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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • 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
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • 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
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • 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
  • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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

Definitions

• the present invention relates to the use of citrulline for the preparation of a medicament for the treatment of certain malnutrition states.
• intestinal insufficiency also referred to as aging-related intestinal insufficiency
• aging-related intestinal insufficiency resulting essentially from a mechanism of splanchnic sequestration of amino acids which no longer circulate at the periphery ( Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S et al, Almost garlic about citrulline in mammals, Amino Acids 2005; 29: 177-205).
• citrulline was not captured by the splanchnic area, the inventors hypothesized that citrulline could be a vector of nitrogen at the periphery.
• citrulline can be used in the context of the treatment of age-related intestinal insufficiency (as mentioned in the patent application FR03 08349).
• the inventors have studied the effect of citrulline directly on the muscle by carrying out in vitro citrulline addition experiments on muscles isolated from healthy or malnourished adult rats.
• citrulline to undrained adult rat muscles increases the protein synthesis of these muscles by up to 30%, while no effects are observed. on protein synthesis by in vitro addition of citrulline to healthy adult rat muscles.
• citrulline is not metabolized in muscle and has a direct action on muscle protein synthesis which is independent of intestinal insufficiency related to any digestive pathology or any modification of the digestive metabolism.
• one of the aims of the present invention is to provide a means of treating malnutrition states, and more particularly cachexia when it is linked to a decrease in protein synthesis in the context of pathologies unrelated to intestinal insufficiency. .
• Another object of the invention is to provide a means of increasing the abnormally low intramuscular protein synthesis in patients in a state of undernutrition related to a decrease in protein synthesis in the context of pathologies not resulting from intestinal insufficiency.
• the present invention relates to the use of L-citrulline (I)
• L-citrulline is understood to mean the product commercially available, in particular provided by Sigma or the natural product derived from plants, in particular watermelon or watermelon (Citrullus lanatus) in the form, in particular, of juice, of pulp or extract.
• “Intestinal insufficiency” refers to a pathological condition of the intestine, including the small intestine, in which nutrient absorption is reduced from normal, with decreased nutrient absorption related to a decrease in intestinal absorption. the number and / or the functionality of intestinal cells capable of ensuring this absorption, this reduction in the number and / or the functionality of intestinal cells being itself due either to a physical elimination of these cells (in particular by surgery or by radiation), or to pathological dysfunction of these cells.
• the present invention relates to the use of L-citrulline for the preparation of a medicament for increasing abnormally low intramuscular protein synthesis in patients in a state of malnutrition related to a decrease in protein synthesis in the context of pathological conditions. resulting not from intestinal insufficiency.
• the present invention more particularly relates to the aforementioned use of L-citrulline, for the preparation of a medicament for the treatment of the following disorders or pathologies:
• the present invention also relates to a method of therapeutic treatment of the aforementioned disorders and pathologies comprising administering to a patient an effective dose of citrulline or a salt thereof.
• the present invention relates to L-citrulline for the treatment of the disorders and pathologies mentioned above.
• the present invention more particularly relates to the use of L-citrulline for the preparation of a medicinal product intended for the treatment of patients suffering from a state of malnutrition linked to a decrease in protein synthesis in the context of pathologies not resulting from intestinal insufficiency.
• the subject of the present invention is therefore L-citrulline for the treatment of patients suffering from a state of malnutrition linked to a decrease in protein synthesis in the context of pathologies not resulting from intestinal insufficiency.
• the present invention relates to the aforementioned use of L-citrulline, for the preparation of a pharmaceutical composition comprising, as active principle, L-citrulline, or a pharmaceutically acceptable salt thereof. ci, in association with a pharmaceutically acceptable vehicle.
• pharmaceutically acceptable salt denotes citrulline salts such as citrulline malate, citrulline ⁇ -ketoglutarate, citrulline citrate or citrulline ⁇ -ketoisocaproate.
• the invention relates in particular to the aforementioned use of L-citrulline, for the preparation of a pharmaceutical composition characterized in that the unit dose of L-citrulline is from about 2 g to about 20 g, in particular about 10 g, for a dosage of about 0.1 g / kg / day to about 0.5 g / kg / day, especially about
• the invention relates more particularly to the aforementioned use of L-citrulline, for the preparation of a pharmaceutical composition in dry form or in the form of aqueous solution.
• the invention relates more particularly to the above-mentioned use of L-citrulline, for the preparation of a pharmaceutical composition in an orally, subcutaneously, enterally or parenterally administrable form.
• the enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrotomy or jejunostomy
• parenteral administration corresponds in particular to administration by central, peripheral or subcutaneous intravenous infusion.
• the invention more particularly relates to the aforementioned use of L-citrulline, for the preparation of a pharmaceutical composition also comprising one or more other compounds for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, pomithine and their various usable salts such as ⁇ -ketoglutarate or P ⁇ -ketoisocaproate, alone or in a nutritional mixture intended for parenteral nutrition, or a mixture intended for enteral nutrition or a mixture intended for oral nutrition.
• malnutrition-related cachexia such as leucine, glutamine, arginine, pomithine and their various usable salts such as ⁇ -ketoglutarate or P ⁇ -ketoisocaproate
• the present invention relates to a pharmaceutical composition characterized in that it comprises, as active principle, L-citrulline, or a pharmaceutically acceptable salt thereof, in combination with at least one other compound for the treatment of cachexia related to malnutrition such as leucine, glutamine, arginine, ornithine and their various usable salts such as ⁇ -ketoglutarate or ⁇ -ketoisocaproate, alone or within a nutritional mixture for parenteral nutrition, or a mixture for enteral nutrition or a mixture for oral nutrition, and a pharmaceutically acceptable carrier.
• cachexia related to malnutrition such as leucine, glutamine, arginine, ornithine and their various usable salts such as ⁇ -ketoglutarate or ⁇ -ketoisocaproate, alone or within a nutritional mixture for parenteral nutrition, or a mixture for enteral nutrition or a mixture for oral nutrition, and a pharmaceutically acceptable carrier.
• At least one other compound intended for the treatment of cachexia linked to undernutrition such as leucine, glutamine, arginine, ornithine and their various usable salts such as ⁇ -ketoglutarate or ⁇ -ketoisocaproate , alone or in a c nutritional mixture for parenteral nutrition, or a mixture for enteral nutrition or a mixture intended for oral nutrition, as combination products for simultaneous, separate or spread over time, as part of the treatment of intestinal insufficiency.
• FIG. 1A shows the fractional protein synthesis (FSR) of epitrochlearis from healthy rats (left columns) or malnourished (right columns) and incubated in the presence of citrulline (black columns) or in the absence of citrulline (control - white columns) measured according to the procedure of Example 1. The results are expressed in% / hour.
• Figure IB shows fractional protein synthesis (FSR) & epitrochlearis from healthy rats (left columns) or malnourished (right columns) and incubated in the presence of citrulline (black columns) or in the absence of citrulline (control - white columns) measured according to the procedure of Example 1. The results are expressed in% / control.
• FIG. 2A shows the Western Blot after 1h of revelation illustrating the activation of P70S6kinase on the muscles of malnourished aged rats measured according to the procedure described in Example 2.
• FIG. 2B is a graphical representation of the activation of P70S6kinase on the muscles
• rats are randomized into 2 groups: a control group consisting of rats fed ad libitum (AL) and a group subjected to dietary restriction during the same period: rats are fed 50% of spontaneous ingesta for 6 weeks on a 5% protein diet (Walrand S, Chambon-Savanovitch C, Felgines C 5 Chassagne J, Raul F, Normand B et al. Aging: A Barrier to Nutritional and Immunological Evidence in Am J Clin Nutr 2000; 72: 816-824).
• Epitrochlearis is used because it is the most suitable for this type of study. After dissection, the epitrochlearis are incubated in 3 ml of Krebs-Ringer buffer (119 mM NaCl, 4.8 mM KCl, 1.25 mM MgSO 4 , 25 mM NaHCO 3 , 1.24 mM NaHPO 4 , 1.0 mM CaCl 2 2 ; 2 mM HEPES, pH 7.4), also containing glucose (8 mM), insulin (0.01 U / ml) and serum bovine albumin (BSA) (0.1% w / w). v).
• Krebs-Ringer buffer 119 mM NaCl, 4.8 mM KCl, 1.25 mM MgSO 4 , 25 mM NaHCO 3 , 1.24 mM NaHPO 4 , 1.0 mM CaCl 2 2 ; 2 mM HEPES, pH 7.4
• glucose 8 mM
• insulin
• the muscles are pre-incubated for 30 minutes at 37 ° C with 95% O 2 : 5% C ⁇ 2 -
• the muscles are then transferred to a tube containing 3 ml of incubation medium (containing 13 C-phenylalanine (1 mM) with or without 2.5 mM citrulline) and incubated for 2 hours.
• incubation medium containing 13 C-phenylalanine (1 mM) with or without 2.5 mM citrulline
• the muscles are collected and stored at -80 ° C until the incorporation of 13 C-phenylalanine by mass spectrometry to determine fractional protein synthesis (FSR) (Guillet C, Boirie Y, Walrand S.
• FSR fractional protein synthesis
• Citrulline is not metabolized by muscle since no amino acids metabolically bound to citrulline are released into the incubation medium (results not shown).
• L-citrulline is an amino acid whose structure is very different from leucine; it does not enter the protein composition, and is almost absent from the diet.
• non-essential amino acids AIa, GIy, His, Asp, Ser in a ratio
• n 10, group R + AANE.
• Ten rats constitute the control group (LA); they are fed ad libitum throughout the study before being sacrificed. The rats are then sacrificed. The tibialis muscles are removed and frozen rapidly in liquid nitrogen and stored at -80 ° C until analysis.
• Protein Extraction and Dosage The muscles are ground into liquid nitrogen using a mortar. The powder thus obtained is weighed and then taken up in 10 volumes of solubilization buffer containing a cocktail of phosphatase inhibitors and proteases. The samples are placed at least 1 hour on a wheel in a cold room. After centrifugation for 30 minutes at + 4 ° C. at 13000 g, the supernatant is divided into aliquots and then stored at -80 ° C. The proteins are assayed by the bicinchoninic acid method.
• mTOR mammalian Target of Rapamycin pathway
• Western Blot highlighting the phosphorylated forms of the different mTOR targets. Protein integrity is verified by polyacrylamide gel electrophoresis (SDS-PAGE), followed by staining with Coomassie Blue.
• the transfer is carried out in cold transfer buffer IX (Tris 25mM, Glycine
• the TBST IX buffer 1% skimmed milk, 4% BSA, is mixed with the antibody
• TBSA buffer (TBST IX, 5% skim milk)
• X-ray film is performed in the dark room using the ECL kit.
• a diet supplemented with non-essential amino acids restores part of this activity but in a non-significant way, said activity remaining significantly lower than that observed in the controls (-45% compared to the AL control group).
• citrulline has a direct activity on protein synthesis via the activation of the mTOR system.

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• 2006
  • 2006-10-17 FR FR0609077A patent/FR2907011B1/fr not_active Expired - Fee Related
• 2007
  • 2007-08-29 US US12/445,820 patent/US20100298437A1/en not_active Abandoned
  • 2007-08-29 CA CA002666538A patent/CA2666538A1/fr not_active Abandoned
  • 2007-08-29 CN CNA2007800424825A patent/CN101605538A/zh active Pending
  • 2007-08-29 WO PCT/FR2007/001407 patent/WO2008049984A2/fr not_active Ceased
  • 2007-08-29 JP JP2009532837A patent/JP2010506887A/ja active Pending
  • 2007-08-29 EP EP07823453.1A patent/EP2081564B1/fr active Active
• 2009
  • 2009-04-16 IL IL198182A patent/IL198182A0/en unknown

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