EP2136777A2 - Verwendung von citrullin zur behandlung von mit vermehrter protein-carbonylierung assoziierten leiden - Google Patents

Verwendung von citrullin zur behandlung von mit vermehrter protein-carbonylierung assoziierten leiden

Info

Publication number
EP2136777A2
EP2136777A2 EP08787826A EP08787826A EP2136777A2 EP 2136777 A2 EP2136777 A2 EP 2136777A2 EP 08787826 A EP08787826 A EP 08787826A EP 08787826 A EP08787826 A EP 08787826A EP 2136777 A2 EP2136777 A2 EP 2136777A2
Authority
EP
European Patent Office
Prior art keywords
treatment
citrulline
composition
intended
nutrition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP08787826A
Other languages
English (en)
French (fr)
Inventor
Christophe Moinard
Stéphane WALRAND
Yves Boirie
Luc Cynober
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Assistance Publique Hopitaux de Paris APHP
Institut National de la Recherche Agronomique INRA
Universite Paris 5 Rene Descartes
Centre Hospitalier Universitaire de Clermont Ferrand
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Institut National de la Recherche Agronomique INRA
Universite Paris 5 Rene Descartes
Centre Hospitalier Universitaire de Clermont Ferrand
Universite dAuvergne
Centre Hospitalier Universitaire dAngers
Universite Clermont Auvergne
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Assistance Publique Hopitaux de Paris APHP, Institut National de la Recherche Agronomique INRA, Universite Paris 5 Rene Descartes, Centre Hospitalier Universitaire de Clermont Ferrand, Universite dAuvergne, Centre Hospitalier Universitaire dAngers, Universite Clermont Auvergne filed Critical Assistance Publique Hopitaux de Paris APHP
Publication of EP2136777A2 publication Critical patent/EP2136777A2/de
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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

Definitions

  • protein carbonylation refers to a chemical modification of proteins related to the production of CO groups. This carbonylation (which may be a special case of protein oxidation) then leads to a loss of protein function (see Nystrom, The EMBO Journal (2005) 24, 1311-1317 and Dalle-Donne et al, J. Mol. Med, Vol.10, No. 2, 2006, pp. 389-406). Although the body has a number of defense systems (glutathione, catalase, SOD, etc.), these can be out of date and insufficient in certain situations. Carbonyl compounds are an interesting marker that accompanies aging and many pathologies.
  • Citrulline is used to date in some pharmaceutical applications.
  • EP 1 495 755 relates to the use of citrulline for the preparation of a medicament for the treatment of pathologies related to intestinal insufficiency. More particularly, the pathologies mentioned in this application are as follows: short bowel syndrome following intestinal resection, celiac disease, inflammatory bowel diseases, age-related intestinal insufficiency and intestinal insufficiency related to irradiation.
  • this application does not mention the carbonylation of proteins.
  • compositions comprising a statin associated with citrulline for the preparation of a medicament used in the treatment of primary or secondary atherosclerosis, and in that of degenerative diseases such as Alzheimer's disease.
  • the use of these compositions is synergistic compared to compositions comprising a statin or citrulline alone.
  • Application FR 2691359 describes the use of citrulline malate in a patient suffering from chronic obstructive pulmonary disease (COPD) and in a patient suffering from REYE-JOHNSON myopathy (mitochondrial myopathy). This beneficial effect of citrulline malate would be due to a better muscle utilization of fats leading to an economy of muscle proteolysis.
  • COPD chronic obstructive pulmonary disease
  • REYE-JOHNSON myopathy mitochondrial myopathy
  • United States Patent Application US 2001/0056068 relates to the use of L-citrulline for the treatment of diseases related to nitrogen oxide deficiency such as atherosclerosis, cerebral ischemia and Alzheimer's disease. Alzheimer.
  • European Patent Application EP 1752156 discloses an oxygen scavenger containing a wild watermelon extract containing citrulline and its use especially in Alzheimer's dementia, cataract problems, and cutaneous lesions.
  • a pharmaceutical composition intended to inhibit the increase of the carbonylation of the responsible proteins observed in certain pathologies therefore especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, for the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, the treatment of cataract problems or generalized infections (sepsis), the treatment of pathologies related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of tissues such as eye, muscle and brain, to the treatment of pathologies related to the dysfunction of mitochondria, namely the myopathies resulting from mitochondriopathies, the treatment of cachexia linked to undernutrition and increase n the longevity of mammals, especially that of pets.
  • neurodegenerative diseases such as Alzheimer's or Parkinson's diseases
  • retinopathy retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral
  • the present invention also relates to the use of a composition comprising L-citrulline or a nutraceutically acceptable salt thereof, for the nutraceutical treatment of disorders related to the increase in the carbonylation of proteins, by inhibition of the increase of the carbonylation of the responsible proteins, thus especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, sclerosis amyotrophic lateral, from cerebral ischemia, to the treatment of cataract problems or generalized infections (sepsis), to the treatment of diseases related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of the tissues such as eye, muscle and brain, to the treatment of the pathologies l Mitochondrial dysfunction, namely myopathies from mitochondriopathies, treatment of cachexia related to malnutrition and increased mammalian longevity.
  • neurodegenerative diseases such as Alzheimer's or
  • pharmaceutically acceptable salt means citrulline salts such as citrulline malate, citrulline ⁇ -ketoglutarate, citrulline citrate or citrulline paracetoisocaproate. .
  • L-citrulline as defined above, for the preparation of a composition for the cosmetic treatment in a form that can be administered topically. It also relates to the use of L-citrulline as defined above, for the preparation of a composition for the nutraceutical treatment in an orally administrable form.
  • the enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrostomy or jejunostomy; the parenteral administration corresponds in particular to administration by central, peripheral or subcutaneous intravenous infusion.
  • L-citrulline is used in the context of the invention for the preparation of a pharmaceutical composition, a composition for the cosmetic treatment, a composition for a food supplement or a health food for the nutraceutical treatment also comprising one or more other compounds intended for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, restroomthine and their various usable salts such as ⁇ -ketoglutarate or ⁇ -ketoisocaproate.
  • the compounds can be used alone or in a nutritional mixture for oral nutrition.
  • the processes of oxidation of proteins affecting the structure of the amino acids that compose them are complex and all give rise to the formation of carbonyl groups. This is why it was chosen to evaluate overall the oxidation of muscle proteins by quantifying the carbonyl derivatives from a 300 mg sample of tibialis anterior.
  • the method used is therefore a non-specific technique of the amino acid type which is based on the spectrophotometric assay of the complex formed by the binding of a compound called dinitrophenyl hydrazine (DNPH) on the carbonyl groups.
  • DNPH dinitrophenyl hydrazine
  • the solubilized proteins are separated into two equal fractions so as to have two wells containing the same amount of protein (1-1.5 mg / ml).
  • One of the cups serves as a blank and the other to quantify the carbonyl groups.
  • 500 ⁇ l of 12.5 mM DNPH are added to the measuring cup and 500 ⁇ l of 2M HCl to the white cup. After incubation for 15 minutes at room temperature, the samples are precipitated with 500 ⁇ l of 30% TCA and centrifuged for 10 minutes at 15,000 rpm. The pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate.
  • CIT group (n 5): the animals receive a standard diet enriched in CIT (lg / kg / d) for 1 month
  • the animals were euthanized and the brain was removed, weighed, frozen with liquid nitrogen and stored at -80 ° C until the tests were performed.
  • the samples are precipitated with 500 ⁇ l of 30% TCA and centrifuged for 10 minutes at 15,000 rpm.
  • the pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate.
  • the final pellet is heated for 30 min in a water bath at 50 ° C. After a new centrifugation of 5 min at 15000 rpm, the spectrophotometric reading is performed on 800 ⁇ l of supernatant at 280 nm (protein assay) and at 380 nm (DNPH assay). The carbonyl content is expressed in ⁇ mol / g of organ.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Mycology (AREA)
  • Psychology (AREA)
  • Diabetes (AREA)
  • Birds (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
EP08787826A 2007-03-22 2008-03-20 Verwendung von citrullin zur behandlung von mit vermehrter protein-carbonylierung assoziierten leiden Ceased EP2136777A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0702090A FR2913885B1 (fr) 2007-03-22 2007-03-22 Utilisation de la citrulline pour le traitement des pathologies liees a une augmentation de la carbonylation des proteines
PCT/FR2008/000379 WO2008135661A2 (fr) 2007-03-22 2008-03-20 Utilisation de la citrulline pour pour le traitement de pathologies liees a une augmentation de la carbonylation des protéines

Publications (1)

Publication Number Publication Date
EP2136777A2 true EP2136777A2 (de) 2009-12-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP08787826A Ceased EP2136777A2 (de) 2007-03-22 2008-03-20 Verwendung von citrullin zur behandlung von mit vermehrter protein-carbonylierung assoziierten leiden

Country Status (8)

Country Link
US (1) US20100093863A1 (de)
EP (1) EP2136777A2 (de)
JP (1) JP2010522146A (de)
CN (1) CN101686919A (de)
CA (1) CA2689608A1 (de)
FR (1) FR2913885B1 (de)
IL (1) IL200830A0 (de)
WO (1) WO2008135661A2 (de)

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US20140037604A1 (en) * 2011-04-18 2014-02-06 Nestec S.A. Nutritional compositions comprising alpha-hydroxyisocaproic acid
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CN106137782A (zh) * 2015-04-22 2016-11-23 捷通国际有限公司 包含青藤碱的局部组合物及用于抑制蛋白羰基化的方法
JP7220838B2 (ja) * 2015-09-29 2023-02-13 学校法人北里研究所 経口組成物
CN105147684B (zh) * 2015-09-30 2017-12-12 暨南大学 胡椒碱在制备防治败血症药物中的应用

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Also Published As

Publication number Publication date
WO2008135661A3 (fr) 2009-01-15
WO2008135661A2 (fr) 2008-11-13
JP2010522146A (ja) 2010-07-01
CN101686919A (zh) 2010-03-31
CA2689608A1 (fr) 2008-11-13
IL200830A0 (en) 2010-05-17
FR2913885A1 (fr) 2008-09-26
US20100093863A1 (en) 2010-04-15
FR2913885B1 (fr) 2012-07-20

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