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  • 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]
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  • 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
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• • A—HUMAN NECESSITIES
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  • 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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• 2007
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