table 7), particularly constipation and crampy abdominal pain, which subsided by the end of the washout and synbiotic treatment period.
- the improvement in these symptoms may be correlated with the large increase (four log) in the number of bifidobacteria (figure 5) at the end of the synbiotic treatment period.
- the increase in bifidobacteria indicates that the administration of RS during the synbiotic treatment period has stimulated the growth of bifidobacteria.
- Administration of dietary fibre e.g. RS
- lactobacilli numbers remained low compared to the bifidobacteria during the trial, it is possible that ifthe trial extended for a longer period of time, lactobacilli may increase in numbers to a larger extent.
- Enteric bacteria also decreased (one log) by the end of the synbiotic treatment period and though only a minor decrease, it may have also contributed to the decrease in the severity of these symptoms. Alternating diarrhoea and constipation predominant subject
- Subject 7 displays improvement in all symptoms (table 6) during the placebo treatment period, whilst exhibiting an increase in the severity of symptoms during the synbiotic treatment period.
- a gradual increase in the numbers of enteric bacteria (figure 15) were observed during the trial, which suggests that an increase in enteric bacteria may be related to an increase in symptoms such as bloating and diarrhoea.
- An important note to be considered however, is that administration of prebiotics, such as RS, are likely to increase symptoms of bloating and flatulence, even in healthy subjects (Cummings et al., 2001; Munster et al., 1994), so an increase in these symptoms experienced by an IBS subject is not unlikely.
- Bifidobacteria were also observed to increase in numbers during the washout period, while not being able to detected during the placebo treatment period, implying that an increase in bifidobacteria may perhaps be related to an increase in severity of these symptoms. Bifidobacteria were also observed to be detected in very high numbers on RB media and it has been noted that other species of bacteria apart from bifidobacteria may be detected on these plates, such as lactobacilli species (Hartemirik et ⁇ /.,T996). Thus biochemical tests may have to be performed on the colonies growing on RB media to confirm that they were all bifidobacteria species. Although symptoms appeared to increase m severity during the synbiotic treatment period, comments from the weekly questionnaire indicate that experience of these symptoms were normal in relation to the baseline.
- bifidobacteria An increase in bifidobacteria may be observed to be related to a decrease in constipation and crampy abdominal pain (subject #3), however increases in bifidobacteria may also be associated with an increase in flatulence and crampy abdominal pain (subject #7). Perhaps different species of bifidobacteria may be involved in increases or decreases in symptom severity, or it may be that different patients are affected by colonization of different gut microorganisms which affect the levels of bifidobacteria in the gastrointestinal tract.
- Each capsule contained 3xl0 10 VRI-003/ capsule, Symptoms Assessment: Taking 1 capsule of . fermentum VRI-003 in the morning and in the evemng resulted to regular bowel movement. Faeces became firmer and consistent and there was reduction in the intensity of bloating. However, L. fermentum VRI-003 did not n ⁇ mize the severity of the symptoms when sugar rich food was taken in the diet nor did it worsen the symptoms. Example 11. Benefits of L fermentum VRI 003 for Rosacea symptoms
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EP03793503A EP1539927B1 (en) | 2002-09-06 | 2003-09-08 | Probiotic bacterium: lactobacillus fermentum |
JP2004533080A JP4455333B2 (en) | 2002-09-06 | 2003-09-08 | Probiotic bacteria: Lactobacillus fermentum |
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AU2003258366A AU2003258366B2 (en) | 2002-09-06 | 2003-09-08 | Probiotic bacterium: lactobacillus fermentum |
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DK03793503T DK1539927T3 (en) | 2002-09-06 | 2003-09-08 | Probiotic Bacteria: Lactobacillus fermentum |
CA2497989A CA2497989C (en) | 2002-09-06 | 2003-09-08 | Probiotic bacterium: lactobacillus fermentum |
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Also Published As
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DK1539927T3 (en) | 2009-07-13 |
US20100074878A1 (en) | 2010-03-25 |
AU2003258366B2 (en) | 2007-01-25 |
JP2005537791A (en) | 2005-12-15 |
CN1701116A (en) | 2005-11-23 |
CN100378214C (en) | 2008-04-02 |
BR0314060A (en) | 2005-07-19 |
DE60326738D1 (en) | 2009-04-30 |
JP4455333B2 (en) | 2010-04-21 |
EP1539927B1 (en) | 2009-03-18 |
CA2497989A1 (en) | 2004-03-18 |
NZ538640A (en) | 2007-05-31 |
BRPI0314060B1 (en) | 2016-05-10 |
ATE426014T1 (en) | 2009-04-15 |
CA2497989C (en) | 2013-08-27 |
EP1539927A4 (en) | 2005-09-21 |
ES2324532T3 (en) | 2009-08-10 |
EP1539927A1 (en) | 2005-06-15 |
KR20050057259A (en) | 2005-06-16 |
US20060067921A1 (en) | 2006-03-30 |
AU2003258366A1 (en) | 2004-03-29 |
AU2002951270A0 (en) | 2002-09-19 |
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