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WO2019115576A1 - Méthodes de traitement de l'insuffisance cardiaque - Google Patents

Méthodes de traitement de l'insuffisance cardiaque Download PDF

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Publication number
WO2019115576A1
WO2019115576A1 PCT/EP2018/084457 EP2018084457W WO2019115576A1 WO 2019115576 A1 WO2019115576 A1 WO 2019115576A1 EP 2018084457 W EP2018084457 W EP 2018084457W WO 2019115576 A1 WO2019115576 A1 WO 2019115576A1
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Prior art keywords
lactobacillus reuteri
subject
heart failure
strain
food
Prior art date
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Ceased
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PCT/EP2018/084457
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English (en)
Inventor
Christophe HEYMES
Rémy BURCELIN
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Toulouse
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Toulouse III Paul Sabatier
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Publication of WO2019115576A1 publication Critical patent/WO2019115576A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods of treating heart failure.
  • HF heart failure
  • existing therapies such as renin angiotensin aldosterone system (RAAS) inhibition, b- blockade, and angiotensin receptor-neprilysin inhibitors reduce hospitalization and mortality risk in patients with HF.
  • RAAS renin angiotensin aldosterone system
  • b- blockade renin angiotensin aldosterone system
  • angiotensin receptor-neprilysin inhibitors reduce hospitalization and mortality risk in patients with HF.
  • RAAS renin angiotensin aldosterone system
  • HF heart failure
  • 16S ribosomal RNA gene sequencing of fecal samples from HF patients to determine that gut microbial dysbiosis is associated with HF (Kamo T, Akazawa H, Suda W, et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PFoS One. 20l7;l2:e0l74099).
  • this result is suggestive of the potential impact that the gut microbiota may have on the pathophysiological processes involved in HF.
  • a wide variety of metabolites derived from gut microbes may also influence HF.
  • the present invention relates to methods of treating heart failure.
  • the present invention is defined by the claims.
  • the first object of the present invention relates to a method of treating heart failure in a subject in need thereof comprising administering to the subject an effective amount of Lactobacillus reuteri.
  • the terms "subject,” and “patient,” used interchangeably herein, refer to a mammal, particularly a human who has been previously diagnosed with heart failure or who is at risk for having or developing heart failure. Typically, the subject suffers from a cardiovascular disease leading to heart failure. In some embodiments, the subject has experienced a myocardial infarction, in particular an acute myocardial infarction.
  • heart failure As used herein, the term "heart failure” or“HF has its general meaning in the art and embraces congestive heart failure and/or chronic heart failure. Functional classification of heart failure is generally done by the New York Heart Association Functional Classification (Criteria Committee, New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis, 6th ed. Boston: Little, Brown and co, 1964; 114). This classification stages the severity of heart failure into 4 classes (I -IV).
  • Class I no limitation is experienced in any activities; there are no symptoms from ordinary activities; Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion;Class III: marked limitation of any activity; the patient is comfortable only at rest; Class IV : any physical activity brings on discomfort and symptoms occur at rest.
  • the method of the invention may reduce death or hospitalization in subjects by treating the heart failure. Moreover, the method of the invention will achieve improved cardiac condition of post- myocardial infarction (MI) subjects.
  • the method of the invention is suitable for reducing the risk or progression of heart failure, increasing the left ventricle ejection fraction (LVEF), inhibiting left ventricle enlargement, reducing left ventricle end systolic volume, reducing left ventricle end diastolic volume, ameliorating left ventricle dysfunction, improving myocardial contractibility.
  • LVEF left ventricle ejection fraction
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the term“ Lacotbacillus reuteri” or“L. reuteri” has its general meaning in the art and refers to a Gram-positive bacterium that naturally inhabits the gut of mammals and that belongs to the Lactobacillus genus. Any strain of L. reuteri may be used according to the invention.
  • the L. reuteri is Lactobacillus reuteri DSM 17938, the L. reuteri strain owned by Biogaia AB, Sweden, having the scientific strain designation DSM 17938, formerly L reuteri ATCC 55730.
  • the DSM identification refers to the DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH Inhoffenstr.
  • L. reuteri suitable for use according to the invention L. reuteri are ATCC PTA 6475, L. reuteri ATCC PTA 4659 and L. reuteri ATCC PTA 5289 (available from Biogaia, Sweden), L. reuteri RC-14 (sold by Christian Hansen, France), L. reuteri NCIMB 30242 (sold as supplement called Cardioviva , by Micropharma Ltd., Canada) and L.
  • the L. reuteri is the Lactobacillus reuteri strain 93a that has been deposited under the Budapest Treaty at DSMZ (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, D-38124 Braunschweig, Germany) on December 11, 2015, and has been given the accession number DSM 32229.
  • the L. reuteri is the Lactobacillus reuteri strain 93a that has been deposited under the Budapest Treaty at DSMZ (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, D-38124 Braunschweig, Germany) on December 11, 2015, and has been given the accession number DSM 32229.
  • the Lactobacillus reuteri is the Lactobacillus reuteri strain F33 that has been deposited under the Budapest Treaty at DSMZ (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, D-38124 Braunschweig, Germany) on December 11, 2015, and has been given the accession number DSM 32232.
  • the L. reuteri is the Lactobacillus reuteri strain C30 has been deposited under the Budapest Treaty at DSMZ (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr.
  • the L. reuteri is the Lactobacillus reuteri strain D276 that has been deposited under the Budapest Treaty at DSMZ (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, D-38124 Braunschweig, Germany) on December 11, 2015, and has been given the accession number DSM 32231.
  • the Lactobacillus reuteri is a probiotic strain.
  • probiotic is meant to designate live microorganisms which, they are integrated in a sufficient amount, exert a positive effect on health, comfort and wellness beyond traditional nutritional effects.
  • Probiotic microorganisms have been defined as“Live microorganisms which when administered in adequate amounts confer a health benefit on the host” (FAO/WHO 2001).
  • probiotic Lactobacillus reuteri strain denotes a Lactobacillus reuteri strain that has a beneficial effect on the health and well-being of the host.
  • the probiotic Lactobacillus reuteri is a viable probiotic Lactobacillus reuteri strain.
  • the expression“viable probiotic Lactobacillus reuteri strain” means a microorganism which is metabolically active and that is able to colonize the gastro- intestinal tract of the subject.
  • the probiotic Lactobacillus reuteri strain of the present invention is a non-viable probiotic Lactobacillus reuteri strain consisting of a mixture of bacterial fragments.
  • the mixture of bacterial fragments of the present invention consists of proteins from the Lactobacillus reuteri strain.
  • the probiotic Lactobacillus reuteri strain of the present invention is selected from food grade bacteria.
  • Food grade bacteria means bacteria that are used and generally regarded as safe for use in food.
  • the Lactobacillus reuteri strain of the present invention is produced with any appropriate culture medium well known in the art.
  • Various fermentation media are suitable according to the invention, such as (but not limited to) e.g. firstly an industrial medium, in which the strain(s) is/are grown, and that is used as is or after concentration (e.g. drying) or after addition to another food base or product.
  • bacterial cells, or bacterial cells with medium e.g. the fermentation broth
  • fractions of such cell comprising medium i.e. medium with said bacterial strain/s
  • the cells or the cell comprising medium comprise live or viable bacterial cells and/or dead or non-viable bacterial cells of the strain(s).
  • the medium may thus be treated by, but not limited to, heating or sonication.
  • lyophilized, or frozen, bacteria and/or cell-free media (which may be concentrated) are encompassed in the methods for preparing the Lactobacillus reuteri strain of the present invention.
  • the Lactobacillus reuteri strain of the present invention is encapsulated in order to be protected against the stomach.
  • the Lactobacillus reuteri strain of the present invention is formulated in compositions in an encapsulated form so as significantly to improve their survival time. In such a case, the presence of a capsule may in particular delay or prevent the degradation of the microorganism in the gastrointestinal tract.
  • compositions of the present embodiments can be encapsulated into an enterically-coated, time-released capsule or tablet.
  • the enteric coating allows the capsule/tablet to remain intact (i.e., undissolved) as it passes through the gastrointestinal tract, until such time as it reaches the intestine.
  • Methods of encapsulating live bacterial cells are well known in the art (see, e.g., U.S. patents to General Mills Inc. such as U.S. Pat. No. 6,723,358).
  • micro-encapsulation with alginate and Hi-MaizeTM starch followed by freeze-drying has been proved successful in prolonging shelf-life of bacterial cells in dairy products [see, e.g., Kailasapathy et al. Curr Issues Intest Microbiol. 2002 September; 3(2):39-48]
  • encapsulation can be done with glucomannane fibers such as those extracted from Amorphophallus konjac.
  • entrapment of viable probiotic in sesame oil emulsions may also be used [see, e.g., Hou et al. J. Dairy Sci.
  • agents for enteric coatings are preferably methacrylic acid- alkyl acrylate copolymers, such as Eudragit® polymers.
  • Poly(meth)acrylates have proven particularly suitable as coating materials.
  • EUDRAGIT® is the trade name for copolymers derived from esters of acrylic and methacrylic acid, whose properties are determined by functional groups. The individual EUDRAGIT® grades differ in their proportion of neutral, alkaline or acid groups and thus in terms of physicochemical properties. The skillful use and combination of different EUDRAGIT® polymers offers ideal solutions for controlled drug release in various pharmaceutical and technical applications. EUDRAGIT® provides functional films for sustained-release tablet and pellet coatings.
  • EUDRAGIT® polymers can provide the following possibilities for controlled drug release: gastrointestinal tract targeting (gastroresistance, release in the colon), protective coatings (taste and odor masking, protection against moisture) and delayed drug release (sustained-release formulations).
  • EUDRAGIT® polymers are available in a wide range of different concentrations and physical forms, including aqueous solutions, aqueous dispersion, organic solutions, and solid substances.
  • the pharmaceutical properties of EUDRAGIT® polymers are determined by the chemical properties of their functional groups.
  • EUDRAGIT® L Metal acid copolymer
  • S Metal acid copolymer
  • FS and E basic butylated methacrylate copolymer
  • EUDRAGIT® RL and RS ammonio methacrylate copolymers
  • Enteric EUDRAGIT® coatings provide protection against drug release in the stomach and enable controlled release in the intestine.
  • the dominant criterion for release is the pH-dependent dissolution of the coating, which takes place in a certain section of the intestine (pH 5 to over 7) rather than in the stomach (pH 1-5).
  • anionic EUDRAGIT® grades containing carboxyl groups can be mixed with each other. This makes it possible to finely adjust the dissolution pH, and thus to define the drug release site in the intestine.
  • EUDRAGIT® L and S grades are suitable for enteric coatings.
  • EUDRAGIT® FS 30 D (aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid) is specifically used for controlled release in the colon.
  • the Lactobacillus reuteri strain of the present invention is administered to the subject in the form of a food composition.
  • the food composition is selected from complete food compositions, food supplements, nutraceutical compositions, and the like.
  • the composition of the present invention may be used as a food ingredient and/or feed ingredient.
  • the food ingredient may be in the form of a solution or as a solid— depending on the use and/or the mode of application and/or the mode of administration.
  • the term“food” refers to liquid (i.e. drink), solid or semi-solid dietetic compositions, especially total food compositions (food-replacement), which do not require additional nutrient intake or food supplement compositions.
  • Food supplement compositions do not completely replace nutrient intake by other means.
  • Food and food supplement compositions are for example fermented dairy products or dairy-based products, which are preferably administered or ingested orally one or more times daily. Fermented dairy products can be made directly using the bacteria according to the invention in the production process, e.g. by addition to the food base, using methods known per se.
  • the strain(s) of the invention may be used in addition to the micro-organism usually used, and/or may replace one or more or part of the micro-organism usually used.
  • a bacterium of the invention may be added to or used as part of a starter culture or may be suitably added during such a fermentation.
  • the bacteria may be inactivated or killed later in the production process.
  • Fermented dairy products include milk-based products, such as (but not limited to) deserts, yoghurt, yoghurt drinks, quark, kefir, fermented milk-based drinks, buttermilk, cheeses, dressings, low fat spreads, fresh cheese, soy-based drinks, ice cream, etc.
  • food and/or food supplement compositions may be non-dairy or dairy non fermented products (e.g. strains or cell-free medium in non-fermented milk or in another food medium).
  • the Lactobacillus reuteri strain of the present invention is encapsulated and dispersed in a food (e.g. in milk) or non-food medium.
  • Non-fermented dairy products may include ice cream, nutritional bars and dressings, and the like.
  • Non-dairy products may include powdered beverages and nutritional bars, and the like.
  • the products may be made using known methods, such as adding an effective amount of the strain(s) and/or cell-free culture medium to a food base, such as skimmed milk or milk or a milk-based composition and fermentation as known.
  • Other food bases to which the (compositions comprising the) bacterial cells and/or cell-free culture medium may be added are meat, meat replacers or plant bases.
  • the composition that comprises the Lactobacillus reuteri strain of the present invention may be solid, semi-solid or liquid. It may be in the form of a food product or food supplement, e.g. in the form of tablets, gels, powders, capsules, drinks, bars, etc.
  • the composition may be in the form of a powder packed in a sachet which can be dissolved in water, fruit juice, milk or another beverage.
  • “food ingredient” or“feed ingredient” includes a formulation which is or can be added to functional foods or foodstuffs as a nutritional supplement.
  • nutritional food or“nutraceutical” or“functional” food
  • a foodstuff which contains ingredients having beneficial effects for health or capable of improving physiological functions.
  • “food supplement” is meant a foodstuff having the purpose of completing normal food diet.
  • a food supplement is a concentrated source of nutrients or other substances having a nutritional or physiological effect, when they are taken alone or as a combination in small amounts.
  • “functional food” summarizes foodstuff and corresponding products lately developed to which importance is attributed not only due to them being valuable as to nutrition and taste but due to particular ingredient substances.
  • the middle- or long-term maintenance and promotion of health are of importance.
  • non-therapeutic uses are preferred.
  • the terms“nutriceuticals”,“foodsceuticals” and“designer foods”, which also represent embodiments of the invention, are used as synonyms, partly, however, also in a differentiated way.
  • the preventive aspect and the promotion of health as well as the food character of the products are, however, best made clear by the term functional food. In many cases, these relate to products accumulated by assortment and selection (as is also the case in the present invention), purification, concentration, increasingly also by addition. Isolated effective substances, in particular in form of tablets or pills, are not included.
  • functional foods are ordinary foods that have components or ingredients (such as those described herein) incorporated into them that impart to the food a specific functional e.g. medical or physiological benefit other than a purely nutritional effect.
  • the drink is a functional drink or a therapeutic drink, a thirst- quencher or an ordinary drink.
  • the composition of the present invention can be used as an ingredient to soft drinks, a fruit juice or a beverage comprising whey protein, health teas, cocoa drinks, milk drinks and lactic acid bacteria drinks, yoghurt and drinking yoghurt, cheese, ice cream, water ices and desserts, confectionery, biscuits cakes and cake mixes, snack foods, balanced foods and drinks, fruit fillings, care glaze, chocolate bakery filling, cheese cake flavoured filling, fruit flavoured cake filling, cake and doughnut icing, instant bakery filling creams, fillings for cookies, ready-to-use bakery filling, reduced calorie filling, adult nutritional beverage, acidified soy/juice beverage, aseptic/retorted chocolate drink, bar mixes, beverage powders, calcium fortified soy/plain and chocolate milk, calcium fortified coffee beverage.
  • the composition that comprises the Lactobacillus reuteri strain of the present invention is used with yoghurt production, such as fermented yoghurt drink, yoghurt, drinking yoghurt, cheese, fermented cream, milk based desserts and others.
  • yoghurt production such as fermented yoghurt drink, yoghurt, drinking yoghurt, cheese, fermented cream, milk based desserts and others.
  • the composition can be further used as an ingredient in one or more of cheese applications, meat applications, or applications comprising protective cultures.
  • the food composition that comprises the Lactobacillus reuteri strain of the present invention typically comprises carriers or vehicles.
  • “Carriers” or“vehicles” mean materials suitable for administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • Examples of nutritionally acceptable carriers include, for example, water, salt solutions, alcohol, silicone, waxes, petroleum jelly, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • the food composition that comprises the Lactobacillus reuteri strain of the present invention comprises an amount of dietary fibres.
  • Dietary fibre passes through the small intestine undigested by enzymes and functions as a natural bulking agent and laxative. Dietary fibre may be soluble or insoluble and in general a blend of the two types is preferred. Suitable sources of dietary fibre include soy, pea, oat, pectin, guar gum, gum Arabic, ffuctooligosaccharides, galacto-oligosaccharides, sialyl-lactose and oligosaccharides derived from animal milks. In some embodiments, the dietary fiber is selected among mannans.
  • Mannans such as glucomannans and galactomannans
  • guar gum such as glucomannans and galactomannans
  • the glucomannans are generally comprised of ( 1 -4)-b-1 inked glucose and mannose units
  • the galactomannans are generally comprised of a (l-4)-P-mannan backbone substituted with single units of (l-6)-a- galactose.
  • Many endospermic legumes, such as guar and locust bean contain galactomannans in the endosperm during seed development.
  • Glucomannans have also been found as a minor component of cereal grains.
  • the composition that comprises the Lactobacillus reuteri strain of the present invention contains emulsifiers.
  • emulsifiers typically include diacetyl tartaric acid esters of mono- and di-glycerides, lecithin and mono- and di- glycerides. Similarly suitable salts and stabilisers may be included.
  • the food composition that comprises the Lactobacillus reuteri strain of the present invention contains at least one prebiotic.
  • prebiotic means food substances intended to promote the growth of the Lactobacillus reuteri strain of the present invention in the intestines.
  • the prebiotic may be selected from the group consisting of oligosaccharides and optionally contains fructose, galactose, mannose, soy and/or inulin; and/or dietary fibers.
  • the composition that comprises the Lactobacillus reuteri strain of the present invention contains protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents, gel forming agents, antioxidants and antimicrobials.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents
  • encapsulating agents/materials, wall/shell materials such as binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents
  • composition may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like. In all cases, such further components will be selected having regard to their suitability for the intended recipient.
  • conventional pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatine of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fill
  • the administration of the Lactobacillus reuteri strain is repeated, for example, 2 to 3 times a day, for one day or more and generally for a sustained period of at least 4 days, or even 4 to 15 weeks, with, where appropriate, one or more periods of interruption.
  • the Lactobacillus reuteri strain is administered simultaneously or sequentially one meal of the subject.
  • the term "effective amount" refers to a quantity sufficient of the Lactobacillus reuteri strain to achieve the beneficial effect (e.g. treating heart failure).
  • the amount of the Lactobacillus reuteri strain administered to the subject will depend on the characteristics of the individual, such as general health, age, sex, body weight... The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • the Lactobacillus reuteri strain shall be able to generate a colony is sufficient to generate a beneficial effect on the subject.
  • the Lactobacillus reuteri strain is administered in the form of a food product, it typically may comprise between 10 3 and 10 12 cfu of the Lactobacillus reuteri strain of the present invention per g of the dry weight of the food composition.
  • L. reuteri produces some particular metabolites that are suitable for the treatment of heart failure.
  • AHR aryl hydrocarbon receptor
  • a further object of the present invention relates to a method of treating heart failure in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one ligand of aryl hydrocarbon receptor (AHR).
  • AHR aryl hydrocarbon receptor
  • the“ayrl hydrocarbon receptor” or“AHR” has its general meaning in the art and is a ligand activated transcription factor of the basic region helix-loop-helix- PER/ARNT/SIM homology family. Accordingly, the term“ligand of AHR” refers to any compound natural or not that is capable to binding AHR and promotes activation of the signaling pathway of AHR.
  • the prototypic signaling pathway of AHR-mediated transcriptional activity is characterized by transcription of a battery of drug-metabolizing enzymes, which includes cytochrome P450 enzymes 1A1, 1A2, and 1B1.
  • the ligand is selected from the group consisting of 2, 3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD), lndole-3-carbinol (I3C), lndole-3 -acetonitrile (I3ACN), 3,3-Diindolylmethane (DIM), 2-(Indol-3-ylmethyl)-3,3’-diindolylmethane (Ltr-l), Indolo[3,2- bjcarbazole (ICZ), 2-(l ' H-indole-3 ' -carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), Indole, lndole-3 -acetic acid (IAA), lndole-3 -aldehyde (IAld), Tryptamine, 3-Methyl- indole (skatole), lndoxyl-3 -sulfate (I
  • the ligand of AHR is administered to the subject in a food composition as described above.
  • the ligand of AHR is administered to the subject in a form of a pharmaceutical composition.
  • the ligand of AHR may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • pharmaceutically acceptable excipients such as biodegradable polymers
  • sustained-release matrices such as biodegradable polymers
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the ligand of AHR can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 demonstrated that heart failure is associated with a decreased fecal expression of L. reuteri in mice following 3 days of myocardial infarction, as compared to sham-operated mice. *: P ⁇ 0.05 versus Sham.
  • Figure 2 demonstrated that L. reuteri treatment ameliorates mice survival following myocardial infarction. *: P ⁇ 0.05 versus MI.
  • Figure 3 shows the left ventricular ejection fraction (EF %) ( Figure 3 A) and cardiac volumes of mice which underwent a thoracotomy but no coronary ligation (Sham) ( Figure 3B), mice which underwent a thoracotomy with coronary ligation (MI d+28), mice which underwent a thoracotomy with coronary ligation and were treated with L. reuteri 7 days before and during 28 days after the surgery (MI d+28 + L-Reu d-7), as disclosed in the example below a: P ⁇ 0.05 versus Sham; b: P ⁇ 0.05 versus MI d+28.
  • Figure 4 shows the left ventricular ejection fraction (EF %) of mice which underwent a thoracotomy but no coronary ligation (Sham), mice which underwent a thoracotomy with coronary ligation (MI d+28), mice which underwent a thoracotomy with coronary ligation and were treated with Indole 7 days before and during 28 days after the surgery (MI d+28 + Indole d-7), as disclosed in the example below a: P ⁇ 0.05 versus Sham; b: P ⁇ 0.05 versus MI d+28.
  • Figure 5 shows the left ventricular ejection fraction (EF %) of mice which underwent a thoracotomy but no coronary ligation (Sham), mice which underwent a thoracotomy with coronary ligation (MI d+28), mice which underwent a thoracotomy with coronary ligation and were treated with FICZ 7 days before and during 28 days after the surgery (MI d+28 + FICZ d- 7), as disclosed in the example below a: P ⁇ 0.05 versus Sham; b: P ⁇ 0.05 versus MI d+28.
  • EXAMPLE EXAMPLE:
  • mice Five groups of mice were formed.
  • mice The first control group of mice (Sham) underwent a thoracotomy but no coronary ligation.
  • mice The second group of mice (MI d+28) underwent a thoracotomy with coronary ligation.
  • mice (MI d+28 + L-Reu d-7) underwent a thoracotomy with coronary ligation and was treated with Lactobacillus reuteri 7 days before and during 28 days after the surgery.
  • mice (MI d+28 + Indole d-7) underwent a thoracotomy with coronary ligation and was treated with Indole 7 days before and during 28 days after the surgery.
  • mice (MI d+28 + FICZ d-7) underwent a thoracotomy with coronary ligation and was treated with FICZ (5,1 l-Dihydroindolo[3,2-£>]carbazole-6-carboxaldehyde), a specific agonist of Ahr receptor, 7 days before and during 28 days after the surgery.
  • the treatment with L. reuteri was administered daily by gavage (3.9 10 9 cfu /mice /day, ATCC).
  • the treatment with Indole was administered daily by gavage (400 pg/ 20 g BW / day, Sigma).
  • the treatment with FICZ was administered every 2 days by intraperitoneal injection (IP, 2.5 pg/ mice, Tocris).
  • Lactobacillus reuteri primers were used as follows: Forward: 5'-ACCGAGAACACCGCGTTATTT-3' (SEQ ID NO: l), Reverse: 5'-
  • MI Myocardial infarction
  • mice were anesthetized by an intraperitoneal (i.p.) injection of a cocktail of ketamine (100 mg/kg) and xylazine (10 mg/kg), intubated, and connected to a mouse ventilator (MiniVent, Harvard Apparatus, Holliston, MA). Permanent ligation of the left anterior descending artery was blocked using a segment of saline 9-0 prolene. The sham group (without ligation of the left anterior descending artery) was set up as the control group. All surgical procedures were performed under sterile conditions. Successful cardiac infarction was confirmed by apparent S-T segment elevation. 4 weeks post- surgery, echocardiography; subsequently, cardiac tissues from different regions were harvested for further analysis.
  • Non-invasive ultrasound examination of the cardiovascular system was performed using a General Electric instrument equipped with a linear 8-l4-MHz transducer. The surgeon and echocardiographer were blinded to animal genotype.
  • Figure 1 demonstrated that heart failure is associated with a decreased fecal expression of L. reuteri in mice following 3 days of myocardial infarction, as compared to sham-operated mice.
  • Figure 2 demonstrated that L. reuteri treatment ameliorates mice survival following myocardial infarction.
  • Figure 3 A and B demonstrated that L. reuteri treatment prevented the decrease of both cardiac function, (estimated by the % of ejection fraction) and cardiac remodeling (estimated by the left ventricular end-diastolic and end-systolic volumes) following 28 days of MI.
  • Figure 4 demonstrated that Indole (first metabolite of tryptophan produced by
  • L. reuteri L. reuteri treatment prevented the decrease of cardiac function, (estimated by the % of ejection fraction) following 28 days of MI.
  • Figure 5 demonstrated that FICZ treatment prevented the decrease of cardiac function, (estimated by the % of ejection fraction) following 28 days of MI.

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Abstract

Dans le monde entier, 1 % à 2 % de la population adulte générale ont une insuffisance cardiaque (HF), qui est accompagnée d'une qualité de vie réduite, d'une morbidité et d'une mortalité élevées et de coûts financiers significatifs. Récemment, le rôle potentiel de l'intestin dans la pathophysiologie de l'insuffisance cardiaque (HF) a récemment commencé à attirer une attention accrue. Dans ce contexte, les inventeurs ont démontré qu'un traitement avec du Lactobbacillus reuteri améliore la survie des souris suite à un infarctus du myocarde et que ledit traitement a empêché la diminution de la fonction cardiaque, (estimée par le % de fraction d'éjection) et du remodelage cardiaque. De plus, les inventeurs montrent que des ligands de récepteur d'hydrocarbure aryle (AHR) qui comprennent certains métabolites produits par le Lactobacillus reuteri sont également particulièrement appropriés pour le traitement d'une insuffisance cardiaque. En conséquence, la présente invention concerne des procédés de traitement d'une insuffisance cardiaque chez un sujet qui en a besoin, consistant à administrer au sujet une quantité efficace de Lactobacillus reuteri ou d'au moins un ligand d'AHR.
PCT/EP2018/084457 2017-12-13 2018-12-12 Méthodes de traitement de l'insuffisance cardiaque Ceased WO2019115576A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2022045673A1 (fr) * 2020-08-24 2022-03-03 가톨릭대학교 산학협력단 Composition comprenant un nouveau composé en tant que principe actif pour la prévention ou le traitement de l'insuffisance cardiaque consécutive à un infarctus du myocarde et utilisation associée
CN114990023A (zh) * 2022-06-23 2022-09-02 陕西科技大学 一株高产吲哚衍生物且具有耐酸耐胆盐特性的罗伊氏乳杆菌及其筛选方法与应用
CN114990023B (zh) * 2022-06-23 2023-11-28 海南丝路众享控股有限公司 一株高产吲哚衍生物且具有耐酸耐胆盐特性的罗伊氏乳杆菌及其筛选方法与应用

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