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WO1993023027A1 - Utilisation de l'alpha-cetoglutarate - Google Patents

Utilisation de l'alpha-cetoglutarate Download PDF

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Publication number
WO1993023027A1
WO1993023027A1 PCT/SE1993/000426 SE9300426W WO9323027A1 WO 1993023027 A1 WO1993023027 A1 WO 1993023027A1 SE 9300426 W SE9300426 W SE 9300426W WO 9323027 A1 WO9323027 A1 WO 9323027A1
Authority
WO
WIPO (PCT)
Prior art keywords
ketoglutarate
alpha
glutamine
analogues
amino acid
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
PCT/SE1993/000426
Other languages
English (en)
Inventor
Erik Vinnars
Jan Wernerman
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.)
Vinnars Erik AB
Original Assignee
Vinnars Erik AB
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 Vinnars Erik AB filed Critical Vinnars Erik AB
Priority to JP5520133A priority Critical patent/JPH06509362A/ja
Priority to EP93910529A priority patent/EP0612245A1/fr
Priority to AU40989/93A priority patent/AU661399B2/en
Publication of WO1993023027A1 publication Critical patent/WO1993023027A1/fr
Priority to NO940190A priority patent/NO306195B1/no
Anticipated expiration legal-status Critical
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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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

Definitions

  • the present application relates to the use of alpha-ketoglutarate in the preparation of a medicament for treatment of critically ill patients for improving protein synthesis capacity and preserving the lean body mass and for improving the glutamine content and maintaining energy status in skeletal muscle, especially of a medicament containing alpha-ketoglutarate in such an amount, so that it provides more than 0.25 g/kg body weight /day of alpha- ketoglutarate, when administered to the patient.
  • composition containing conventional amino acid mixture and alpha-ketoglutarate in such an amount, so that it provides more than 17,5 g/day, ( 17,5 g/L) of alpha-ketoglutarate, optionally with the addition of glutamine or analogues thereof, glucose and/or fat.
  • the glutamine content in skeletal muscle of critically ill patients who are treated with TPN (Total Parenteral Nutrition) according to common method of today is not influenced by this conventional treatment. Also when glutamine is given additionally in an amount of 20g/day per person, only a moderate influence on the skeletal muscle glutamine of critically ill patients could be established.
  • TPN Total Parenteral Nutrition
  • alpha-ketoglutarate has an influence on the glutamine content in skeletal muscle of critically ill patients.
  • parenteral nutritional support In critical states of illness and injuries, parenteral nutritional support is generally applied.
  • preparations for intravenous nutritional support generally contained an aqueous solution of a high caloric content carbohydrate, such as glucose and the like, fat and electrolytes.
  • the nitrogen balance of the body In prolonged states of illness or in injuries the nitrogen balance of the body must however be considered, i.e. the ratio of nitrogen loss to nitrogen intake.
  • the parenteral nutritional support can be supplemented with amino acid supply to improve the nitrogen balance. Different amino acid compositions for parenteral supply are previously known, see e.g.
  • WO 89/03688 discloses that alpha- ketoglutarate has the same effect as glutamine when given to postoperative patients. Preliminary tests on patients subjected to a biliary tract operation showed that an addition of alpha- ketoglutarate to a conventional parenteral nutritional support program improves the nitrogen balance of the patients. Besides, the pathological amino acid changes which normally occur after injury or surgical operation are normalised and, also, the reduction of the ribosome activity is prevented.
  • Critically ill patients is a group of patients who are very ill. They have one or multiple organ failure, such as respiratory problem, renal, liver and/or intestinal insufficiency, a general protein catabolism and must be under intensive care. This group is different from the group of postoperative patients, who often has normal glutamine and protein values before the operation and for who the drop in glutamine level is due to the operation. Critically ill patients have a pronounced protein catabolism and a lower skeletal glutamine content than postoperative patients.
  • Jeppson et al (Am J Physiol 1988, 255, E166-172) has shown a correlation between the protein synthesis and glutamine level in skeletal muscle. By improving the glutamine level in skeletal muscle the protein synthesis capacity is improved and the lean body mass is preserved. This correlation is of importance for the interpretation of the results given in the example below.
  • the present invention relates to the use of alpha-ketoglutarate or analogues thereof in the preparation of a medicament for treatment of critically ill patients for improving protein synthesis capacity, maintaining energy level and preserving the lean body mass and for improving the glutamine content, especially in such an amount so that it provides more than 0.25 g/kg body weight (bw) /day of alpha-ketoglutarate when administered to the patient.
  • the medicament can also comprise conventional amino acid solution and / or glutamine or analogues thereof, L-asparagine and/or acetoacetate.
  • analogues e.g. salts, esters and dipeptides.
  • the present invention also relates to a method for treatment of critically ill patients for improving the glutamine content in skeletal muscle and thereby improving protein synthesis capacity, maintaining energy level and preserving the lean body mass comprising administration of alpha- ketoglutarate or an analogue thereof.
  • Alpha-ketoglutarate may be given alone or in combination with a conventional amino acid solution, optionally with the addition of L-glutamine or analogues thereof, L-asparagine and/or acetoacetate, glucose and/or fat.
  • the invention also refers to a composition for treatment of critically ill patients for improving protein synthesis capacity, Maintaining energy level, preserving the lean body mass and for improving the glutamine content in skeletal muscle comprising conventional amino acid mixture and alpha-ketoglutarate or analogues thereof, in such an amount, so that it provides more than 0.25 g/kg body Weight /day of alpha-ketoglutarate, when administered to the patient, i.e. 17,5 g/day for a person of 70 kg, optionally with the addition of glutamine or analogues thereof, L-asparagine and/or acetoacetate. Glucose and/or fat can also be added.
  • the composition contains alpha-ketoglutarate in a higher amount than 17,5 g/L, or more preferably in a higher amount than 25 g//L.
  • An upper limit of the dose of alpha-ketoglutarate is related to the tolerated level for the patient. No investigations have been done, but an upper limit could be estimated to be about 80 -100 g/ day per patient.
  • alpha-ketoglutarate is not limited to parenteral administration but can also be administered orally.
  • the suggested doses for alpha-ketoglutarate is applicable both for parenteral and oral administration.
  • the conventional amino acid solution is given parenterally.
  • critically ill patients a group of patients who have one or multiple organ failure, and a general protein catabolism. They are treated in intensive care units, often under mechanical ventilation and/or dialysis.
  • the amount of afpha-ketoglutarate is here calculated on the need of the patient per day (i.e. 24 hours). It is the only proper way of defining the amount, as the amount always must depend on body weight (bw) of the patient and the time period for the amount.
  • the alpha-ketoglutarate or its analogue is given together with the solution comprising conventional amino acids.
  • the amount for such a solution is often about one litre per day, but this very much depending on concentration of the solution and the amount of liquid that can be given to the patient.
  • the concentration of at least 0.25 g/kg body weight/ day corresponds to at least 17,5 g component/L aqueous solution if 1 L amino acid solution/day is given to a patient weighing 70 kg.
  • a conventional amino acid solution expressed in g dry component/L aqueous solution is:
  • the added amount of L-glutamine to be given together with this amino solution is at least 17,5 g/L and an especially preferred amount is more than 25 g/L.
  • compositions could include the following suitable components (expressed in g dry component/I aqueous solution):
  • alpha-ketoglutarate should then be added to these solutions in an amount of more than 17,5 g/L, preferably 25 g/L or more.
  • alpha-ketoglutarate When alpha-ketoglutarate is included in the composition, it must be added in the form of its sodium salt or its esters, since it is otherwise extremely sparingly soluble and unstable. Glutamine can also be added in the form of the sodium salt thereof, thus improving its solubility.
  • heat sterilization can be used if the components are not heat sensitive.
  • heat sensitive components such as L-glutamine
  • they can be dissolved in sterile pyrogen-free water at 30-50°C.
  • the solution is sterile- filtered and rapidly cooled and may thereafter be stored for a few months in a solution in a cooled state or for an even longer time in the frozen state, or stored after freeze-drying for several years in sterile powder form, until it should be used together with an amino acid solution of conventional commercial type, for instance of the Vamin® type (amino acid nutrient composition from Kabi Pharmacia AB).
  • Carbohydrates and fatty substances can also be added to the infusion solution.
  • alpha-ketoglutarate this must be added in the form of its sodium salt or its esters, which is also possible, but not necessary, in the case of L-glutamine.
  • the administration being conducted during a period of from 2-4 days to several weeks e.g. with an addition of nutrition to reach a dosage of 120-170 kJ/kg body weight/day, including 0.1- 0.2 g amino acid nitrogen/kg body weight/day.
  • the treatment with alpha-ketoglutarate reduces a lowering of glutamine level in skeletal muscle. By preserving the lean body mass of the patients they are less susceptible for complications during illness and can recover faster from convalescence.
  • RNA Unro & Fleck
  • ASP alkali soluble protein
  • ATP ATP
  • Cr creatine
  • PCr phosphocreatine
  • TPN supplemented with glutamine or AGK does not alter the content of protein or RNA in muscle of critically ill patients during 5 days of treatment.
  • supplementation with AKG improves significantly the energy status of the tissue in terms of maintained levels of ATP and PCr in parallel with an elevation of the free creatine level.
  • This finding is a very important and surprising finding, which can have a great impact for the treatment of critically ill patients.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Utilisation de l'alpha-cétoglutarate, ou de ses analogues, dans la préparation d'un médicament destiné au traitement des patients en état critique, afin d'améliorer leur aptitude à la synthèse des protéines, de maintenir leur niveau énergétique, de préserver la masse des tissus maigres et d'améliorer la teneur en glutamines des muscles du squelette. Ce médicament contient de préférence de l'alpha-cétoglutarate en une dose telle qu'il apporte plus de 0,25g/kg de poids corporel par jour d'alpha-cétoglutarate. Ce médicament peut également renfermer une solution d'acides aminés traditionnelle et/ou une glutamine ou des analogues de celle-ci, une asparagine-L et/ou un acétoacétate. L'invention porte également sur une composition comprenant un mélange d'acides aminés traditionnel et un alpha-cétoglutarate ou ses analogues, en une dose telle qu'il apporte plus de 0,25g/kg de poids corporel par jour d'alpha-cétoglutarate au patient, facultativement avec addition de glutamine ou d'analogues de glutamine, d'asparagine-L et/ou d'acétoacétate, de glucose et/ou de matière grasse.
PCT/SE1993/000426 1992-05-20 1993-05-14 Utilisation de l'alpha-cetoglutarate Ceased WO1993023027A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP5520133A JPH06509362A (ja) 1992-05-20 1993-05-14 アルファ−ケトルグルタル酸塩の用法
EP93910529A EP0612245A1 (fr) 1992-05-20 1993-05-14 Utilisation de l'alpha-cetoglutarate
AU40989/93A AU661399B2 (en) 1992-05-20 1993-05-14 Use of alpha-ketoglutarate
NO940190A NO306195B1 (no) 1992-05-20 1994-01-19 Anvendelse av <alfa>-ketoglutarat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9201584-1 1992-05-20
SE9201584A SE9201584D0 (sv) 1992-05-20 1992-05-20 Use of alpha-ketoglutarate

Publications (1)

Publication Number Publication Date
WO1993023027A1 true WO1993023027A1 (fr) 1993-11-25

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ID=20386290

Family Applications (1)

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PCT/SE1993/000426 Ceased WO1993023027A1 (fr) 1992-05-20 1993-05-14 Utilisation de l'alpha-cetoglutarate

Country Status (7)

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EP (1) EP0612245A1 (fr)
JP (1) JPH06509362A (fr)
AU (1) AU661399B2 (fr)
CA (1) CA2113279A1 (fr)
NO (1) NO306195B1 (fr)
SE (1) SE9201584D0 (fr)
WO (1) WO1993023027A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012991A1 (fr) * 1993-11-09 1995-05-18 Gramineer Ab Nouvelle boisson
WO1995034301A1 (fr) * 1994-06-10 1995-12-21 Pharmacia & Upjohn Ab Substrats energetiques
WO2002060429A1 (fr) * 2001-01-31 2002-08-08 Pharmalink Basläkemedel Ab Conservation d'une proteine corporelle
WO2002064129A3 (fr) * 2001-02-14 2003-05-08 Rath Matthias Compositions de composes biochimiques impliques dans le metabolisme bioenergetique cellulaire et procede d'utilisation
WO2012143405A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de l'alpha-cétoglutarate

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050085498A1 (en) * 1998-05-28 2005-04-21 Byrd Edward A. Oral formulation of lipid soluble thiamine, lipoic acid, creatine derivative, and L-arginine alpha-ketoglutarate
SE0301947D0 (sv) * 2003-07-01 2003-07-01 Gramineer Internat Ab New method and uses
CA2628265A1 (fr) * 2005-11-08 2007-05-18 Multi Formulations Ltd. Utilisation de compositions comprenant des cetoacides et des acides amines pour accroitre la masse et les performances musculaires

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987003806A1 (fr) * 1985-12-18 1987-07-02 Veech Richard L Therapie de nutrition parenterale avec acides amines
WO1989003688A1 (fr) * 1987-10-29 1989-05-05 Ab Erik Vinnars Composition d'amino acide destinee au soutien nutritionnel parenteral et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987003806A1 (fr) * 1985-12-18 1987-07-02 Veech Richard L Therapie de nutrition parenterale avec acides amines
WO1989003688A1 (fr) * 1987-10-29 1989-05-05 Ab Erik Vinnars Composition d'amino acide destinee au soutien nutritionnel parenteral et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 111, No. 19, 6 November 1989 (06.11.89), (Columbus, Ohio, USA), WERNERMAN JAN et al., "Glutamine and ornithine-alfa-ketoglutarate but not branched-chain amino acids reduce the loss off muscle glutamine after surgical trauma", The Abstract No. 172866p. Metab., Clin. Exp. 1989, 38 (8), 63-66. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012991A1 (fr) * 1993-11-09 1995-05-18 Gramineer Ab Nouvelle boisson
US5817364A (en) * 1993-11-09 1998-10-06 Gramineer Ab Beverage containing alpha-ketoglutaric acid and method of making
CN1076183C (zh) * 1993-11-09 2001-12-19 格兰姆尼尔股份公司 新的饮料
WO1995034301A1 (fr) * 1994-06-10 1995-12-21 Pharmacia & Upjohn Ab Substrats energetiques
WO2002060429A1 (fr) * 2001-01-31 2002-08-08 Pharmalink Basläkemedel Ab Conservation d'une proteine corporelle
WO2002064129A3 (fr) * 2001-02-14 2003-05-08 Rath Matthias Compositions de composes biochimiques impliques dans le metabolisme bioenergetique cellulaire et procede d'utilisation
US7056950B2 (en) 2001-02-14 2006-06-06 Matthias Rath Compositions of biochemical compounds involved in bioenergy metabolism of cells
WO2012143405A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de l'alpha-cétoglutarate
CN103476274A (zh) * 2011-04-18 2013-12-25 雀巢产品技术援助有限公司 具有α-HICA和α-酮戊二酸的营养组合物

Also Published As

Publication number Publication date
JPH06509362A (ja) 1994-10-20
EP0612245A1 (fr) 1994-08-31
NO306195B1 (no) 1999-10-04
AU4098993A (en) 1993-12-13
AU661399B2 (en) 1995-07-20
SE9201584D0 (sv) 1992-05-20
NO940190L (no) 1994-01-19
CA2113279A1 (fr) 1993-11-25
NO940190D0 (no) 1994-01-19

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