WO2011069932A1 - Novel therapeutic uses for an ornithine alpha-ketoglutarate complex - Google Patents

Novel therapeutic uses for an ornithine alpha-ketoglutarate complex Download PDF

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WO2011069932A1
WO2011069932A1 PCT/EP2010/068910 EP2010068910W WO2011069932A1 WO 2011069932 A1 WO2011069932 A1 WO 2011069932A1 EP 2010068910 W EP2010068910 W EP 2010068910W WO 2011069932 A1 WO2011069932 A1 WO 2011069932A1
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people
glutamine
complex
glaco
ketoglutarate
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Luc Cynober
Colette Coudray-Lucas
Jacques Le Boucher
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Chiesi Farmaceutici S.P.A.
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    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to novel therapeutic applications of a complex of alpha-ketoglutarate and ornithine.
  • glutamine in the form of a di-peptide makes it possible to restore the intramuscular concentration of this amino acid (Furst P. et al., (1987) Infusion Control Ther., Clin Nutri, 17, 17-136).
  • glutamine in free form is difficult to use for clinical use: glutamine is poorly soluble in solution and during a sterilizing filtration, it can form pyroglutamate and ammonia which are potentially neurotoxic. However, it is essential to preserve glutaminemia in aggression.
  • Ornithine is known for its secretagogues properties (growth hormone and insulin), to stimulate cell growth and protein synthesis and to limit protein catabolism.
  • it is used in the form of ornithine alpha-ketoglutarate (ACO), in particular to improve the protein metabolism and the nitrogen balance of undernourished subjects or in a traumatic situation (patent FR 1 424 480).
  • ACO ornithine alpha-ketoglutarate
  • the inventors have surprisingly discovered that the ornithine and glutamine alpha-ketoglutarate complex has a much greater effect than the ornithine alpha-ketoglutarate complex on the nitrogen balance in a state pathological model. catabolic.
  • the subject of the present invention is a complex of glutamine and ornithine alpha-ketoglutarate (GLACO) for its use in the treatment of patients suffering from disorders related to a decrease in plasma and / or muscle concentrations.
  • glutamine said patients being selected from the group consisting of:
  • the complex is an equimolar complex of glutamine and ornithine alpha-ketoglutarate.
  • the complex may be in any form that can be administered orally or parenterally, in particular in the form of sachets, tablets, capsules, tablets, dragees, drinkable ampoules, aqueous or alcoholic solutes, syrups, suspensions or hydrosols.
  • the enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrotomy or jejunostomy, by direct instillation into an anastomosis segment or any other approach allowing enteral nutrition
  • the administration parenterally corresponds to administration by central, peripheral or subcutaneous intravenous infusion.
  • the complex is presented for a daily dosage of between 10 and 500 mg / kg of weight, advantageously between 14 and 300 mg / kg of weight.
  • the complex is presented for a daily dosage of between 10 and 50 mg / kg of weight, more preferably between 14 and 30 mg / kg of weight.
  • Another subject of the invention is a pharmaceutical composition comprising a glutamine and ornithine alpha-ketoglutarate complex as defined above in combination with a pharmaceutically acceptable excipient for its use in the treatment of patients suffering from disorders related to an decreased plasma and / or muscle glutamine concentrations, said patients being selected from the group consisting of:
  • the pharmaceutical compositions may also comprise other active principles chosen according to the diseases to be treated.
  • other amino acids such as arginine, leucine
  • polyunsaturated fatty acids such as arginine, leucine
  • water-soluble or liposoluble vitamins such as calcium, zinc and selenium
  • minerals such as calcium, zinc and selenium
  • any other nutrient such as reverastrol, curcumin, luterin, lycopene or other polyphenols
  • pharmacological agent known to modulate protein metabolism.
  • compositions according to the invention especially when they are in the form of aqueous solutions, have properties organoleptics significantly improved compared to those containing ACO.
  • FIG. 1 represents the cumulative nitrogen urinary excretion measured according to Example 1 in burned rats treated with GLACO or ACO at doses of 0.5 g / kg / day and 5 g / kg / day; ** p ⁇ 0.01 versus ACO 0.5 g / kg / day (Student's test).
  • Figure 2 shows the daily nitrogen balance in the burned rat measured according to Example 1. * p ⁇ 0.5; ** p ⁇ 0.01 (Student's test).
  • EXAMPLE 1 COMPARISON OF THE EFFECT ON NITROGEN OF GLUTAMINE AND GLACO IN A MODEL OF RAT BRULE
  • the insoluble material is collected by filtration, washing with acetone and drying under vacuum.
  • Wistar male rats of average weight 80-90 g were acclimated to the animal house (temperature: 22 ⁇ 2 ° C) for 3 days in cage metabolism (A03 UAR kibble, 23.5% nitrogen), in reverse cycle 12 hours night / 12 hours day.
  • the rats, except the controls were anesthetized and burned by immersion of the back for 1 second in water heated to 95 ° C. They receive immediately intraperitoneally 10 ml per 100 g of weight of a 0.9% sodium chloride solution and are then returned to the metabolism cages. They are deprived of food for 24 hours (D0 to D) with access to ad libitum water.
  • the animals receive 3 daily gavages of 210 Kcal / kg / day and 1.18 g of nitrogen / kg / day in the form of Osmolite ® from day 1 to day 3.
  • the animals are administered either 0.5 g / kg / day of GLACO or ACO, or 5 g / kg / day of GLACO or ACO respectively corresponding to 0.066 g of nitrogen / kg / and 0.66 g of nitrogen / kg / day and representing respectively 5 and 36% of the total nitrogen supply.
  • the doses chosen are those relevant for assaulted rats. Extrapolation to humans leads to a dose 10 times lower.
  • the rats are euthanized after 48 hours of nutrition.
  • GLACO decreases the cumulative nitrogen excretion significantly compared to ACO administered at the same dose ( Figure 2).
  • Example 1 The complex is prepared as shown in Example 1 and the model burned rat is the one described in this same example.
  • Animals receive 0.066 g of nitrogen / kg / day (5% of the total nitrogen supply) in the form of GLACO, ie 0.5 g / kg / day of the GLACO complex or in the form of a mixture of glutamine and glycine ( Gin + Gly) to provide the same amount of glutamine (0.17 g / kg / day) as in the group receiving GLACO while remaining isoazoté.
  • rats were subjected to the same enteral nutrition (Osmolyte®) supplemented with iso-nitrogen glycine. These rats are either burned (Lot Gly) or not and are the control group.
  • enteral nutrition Osmolyte®
  • iso-nitrogen glycine iso-nitrogen glycine
  • the rats are euthanized after 48 hours of nutrition.
  • the extensor digitalorum longus (EDL) muscles are removed and immediately frozen in liquid nitrogen and stored at -80 ° C.
  • the samples were ground at 4 ° C in a 0.6 M trichloroacetic acid solution containing 0.5 mM EDTA using an Ultraturrax ®. After centrifugation, the amino acids are assayed in the supernatant by liquid chromatography on a cation exchange column on a Biotronik LC 500 analyzer.
  • Muscle glutamine concentration is significantly decreased in burned rats (Gly); treatment with GLACO at the dose of 0.5 g / kg / day significantly restores glutamine muscle concentration (GLACO) while iso-nitrogen-only treatment with glutamine has no effect (Gin + Gly).
  • EXAMPLE 3 MEASUREMENT OF MUSCLE CONCENTRATIONS OF GLUTAMINE IN THE RAT BRULE COMPARISON BETWEEN ACO AND GLACO
  • Example 2 A protocol identical to that described in Example 2 is applied. In this experiment a lot of animals receive ACO at the dose of 0.5 g / kg / day, that is to say at the same dose as GLACO.
  • EXAMPLE 4 MEASUREMENT OF MUSCLE CONCENTRATIONS OF GLUTAMINE IN THE ENDOTOXEMIC RAT
  • Wistar adult male rats weighing 163 ⁇ 7 g were used after acclimation for 3 days in a metabolism cage (croquettes UA AO3; 23.5% nitrogen), inverted cycle 12h night / 12h day.
  • the rats On day 0, the rats, except the control rats, receive an intraperitoneal injection of an endotoxin (E. Lipopolysaccharide). Coli serotype 127 B: 8) solubilized in 0.9% NaCl at a dose of 3 mg / kg.
  • the controls receive only one intraperitoneal injection of NaCl under the same volume.
  • the animals are euthanized and the muscles removed as indicated in Example 2.
  • the muscle glutamine assay is also performed according to the procedure described in Example 2.
  • Muscle glutamine concentration is significantly decreased in endotoxemic (Gly) rats; treatment with GLACO at a dose of 0.5 g / kg / day restores glutamine muscle concentration significantly (GLACO) while iso-nitrogen treatment with glutamine alone has no effect (Gin + Gly).

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Abstract

The invention relates to novel therapeutic uses for a glutamine and ornithine alpha-ketoglutarate complex in treating patients suffering from disorders related to a decrease in plasma and/or muscle glutamine concentrations.

Description

NOUVELLES APPLICATIONS THERAPEUTIQUES D'UN NEW THERAPEUTIC APPLICATIONS OF A
COMPLEXE D'ALPHA-CETOGLUTARATE ET D'ORNITHTNE ALPHA-CETOGLUTARATE AND ORNITHTNE COMPLEX
La présente invention a pour objet de nouvelles applications thérapeutiques d'un complexe d'alpha-cétoglutarate et d'ornithine. The present invention relates to novel therapeutic applications of a complex of alpha-ketoglutarate and ornithine.
De nombreuses situations de stress telles que les traumatismes chirurgicaux ou les chocs septiques induisent un hypercatabolisme protéique c'est-à-dire une dégradation anormalement exagérée des protéines de l'organisme dont le réservoir essentiel est représenté par les muscles. Par ailleurs, dans ces situations, des modifications du métabolisme de certains acides aminés, tels que la glutamine, sont également observés. En situation catabolique, la glutamine est considérée comme conditionnellement essentielle car sa synthèse endogène n'est pas suffisante pour couvrir les besoins accrus de l'organisme. Or la glutamine a de nombreuses actions sur le métabolisme protéique et l'hypercatabolisme observé pourrait être, en partie, la conséquence d'altération du métabolisme de la glutamine (Boelens et al. (2001), J. Nutr.l31:2569S-2577S, brevet F 3.533 M). Enfin, l'administration intraveineuse de glutamine sous forme de di-peptide permet de restaurer la concentration intramusculaire de cet acide aminé (Furst P. et al. (1987) Contr. Infusion Thér. Clin. Nutri. 17, 1 17-136). Toutefois la glutamine sous forme libre est difficilement utilisable pour un usage clinique: la glutamine est faiblement soluble en solution et lors d'une filtration stérilisante, elle peut former du pyroglutamate et de l'ammoniac qui sont potentiellement neurotoxiques. Cependant, il est essentiel de préserver la glutaminémie en situation d'agression.  Many stressful situations such as surgical trauma or septic shock induce a protein hypercatabolism that is to say an abnormally exaggerated degradation of the proteins of the body whose essential reservoir is represented by the muscles. Moreover, in these situations, changes in the metabolism of certain amino acids, such as glutamine, are also observed. In a catabolic situation, glutamine is considered conditionally essential because its endogenous synthesis is not sufficient to cover the increased needs of the body. However, glutamine has many actions on protein metabolism and observed hypercatabolism could be, in part, the consequence of impaired metabolism of glutamine (Boelens et al (2001) J. Nutr.l31: 2569S-2577S , patent F 3.533 M). Finally, the intravenous administration of glutamine in the form of a di-peptide makes it possible to restore the intramuscular concentration of this amino acid (Furst P. et al., (1987) Infusion Control Ther., Clin Nutri, 17, 17-136). . However, glutamine in free form is difficult to use for clinical use: glutamine is poorly soluble in solution and during a sterilizing filtration, it can form pyroglutamate and ammonia which are potentially neurotoxic. However, it is essential to preserve glutaminemia in aggression.
L'ornithine est connue pour ses propriétés sécrétagogues (hormone de croissance et insuline), pour stimuler la croissance cellulaire et la synthèse protéique et limiter le catabolisme protéique. Elle est en particulier utilisée sous forme d'alpha-cétoglutarate d'ornithine (ACO), notamment pour améliorer le métabolisme protéique et le bilan azoté de sujets dénutris ou en situation traumatique (brevet FR 1 424 480). Ornithine is known for its secretagogues properties (growth hormone and insulin), to stimulate cell growth and protein synthesis and to limit protein catabolism. In particular, it is used in the form of ornithine alpha-ketoglutarate (ACO), in particular to improve the protein metabolism and the nitrogen balance of undernourished subjects or in a traumatic situation (patent FR 1 424 480).
La demande internationale WO 99/47134 décrit l'utilisation des complexes comprenant un céto-acide et un ou deux acides aminés naturels, en particulier le complexe d'alpha-cétoglutarate d'ornithine et de glutamine (GLACO) et leur utilisation dans le traitement des douleurs associées aux pathologies du tube digestif, de la vessie et des voies biliaires dans lesquelles sont impliqués les neurones silencieux. GLACO diminuerait ces douleurs à partir d'une dose de 1 mg/kg p.o.  International application WO 99/47134 describes the use of complexes comprising a keto acid and one or two natural amino acids, in particular the ornithine and glutamine alpha-ketoglutarate complex (GLACO) and their use in the treatment. pain associated with diseases of the digestive tract, bladder and bile ducts in which silent neurons are involved. GLACO would reduce these pains from a dose of 1 mg / kg p.o.
La demande internationale WO 02/078676 décrit des compositions gastro-résistantes contenant des complexes comprenant un céto-acide et un ou deux acides aminés naturels et leur utilisation dans différentes pathologies. Ces compositions présentent un goût amélioré du fait de l'enrobage. Bien que GLACO soit cité parmi les nombreux complexes possibles, aucun résultat n'est donné pour ce complexe particulier, les seuls résultats présentés concernant ACO.  International application WO 02/078676 describes gastroresistant compositions containing complexes comprising a keto acid and one or two natural amino acids and their use in various pathologies. These compositions have an improved taste due to the coating. Although GLACO is cited among the many possible complexes, no results are given for this particular complex, the only results presented concerning ACO.
Or les inventeurs ont découvert de manière surprenante que le complexe d'alpha-cétoglutarate d'ornithine et de glutamine présente un effet très supérieur à celui du complexe d'alpha-cétoglutarate d'ornithine sur le bilan azoté dans un modèle pathologique d'état hypercatabolique.  However, the inventors have surprisingly discovered that the ornithine and glutamine alpha-ketoglutarate complex has a much greater effect than the ornithine alpha-ketoglutarate complex on the nitrogen balance in a state pathological model. catabolic.
Aussi la présente invention a-t-elle pour objet, un complexe de glutamine et d'alpha-cétoglutarate d'ornithine (GLACO) pour son utilisation dans le traitement de patients souffrant de troubles liés à une diminution des concentrations plasmatique et/ou musculaire de glutamine, lesdits patients étant choisis dans le groupe comprenant:  Also the subject of the present invention is a complex of glutamine and ornithine alpha-ketoglutarate (GLACO) for its use in the treatment of patients suffering from disorders related to a decrease in plasma and / or muscle concentrations. glutamine, said patients being selected from the group consisting of:
- les traumatisés crâniens,  - the traumatized cranial,
- les personnes ayant eu un accident vasculaire cérébral, - les personnes ayant subi une greffe de moelle ou conditionnées en vue de cette thérapeutique, - people who have had a stroke, - persons who have undergone a marrow transplant or are conditioned for this treatment,
- les personnes en réanimation,  - people in intensive care,
- les personnes souffrant de fractures,  - people with fractures,
- les personnes souffrant des effets de la radiothérapie,  - people suffering from the effects of radiotherapy,
- les personnes en situation pré-opératoire de chirurgie,  - people in a preoperative surgical situation,
- les personnes en continuation post-opératoire d'une nutrition préopératoire et  - people in postoperative continuation of preoperative nutrition and
- les personnes âgées dénutries.  - malnourished elderly people.
Dans un mode de réalisation avantageux de l'invention, le complexe est un complexe équimolaire de glutamine et d'alpha-cétoglutarate d'ornithine.  In an advantageous embodiment of the invention, the complex is an equimolar complex of glutamine and ornithine alpha-ketoglutarate.
Dans un mode de réalisation avantageux de l'invention, le complexe peut se présenter sous toute forme administrable par voie orale ou parentérale, notamment sous forme de sachets, de cachets, de gélules, de comprimés, de dragées, d'ampoules buvables, de solutés aqueux ou alcooliques, de sirops, de suspensions ou d'hydrosols. L'administration par voie entérale correspond notamment à une administration par sonde naso-gastrique ou naso-intestinale, par gastrotomie ou jéjunostomie, par instillation directe dans un segment d'anastomose ou toute autre voie d'abord permettant une nutrition entérale, l'administration par voie parentérale correspond notamment à une administration par perfusion intraveineuse centrale, périphérique ou sous- cutanée.  In an advantageous embodiment of the invention, the complex may be in any form that can be administered orally or parenterally, in particular in the form of sachets, tablets, capsules, tablets, dragees, drinkable ampoules, aqueous or alcoholic solutes, syrups, suspensions or hydrosols. The enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrotomy or jejunostomy, by direct instillation into an anastomosis segment or any other approach allowing enteral nutrition, the administration parenterally corresponds to administration by central, peripheral or subcutaneous intravenous infusion.
Dans un autre mode de réalisation avantageux de l'invention, le complexe est présenté pour une posologie journalière comprise entre 10 et 500 mg/kg de poids, avantageusement entre 14 et 300 mg/kg de poids.  In another advantageous embodiment of the invention, the complex is presented for a daily dosage of between 10 and 500 mg / kg of weight, advantageously between 14 and 300 mg / kg of weight.
Dans un mode de réalisation préférable, le complexe est présenté pour une posologie journalière comprise entre 10 et 50 mg/kg de poids, plus préférablement comprise entre 14 et 30 mg/kg de poids. Un autre objet de l'invention est une composition pharmaceutique comprenant un complexe de glutamine et d'alpha-cétoglutarate d'ornithine tel que défini précédemment en association avec un excipient pharmaceutiquement acceptable pour son utilisation dans le traitement de patients souffrant de troubles liés à une diminution des concentrations plasmatique et/ou musculaire de glutamine, lesdits patients étant choisis dans le groupe comprenant: In a preferable embodiment, the complex is presented for a daily dosage of between 10 and 50 mg / kg of weight, more preferably between 14 and 30 mg / kg of weight. Another subject of the invention is a pharmaceutical composition comprising a glutamine and ornithine alpha-ketoglutarate complex as defined above in combination with a pharmaceutically acceptable excipient for its use in the treatment of patients suffering from disorders related to an decreased plasma and / or muscle glutamine concentrations, said patients being selected from the group consisting of:
- les traumatisés crâniens,  - the traumatized cranial,
- les personnes ayant eu un accident vasculaire cérébral,  - people who have had a stroke,
- les personnes ayant subi une greffe de moelle ou conditionnées en vue de cette thérapeutique,  - persons who have undergone a marrow transplant or are conditioned for this treatment,
- les personnes en réanimation,  - people in intensive care,
- les personnes souffrant de fractures,  - people with fractures,
- les personnes souffrant des effets de la radiothérapie,  - people suffering from the effects of radiotherapy,
- les personnes en situation pré-opératoire de chirurgie,  - people in a preoperative surgical situation,
- les personnes en continuation post-opératoire d'une nutrition préopératoire et  - people in postoperative continuation of preoperative nutrition and
- les personnes âgées dénutries.  - malnourished elderly people.
Conformément à l'invention, les compositions pharmaceutiques peuvent également comprendre d'autres principes actifs choisis en fonction des maladies à traiter. Ainsi on peut citer à titre d'exemple d'autres acides aminés (tels que l'arginine, la leucine), des acides gras polyinsaturés, des vitamines hydrosolubles ou liposolubles, des minéraux (tels que le calcium, le zinc et le sélénium) ou tout autre nutriment (tel que révérastrol, curcumine, lutérine, lycopène ou autres polyphénols) ou agent pharmacologique connu pour moduler le métabolisme protéique.  In accordance with the invention, the pharmaceutical compositions may also comprise other active principles chosen according to the diseases to be treated. Thus, other amino acids (such as arginine, leucine), polyunsaturated fatty acids, water-soluble or liposoluble vitamins, minerals (such as calcium, zinc and selenium) can be mentioned as examples. or any other nutrient (such as reverastrol, curcumin, luterin, lycopene or other polyphenols) or pharmacological agent known to modulate protein metabolism.
Les compositions pharmaceutiques selon l'invention, notamment lorsqu'elles sont sous forme de solutions aqueuses présentent des propriétés organoleptiques nettement améliorées comparativement à celles contenant ACO.The pharmaceutical compositions according to the invention, especially when they are in the form of aqueous solutions, have properties organoleptics significantly improved compared to those containing ACO.
Les exemples 1 à 5 et les figures 1 et 2 qui suivent illustrent l'invention.Examples 1 to 5 and Figures 1 and 2 which follow illustrate the invention.
La figure 1 représente l'excrétion urinaire d'azote cumulée mesurée selon l'exemple 1 chez des rats brûlés traités par GLACO ou ACO aux doses de 0,5 g/kg/j et de 5 g/kg/j; ** p<0,01 versus ACO 0,5 g/kg/j (test de Student). FIG. 1 represents the cumulative nitrogen urinary excretion measured according to Example 1 in burned rats treated with GLACO or ACO at doses of 0.5 g / kg / day and 5 g / kg / day; ** p <0.01 versus ACO 0.5 g / kg / day (Student's test).
La figure 2 représente le bilan quotidien d'azote chez le rat brûlé mesuré selon l'exemple 1. * p<0,5; ** p<0,01 (test de Student).  Figure 2 shows the daily nitrogen balance in the burned rat measured according to Example 1. * p <0.5; ** p <0.01 (Student's test).
EXEMPLE 1: COMPARAISON DE L'EFFET SUR L'AZOTE DE LA GLUTAMINE ET DE GLACO DANS UN MODELE DE RAT BRULE  EXAMPLE 1 COMPARISON OF THE EFFECT ON NITROGEN OF GLUTAMINE AND GLACO IN A MODEL OF RAT BRULE
1.1. Mode opératoire  1.1. Operating mode
1.1.1. Préparation du complexe  1.1.1. Preparation of the complex
58,4 g (0,4 moles) de glutamine et 58,4 g (0,4 mole) d'acide alpha-cétoglutarique sont dissous dans 300 ml d'eau. On ajoute une solution d'ornithine à 40% (1 17 ml; 0,4 mole) puis 500 ml d'éthanol. On refroidit cette solution et on la laisse à - 18°C pour compléter la cristallisation.  58.4 g (0.4 moles) of glutamine and 58.4 g (0.4 mole) of alpha-ketoglutaric acid are dissolved in 300 ml of water. A solution of 40% ornithine (11 ml, 0.4 mole) and then 500 ml of ethanol are added. This solution is cooled and left at -18 ° C. to complete the crystallization.
On collecte l'insoluble par filtration, lavage à l'acétone et séchage sous vide.  The insoluble material is collected by filtration, washing with acetone and drying under vacuum.
On obtient 155 g d'un solide blanc (Rendement = 95%).  155 g of a white solid are obtained (Yield = 95%).
Les dosages des différents constituants effectués par chromatographie liquide haute performance (CLHP) donnent la composition suivante: alpha- cétoglutarate: 1 ; ornithine: 0,91 et glutamine 1 , 13.  The assays of the various constituents carried out by high performance liquid chromatography (HPLC) give the following composition: alpha-ketoglutarate: 1; ornithine: 0.91 and glutamine 1, 13.
1.1.2. Test pharmacologique:  1.1.2. Pharmacological test:
Des rats mâles de souche Wistar de poids moyen 80-90 g ont été acclimatés à l'animalerie (température: 22±2°C) pendant 3 jours en cage à métabolisme (croquette UAR A03; 23,5% d'azote), en cycle inversé 12 heures nuit/12 heures jour. A J0, les rats, exceptés les témoins, sont anesthésiés et brûlés par immersion du dos pendant 1 1 secondes dans de l'eau portée à 95°C. Ils reçoivent immédiatement par voie intrapéritonéale 10 ml pour 100 g de poids d'une solution de chlorure de sodium à 0,9% et sont ensuite replacés dans les cages à métabolisme. Ils sont privés de nourriture pendant 24 heures (J0 à Jl) avec un accès à l'eau ad libitum. Ils reçoivent ensuite 3 gavages quotidiens de 210 Kcal/kg/j et 1 , 18 g d'azote/kg/j sous forme d'Osmolite® de Jl à J3. En parallèle à cette nutrition, on administre aux animaux soit 0,5 g/kg/j de GLACO ou d'ACO, soit 5 g/kg/j de GLACO ou d'ACO correspondant respectivement à 0,066 g d'azote/kg/j et à 0,66 g d'azote/kg/j et représentant respectivement 5 et 36% de l'apport azoté total. Les doses choisies sont celles pertinentes pour des rats agressés. L'extrapolation à l'homme conduit à une dose 10 fois moins élevée. Wistar male rats of average weight 80-90 g were acclimated to the animal house (temperature: 22 ± 2 ° C) for 3 days in cage metabolism (A03 UAR kibble, 23.5% nitrogen), in reverse cycle 12 hours night / 12 hours day. At day 0, the rats, except the controls, were anesthetized and burned by immersion of the back for 1 second in water heated to 95 ° C. They receive immediately intraperitoneally 10 ml per 100 g of weight of a 0.9% sodium chloride solution and are then returned to the metabolism cages. They are deprived of food for 24 hours (D0 to D) with access to ad libitum water. They then receive 3 daily gavages of 210 Kcal / kg / day and 1.18 g of nitrogen / kg / day in the form of Osmolite ® from day 1 to day 3. In parallel with this nutrition, the animals are administered either 0.5 g / kg / day of GLACO or ACO, or 5 g / kg / day of GLACO or ACO respectively corresponding to 0.066 g of nitrogen / kg / and 0.66 g of nitrogen / kg / day and representing respectively 5 and 36% of the total nitrogen supply. The doses chosen are those relevant for assaulted rats. Extrapolation to humans leads to a dose 10 times lower.
Les rats sont euthanasiés après 48 heures de nutrition.  The rats are euthanized after 48 hours of nutrition.
On mesure quotidiennement l'excrétion urinaire d'azote par chimioluminescence avec un détecteur Antek® et l'excrétion d'urée par dosage enzymatique à l'uréase. Was measured daily urinary nitrogen excretion by chemiluminescence with an Antek ® detector and urea excretion by enzymatic assay to urease.
1.2. Résultats  1.2. Results
L'excrétion d'azote cumulée au cours des jours J2 et J3 est représentée dans la figure 1.  The cumulative nitrogen excretion in days D2 and D3 is shown in Figure 1.
Le bilan azoté journalier est donné dans la figure 2.  The daily nitrogen balance is given in Figure 2.
A la dose de 0,5 g/kg/j, GLACO diminue l'excrétion d'azote cumulée de manière significative comparativement à ACO administrée à la même dose (figure 2).  At a dose of 0.5 g / kg / day, GLACO decreases the cumulative nitrogen excretion significantly compared to ACO administered at the same dose (Figure 2).
Le bilan azoté redevient positif dès J2 avec seulement 0,5 g/kg/j de GLACO alors qu'avec ACO, il faut 5 g/kg/j (figure 1).  The nitrogen balance becomes positive again with J2 with only 0.5 g / kg / day of GLACO while with ACO, it takes 5 g / kg / day (Figure 1).
EXEMPLE 2: MESURE DES CONCENTRATIONS MUSCULAIRES DE GLUTAMINE CHEZ LE RAT BRULE - COMPARAISON ENTRE GLUTAMINE ET GLACO  EXAMPLE 2 Measurement of the Muscular Concentrations of Glutamine in the Brain RAT COMPARISON BETWEEN GLUTAMINE AND GLACO
2.1. Mode opératoire  2.1. Operating mode
Le complexe est préparé comme indiqué dans l'exemple 1 et le modèle de rat brûlé est celui décrit dans ce même exemple. The complex is prepared as shown in Example 1 and the model burned rat is the one described in this same example.
Des animaux reçoivent 0,066 g d'azote/kg/j (5% de l'apport azoté total) sous forme de GLACO, soit 0,5 g/kg/j du complexe GLACO ou sous forme d'un mélange glutamine et glycine (Gin + Gly) afin d'apporter la même quantité de glutamine (soit 0, 17 g/kg/j) que dans le groupe recevant GLACO tout en restant isoazoté.  Animals receive 0.066 g of nitrogen / kg / day (5% of the total nitrogen supply) in the form of GLACO, ie 0.5 g / kg / day of the GLACO complex or in the form of a mixture of glutamine and glycine ( Gin + Gly) to provide the same amount of glutamine (0.17 g / kg / day) as in the group receiving GLACO while remaining isoazoté.
Parallèlement, des rats ont été soumis à la même nutrition entérale (Osmolyte®) supplémentée en un apport isoazoté de glycine. Ces rats sont soit soumis à une brûlure (lot Gly), soit ne le sont pas et constituent le groupe témoin.  At the same time, rats were subjected to the same enteral nutrition (Osmolyte®) supplemented with iso-nitrogen glycine. These rats are either burned (Lot Gly) or not and are the control group.
Les rats sont euthanasiés après 48 heures de nutrition. Les muscles extensor digitalorum longus (EDL) sont prélevés et congelés immédiatement dans l'azote liquide puis conservés à -80°C.  The rats are euthanized after 48 hours of nutrition. The extensor digitalorum longus (EDL) muscles are removed and immediately frozen in liquid nitrogen and stored at -80 ° C.
Les échantillons sont broyés à 4°C dans une solution d'acide trichloracétique 0,6 M contenant 0,5 mM d'EDTA à l'aide d'un Ultraturrax®. Après centrifugation les acides aminés sont dosés dans le surnageant par chromatographie liquide sur colonne échangeuse de cations sur un analyseur Biotronik LC 500. The samples were ground at 4 ° C in a 0.6 M trichloroacetic acid solution containing 0.5 mM EDTA using an Ultraturrax ®. After centrifugation, the amino acids are assayed in the supernatant by liquid chromatography on a cation exchange column on a Biotronik LC 500 analyzer.
2.2. Résultats  2.2. Results
Ils sont donnés dans le tableau 1 ci-dessous:  They are given in Table 1 below:
Tableau 1  Table 1
Figure imgf000008_0001
Figure imgf000008_0001
* p< 0,05 par rapport au lot Gly  * p <0.05 compared to the Gly lot
La concentration musculaire en glutamine est diminuée de manière significative chez les rats brûlés (Gly); le traitement par GLACO à la dose de 0,5 g/kg/j rétablit la concentration musculaire de glutamine de manière significative (GLACO) alors qu'un traitement isoazoté contenant seulement la glutamine n'a aucun effet (Gin +Gly). Muscle glutamine concentration is significantly decreased in burned rats (Gly); treatment with GLACO at the dose of 0.5 g / kg / day significantly restores glutamine muscle concentration (GLACO) while iso-nitrogen-only treatment with glutamine has no effect (Gin + Gly).
EXEMPLE 3: MESURE DES CONCENTRATIONS MUSCULAIRES DE GLUTAMINE CHEZ LE RAT BRULE COMPARAISON ENTRE ACO ET GLACO  EXAMPLE 3: MEASUREMENT OF MUSCLE CONCENTRATIONS OF GLUTAMINE IN THE RAT BRULE COMPARISON BETWEEN ACO AND GLACO
3.1. Mode opératoire  3.1. Operating mode
Un protocole identique à celui décrit dans l'exemple 2 est appliqué. Dans cette expérience un lot d'animaux reçoit de l'ACO à la dose de 0,5 g/kg/j, c'est-à-dire à la même dose que GLACO.  A protocol identical to that described in Example 2 is applied. In this experiment a lot of animals receive ACO at the dose of 0.5 g / kg / day, that is to say at the same dose as GLACO.
3.2. Résultats  3.2. Results
Les résultats sont donnés dans le tableau 2 ci-dessous.  The results are given in Table 2 below.
Tableau 2  Table 2
Figure imgf000009_0001
Figure imgf000009_0001
** p< 0,01 et ***p<0,001 par rapport au lot Gly  ** p <0.01 and *** p <0.001 compared to the Gly lot
Les deux complexes ACO et GLACO restaurent les concentrations musculaires de glutamine, mais de manière beaucoup plus significative sous GLACO.  Both ACO and GLACO complexes restore muscle concentrations of glutamine, but much more significantly under GLACO.
EXEMPLE 4: MESURE DES CONCENTRATIONS MUSCULAIRES DE GLUTAMINE CHEZ LE RAT ENDOTOXEMIQUE  EXAMPLE 4: MEASUREMENT OF MUSCLE CONCENTRATIONS OF GLUTAMINE IN THE ENDOTOXEMIC RAT
- COMPARAISON ENTRE GLUTAMINE ET GLACO - COMPARISON BETWEEN GLUTAMINE AND GLACO
4.1. Mode opératoire  4.1. Operating mode
Des rats mâles de souche Wistar adultes de poids 163 ± 7 g ont été utilisés après acclimatation pendant 3 jours en cage à métabolisme (croquettes UA AO3; 23,5% d'azote), en cycle inversé 12 h nuit/12 h jour. Wistar adult male rats weighing 163 ± 7 g were used after acclimation for 3 days in a metabolism cage (croquettes UA AO3; 23.5% nitrogen), inverted cycle 12h night / 12h day.
A J0, les rats exceptés les rats témoins reçoivent une injection intra- péritonéale d'une endotoxine {lipopolysaccharide d 'E. Coli sérotype 127 B:8) solubilisée dans du NaCl à 0,9% à la dose de 3 mg/kg. Les témoins reçoivent seulement une injection intrapéritonéale de NaCl sous le même volume. Les animaux sont euthanasiés et les muscles prélevés comme indiqué dans l'exemple 2. Le dosage de la glutamine musculaire est également réalisé selon le mode opératoire décrit dans l'exemple 2.  On day 0, the rats, except the control rats, receive an intraperitoneal injection of an endotoxin (E. Lipopolysaccharide). Coli serotype 127 B: 8) solubilized in 0.9% NaCl at a dose of 3 mg / kg. The controls receive only one intraperitoneal injection of NaCl under the same volume. The animals are euthanized and the muscles removed as indicated in Example 2. The muscle glutamine assay is also performed according to the procedure described in Example 2.
4.2. Résultats  4.2. Results
Ils sont donnés dans le tableau 3 ci-dessous  They are given in Table 3 below
Tableau 3  Table 3
Figure imgf000010_0001
Figure imgf000010_0001
p<0,05 par rapport au lot Gly  p <0.05 compared to the Gly lot
La concentration musculaire en glutamine est diminuée de manière significative chez les rats endotoxémiques (Gly); le traitement par GLACO à la dose de 0,5 g/kg/j rétablit la concentration musculaire de glutamine de manière significative (GLACO) alors qu'un traitement isoazoté avec la glutamine seule n'a aucun effet (Gin +Gly).  Muscle glutamine concentration is significantly decreased in endotoxemic (Gly) rats; treatment with GLACO at a dose of 0.5 g / kg / day restores glutamine muscle concentration significantly (GLACO) while iso-nitrogen treatment with glutamine alone has no effect (Gin + Gly).
EXEMPLE 5: APPRECIATION DU CARACTERE ORGANOLEPTIQUE  EXAMPLE 5: ASSESSMENT OF THE ORGANOLEPTIC CHARACTER
5.1. Mode opératoire  5.1. Operating mode
Deux solutions aqueuses à 10% d'ACO et de GLACO sont préparées extemporanément.  Two aqueous solutions with 10% ACO and GLACO are prepared extemporaneously.
Elles sont présentées respectivement comme solution Y et X à 34 personnes (19 femmes et 15 hommes) recrutées pour tester les deux solutions. La répartition en fonction de l'âge et du sexe est donnée dans le tableau suivant: They are presented respectively as solution Y and X to 34 people (19 women and 15 men) recruited to test the two solutions. The breakdown by age and sex is given in the following table:
Figure imgf000011_0001
Figure imgf000011_0001
Les personnes ont été interrogées sur l'aspect et la couleur des solutions, sur leur odeur et sur leur saveur. Pour cette dernière caractéristique, chacune des quatre saveurs classiques (sucré, salé, acide et amer) a été codée de 1 à 5 par ordre d'intensité croissante.  People were asked about the appearance and color of the solutions, their smell and flavor. For this last characteristic, each of the four classic flavors (sweet, salty, sour and bitter) has been coded from 1 to 5 in order of increasing intensity.
5.2. Résultats  5.2. Results
5.2.7. Aspect et couleur  5.2.7. Appearance and color
21 personnes ont préféré l'aspect plus limpide et la couleur jaune très pâle de la solution X (GLACO). 3 personnes ont préféré l'aspect plus liquoreux et la couleur jaune foncée de la solution Y (ACO). 10 personnes n'ont montré aucune préférence.  21 people preferred the clearer appearance and the very pale yellow color of solution X (GLACO). 3 people preferred the more syrupy appearance and the dark yellow color of solution Y (ACO). 10 people showed no preference.
5.2.2. Odeur  5.2.2. Odour
L'odeur de la solution Y (ACO) est trouvée désagréable à l'unanimité mais avec des variations importantes en intensité (de « pas très agréable » à « immonde »). En revanche l'odeur de la solution Y (GLACO) a été préférée par l'ensemble des personnes avec toutefois 12 personnes qui ont trouvé la solution X (GLACO) sans odeur.  The odor of the solution Y (ACO) is found unpleasant with unanimity but with significant variations in intensity (from "not very pleasant" to "foul"). On the other hand, the smell of solution Y (GLACO) was preferred by all people with 12 people who found the solution X (GLACO) odorless.
5.2.3. Saveur  5.2.3. Flavor
30 personnes, rebutées par l'odeur de la solution Y (ACO) ont choisi de goûter la solution X (GLACO) en premier. 4 personnes ont choisi de goûter la solution Y (ACO) en premier. La saveur acide dominante a été reconnue pour la solution X (GLACO) par 32 personnes, cette saveur pouvant aller d'agréable (code 1 , 2 ou 3) à pas très agréable (code 4) voire insupportable (code 5). Les résultats sont donnés dans le tableau suivant: 30 people, scared by the smell of the solution Y (ACO) have chosen to taste the solution X (GLACO) first. 4 people chose to taste the Y (ACO) solution first. The dominant acid flavor has been recognized for the solution X (GLACO) by 32 people, this flavor can range from pleasant (code 1, 2 or 3) not very pleasant (code 4) or even unbearable (code 5). The results are given in the following table:
Figure imgf000012_0001
Figure imgf000012_0001
Les 7 personnes qui ont trouvé cette saveur acide insupportable ont dit être incapable de mordre dans un citron.  The 7 people who found this unbearable acidic flavor said they were unable to bite into a lemon.
La solution Y(ACO) a donné globalement un comportement gustatif aversif de l'ensemble des personnes dû avant tout à l'odeur.  The solution Y (ACO) gave overall an aversive taste behavior of all people due above all to the smell.
Les autres saveurs (amer, salé et sucré) ne sont mentionnées que par très peu de personnes pour les deux solutions.  The other flavors (bitter, salty and sweet) are mentioned by very few people for both solutions.
Ainsi, 25 personnes ont préféré la solution X (GLACO) pour son absence d'odeur et son goût acidulé.  Thus, 25 people preferred the solution X (GLACO) for its lack of smell and its acidulous taste.

Claims

REVENDICATIONS
1. Complexe de glutamine et d'alpha-cétoglutarate d'ornithine pour son utilisation dans le traitement de patients souffrant de troubles liés à une diminution des concentrations plasmatique et/ou musculaire de glutamine, lesdits patients étant choisis dans le groupe comprenant:  A complex of ornithine glutamine and alpha-ketoglutarate for use in the treatment of patients suffering from disorders related to decreased plasma and / or muscle glutamine concentrations, said patients being selected from the group consisting of:
- les traumatisés crâniens,  - the traumatized cranial,
- les personnes ayant eu un accident vasculaire cérébral,  - people who have had a stroke,
- les personnes ayant subi une greffe de moelle ou conditionnées en vue de cette thérapie,  - persons who have undergone a bone marrow transplant or are conditioned for this therapy,
- les personnes en réanimation,  - people in intensive care,
- les personnes souffrant de fractures,  - people with fractures,
- les personnes souffrant des effets de la radiothérapie,  - people suffering from the effects of radiotherapy,
- les personnes en situation pré-opératoire de chirurgie,  - people in a preoperative surgical situation,
- les personnes en continuation post-opératoire d'une nutrition préopératoire et  - people in postoperative continuation of preoperative nutrition and
- les personnes âgées dénutries.  - malnourished elderly people.
2. Complexe selon la revendication 1 caractérisé en ce qu'il est sous une forme administrable par voie orale, entérale ou parentérale.  2. Complex according to claim 1 characterized in that it is in a form that can be administered orally, enterally or parenterally.
3. Complexe selon l'une quelconque des revendications 1 ou 2 caractérisé en ce qu'il est sous une forme administrable par voie orale.  3. Complex according to any one of claims 1 or 2 characterized in that it is in an orally administrable form.
4. Complexe selon l'une quelconque des revendications 1 à 3 caractérisé en ce qu'il est présenté pour une posologie journalière comprise entre 10 et 500 mg/kg de poids, avantageusement comprise entre 14 et 300 mg/kg de poids.  4. Complex according to any one of claims 1 to 3 characterized in that it is presented for a daily dosage of between 10 and 500 mg / kg of weight, preferably between 14 and 300 mg / kg of weight.
5. Composition pharmaceutique comprenant un complexe glutamine et d'alpha-cétoglutarate d'ornithine selon l'une quelconque des revendications précédentes en association avec un excipient pharmaceutiquement acceptable pour son utilisation dans le traitement de patients souffrant de troubles liés à une diminution des concentrations plasmatique et/ou musculaires de glutamine, lesdits patients étant choisis dans le groupe comprenant: 5. A pharmaceutical composition comprising a glutamine and ornithine alpha-ketoglutarate complex according to any one of the preceding claims in association with a pharmaceutically acceptable excipient for use in the treatment of patients suffering from disorders related to a decrease in plasma and / or muscle glutamine concentrations, said patients being chosen from the group comprising:
- les traumatisés crâniens,  - the traumatized cranial,
- les personnes ayant eu un accident vasculaire cérébral,  - people who have had a stroke,
- les personnes ayant subi une greffe de moelle conditionnées en vue de cette thérapie,  - persons having undergone a bone marrow transplant conditioned for this therapy,
- les personnes en réanimation,  - people in intensive care,
- les personnes souffrant de fractures,  - people with fractures,
- les personnes souffrant des effets de la radiothérapie,  - people suffering from the effects of radiotherapy,
- les personnes en situation pré-opératoire de chirurgie,  - people in a preoperative surgical situation,
- les personnes en continuation post-opératoire d'une nutrition préopératoire et  - people in postoperative continuation of preoperative nutrition and
les personnes âgées dénutries.  the elderly malnourished.
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