US20190314307A1 - 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment - Google Patents

3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment Download PDF

Info

Publication number
US20190314307A1
US20190314307A1 US16/472,600 US201716472600A US2019314307A1 US 20190314307 A1 US20190314307 A1 US 20190314307A1 US 201716472600 A US201716472600 A US 201716472600A US 2019314307 A1 US2019314307 A1 US 2019314307A1
Authority
US
United States
Prior art keywords
hydroxybutyrate
macronutrient
critical illness
mice
mmol
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.)
Abandoned
Application number
US16/472,600
Other languages
English (en)
Inventor
Chloe Goossens
Lies Langouche
Greet Van Den Berghe
Ilse Vanhorebeek
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.)
Katholieke Universiteit Leuven
Original Assignee
Katholieke Universiteit Leuven
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 Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Priority to US16/472,600 priority Critical patent/US20190314307A1/en
Priority claimed from PCT/EP2017/081394 external-priority patent/WO2018114309A1/en
Publication of US20190314307A1 publication Critical patent/US20190314307A1/en
Assigned to KATHOLIEKE UNIVERSITEIT LEUVEN reassignment KATHOLIEKE UNIVERSITEIT LEUVEN ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VAN DEN BERGHE, GREET, VANHOREBEEK, ILSE, GOOSSENS, CHLOE, LANGOUCHE, LIES
Abandoned legal-status Critical Current

Links

Images

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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/185—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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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

  • This invention relates generally to methods and compositions for the treatment for amelioration or prevention of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy and particularly to the use of a combination of parenteral or enteral feeding with a carboxylic acid.
  • Critical illness is defined as any acute medical condition necessitating vital organ support without which death would be imminent. Whether evoked by sepsis, severe sepsis, septic shock, trauma, major surgery, or other critical illnesses, patients can suffer from critical illness myopathy and/or critical illness polyneuropathy, a clinical manifestation referred to as intensive care unit (ICU) acquired weakness (ICUAW) (Kress J P, Hall J B 2014 NEJM 370(17): 1626-35). Prevalence of ICUAW varies according to the study population, but up to 80% of ICU patients appear to suffer from muscle wasting and/or muscle weakness. ICUAW is associated with impaired weaning from mechanical ventilation, delayed rehabilitation and prolonged hospitalization, late death and greater impaired functional outcome of survivors.
  • ICU intensive care unit acquired weakness
  • an object of the present invention to provide methods and compositions for treating sepsis, severe sepsis, septic shock, critical illness myopathy and critical illness polyneuropathy. It is another object of the invention to decrease the morbidity and more preferably the muscle weakness associated with sepsis, severe sepsis, septic shock, critical illness myopathy and critical illness polyneuropathy.
  • the above methods are used for the treatment of symptoms associated with a critical illness which includes, but is not limited to sepsis, severe sepsis, septic shock, critical illness myopathy and critical illness polyneuropathy.
  • This invention was based in part on the discovery that critical illness and/or sepsis, severe sepsis, septic shock, critical illness myopathy and critical illness polyneuropathy can be prevented, treated or cured, at least to a certain extent, by a composition containing a carboxylic acid, more preferably 3-hydroxybutyric acid in combination with enteral or parenteral feeding.
  • a composition containing a carboxylic acid, more preferably 3-hydroxybutyric acid in combination with enteral or parenteral feeding.
  • the invention relates to a method of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • Critical illness polyneuropathy and critical illness myopathy are overlapping syndromes of diffuse, symmetric, flaccid muscle weakness occurring in critically ill patients and involving all extremities and the diaphragm with relative sparing of the cranial nerves.
  • An example of a for present invention suitable salt is pharmaceutically acceptable or under food law acceptable (R)-3-hydroxybutyric sodium salt or sodium (S)-3-hydroxybutyrate and an example of a for the present invention suitable ester is pharmaceutically acceptable or under food law acceptable (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
  • Examples of a for present invention suitable administering to a subject in need thereof is a parenteral administration of a parenteral composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof or enteral administration of a enteral composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • the delivery can be continuous or as bolus.
  • One aspect of the invention described herein relates to a method of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or multiple dose regime at a dose range of 0.08 g/kg patient body weight to 4.13 g/kg patient body weight per 24 hours.
  • Another aspect of the invention described herein relates to a method of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or multiple dose regime at a dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • Yet another aspect of the invention described herein relates to a method of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or bolus, parenteral or enteral dose range of 0.08 g/kg to 4.13 g/kg patient body weight per 24 hours.
  • this treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) is carried out with 3-hydroxybutyrate as a continuous or bolus, parenteral or enteral dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • this treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) is carried out with 3-hydroxybutyrate that is administered to a patient at a daily dose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg.
  • compositions described herein provide unexpectedly high muscle force improvement and effectively overcome critical illness myopathy or neuromyopathy or critical illness polyneuropathy in combinational therapy formulated together and in individual dosage amounts or formulated separately and in individual dosage amounts with a chemical energy providing macronutrient or caloric organic compound comprising at least one macronutrient member of one of the macronutrient groups 1) a macronutrient group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligosaccharide and polysaccharide or combination thereof.
  • One object of the invention described herein thus concerns a method for treating such for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof such composition comprising an 3-hydroxybutyrate, wherein the 3-hydroxybutyrate is in combinational therapy formulated together and in individual dosage amounts or formulated separately and in individual dosage amounts with a chemical energy providing macronutrient or caloric organic compound comprising at least one macronutrient member of one of the macronutrient groups 1) a macronutrient group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligosaccharide and poly
  • Another object of the invention described herein thus concerns a method for treating such for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof such composition comprising an 3-hydroxybutyrate, wherein the 3-hydroxybutyrate is in combinational therapy formulated together and in individual dosage amounts or formulated separately and in individual dosage amounts with a chemical energy providing macronutrient or caloric organic compound comprising at least one macronutrient member of two macronutrient groups each of the macronutrient groups 1) a macronutrient group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligos
  • Yet another object of the invention described herein thus concerns a method for treating such for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof such composition comprising an 3-hydroxybutyrate, wherein the 3-hydroxybutyrate is in combinational therapy formulated together and in individual dosage amounts or formulated separately and in individual dosage amounts with a chemical energy providing macronutrient or caloric organic compound comprising at least one macronutrient member of each of the three macronutrient groups 1) a macronutrient group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligosaccharide
  • a certain aspect of the invention described herein thus concerns a method for treating such for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) comprising administering to a subject in need thereof such composition comprising an 3-hydroxybutyrate, wherein the patient has a BMI under 24.9, wherein the patient is a normal weight patient with a BMI between 18.5 and 24.9 or wherein the patient is an underweight patient with a BMI under 18.5.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • composition of treatment of present invention can further comprising one or more pharmaceutically acceptable or under food law acceptable adjuvants, carriers, excipients, and/or diluents.
  • the present disclosure relates in an aspect also to a 3-hydroxybutyrate of the groups consisting of an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • these pharmaceutically acceptable or under food law acceptable salts are (R)-3-hydroxybutyric sodium salt or sodium (S)-3-hydroxybutyrate.
  • the pharmaceutically acceptable or under food law acceptable ester is (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
  • a particular aspect of present invention is that the 3-hydroxybutyrate for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof, whereby the treatment with the 3-hydroxybutyrate is carried out with a continuous or multiple dose regime at a dose range of 0.08 g/kg patient body weight to 4.13 g/kg patient body weight per 24 hours.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Another particular aspect of present invention is that the 3-hydroxybutyrate for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or multiple dose regime at a dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Yet another particular aspect of present invention is that the 3-hydroxybutyrate for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or bolus, parenteral or enteral dose range of 0.08 g/kg to 4.13 g/kg patient body weight per 24 hours.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Yet another particular aspect of present invention is that the 3-hydroxybutyrate for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof, wherein the treatment with the 3-hydroxybutyrate is carried out with a continuous or bolus, parenteral or enteral dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Yet another particular aspect of present invention is that the 3-hydroxybutyrate for use in a treatment to prevent or ameliorate critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) in a subject in need thereof, wherein the 3-hydroxybutyrate is administered to a patient at a daily dose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Yet another aspect of present invention is the 3-hydroxybutyrate of present invention for use treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), wherein the 3-hydroxybutyrate is in combinational therapy formulated together and in individual dosage amounts or formulated separately and in individual dosage amounts with a chemical energy providing macronutrient or caloric organic compound comprising at least one macronutrient member of one of the three macronutrient groups or of two of the three macronutrient groups each or of each of the three macronutrient groups 1) a macronutrient group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligosacchari
  • a lean critically ill subject was found to be in high need for the 3-hydroxybutyrate treatment of present invention and the present therapies have been shown to be highly effective in critical ill lean subjects. It is thus an object of present invention to use to provide a 3-hydroxybutyrate for use treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), wherein the patient has a BMI under 24.9.
  • critical illness myopathy 2016/17 ICD-10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Another object of present invention is to provide a 3-hydroxybutyrate for use treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), wherein the patient is a normal weight patient with a BMI between 18.5 and 24.9.
  • critical illness myopathy 2016/17 ICD10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CINM critical illness neuromyopathy
  • Yet another aspect of present invention is to provide a 3-hydroxybutyrate for use treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), wherein the patient is an underweight patient with a BMI under 18.5.
  • This 3-hydroxybutyrate of the composition comprising 3-hydroxybutyrate for use according to present invention can further comprise one or more pharmaceutically acceptable or under food law acceptable adjuvants, carriers, excipients, and/or diluents.
  • the present disclosure relates in another aspect also to a pack or a composition for use in a combinational therapy of treating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), the pack or composition comprising an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically or under food law acceptable salt, for instance (R)-3-hydroxybutyric sodium salt or sodium (S)-3-hydroxybutyrate, or a pharmaceutically acceptable or under food law acceptable ester thereof, for instance (R)-3-hydroxybutyl (R)-3-hydroxybutyrate and a macronutrient mixture comprising at least one macronutrient member of one of the three macronutrient groups or of two of the three macronutrient groups each or of each of the
  • This pack may be for use in a combinational therapy of treating or preventing of a disorder of c critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM), whereby the disorder is evoked, induced or enhanced by disorder of the group consisting of sepsis (2016/17 ICD-10-CM Diagnosis Code A41.9), severe sepsis (2016/17 ICD-10-CM Diagnosis Code R65.2), severe sepsis with septic shock (2016/2017 ICD-10-CM Diagnosis Code R.65.21) or it may be for use in a combinational treatment to prevent or ameliorate muscle weakness (2017 ICD-10-CM Diagnosis Code M62.81) evoked, induced or enhanced by a critical illness myopathy 2016/17 (ICD-10-CM Diagnosis Code G72.81) or critical illness neuromyopathy
  • Such pack or composition of present invention for use for use in a combinational therapy of treating or preventing of critical illness myopathy can comprise the 3-hydroxybutyrate and said macronutrient mixture formulated together and in individual dosage amounts.
  • the pack or composition for use in a combinational therapy of treating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM)
  • the treatment with 3-hydroxybutyrate can be carried out with a continuous or multiple dose regime at a dose range of 0.08 g/kg patient body weight to 4.13 g/kg patient body weight per 24 hours.
  • the pack or composition for use in a combinational therapy of treating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM)
  • the treatment with 3-hydroxybutyrate can be carried out with a continuous or multiple dose regime at a dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • the pack or composition for use in a combinational therapy of treating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM)
  • the treatment with 3-hydroxybutyrate can be carried out with a continuous or bolus, parenteral or enteral dose range of 0.08 g/kg to 4.13 g/kg patient body weight per 24 hours.
  • the pack or composition for use in a combinational therapy of treating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM)
  • the treatment with 3-hydroxybutyrate can be carried out with a continuous or bolus, parenteral or enteral dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient body weight per 24 hours.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof and wherein is designed for 3-hydroxybutyrate administration to a patient at a daily dose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 1-70 grams.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 5-60 grams.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 10-50 grams.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 0.05-10 grams.
  • the present invention provides also a pack or composition for use of treatment for ameliorating or preventing of critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CINM) whereby the pack comprises an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof, wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 0.08-4.13 grams.
  • said composition is formulated for systemic administration.
  • the composition is used without causing or without aggravating a hepato-pancreato-biliary disorder.
  • the composition is used without causing or without aggravating fatty liver or without aggravating or causing nonalcoholic steatohepatitis (NASH) (2017 ICD-10-CM Diagnosis Code K75.81).
  • NASH nonalcoholic steatohepatitis
  • FIG. 1 Mice body composition.
  • (b) Loss of body weight during the 5-day experiment (ANOVA p 0.4).
  • FIG. 2 Mice skeletal muscle mass and cross-sectional area.
  • the graph displays smoothed curves of the percentage of myofibers in each category, gray dotted line, healthy animals; black line, CLP mice. Statistical difference reflects mean myofiber cross-sectional area.
  • CLP cecal ligation and puncture
  • ctrl healthy control animals, fed: parenterally fed, fast: fasted
  • FIG. 3 Mice skeletal muscle atrophy and autophagy.
  • (c) Activity of the 20S-proteasome (ANOVA p 0.9).
  • (d) Cathepsin activity (ANOVA p 0.4).
  • (e) Relative mRNA expression of Atg7 (ANOVA p ⁇ 0.01).
  • (f) Relative mRNA expression of Atg5 (ANOVA p ⁇ 0.01).
  • (g) LC3-II/LC3-1 protein ratio, as detected with western blot (ANOVA p 0.4).
  • FIG. 4 Mice muscle and hepatic triglyceride content.
  • ctrl healthy control animals, fed: parenterally fed, fast: fasted]
  • FIG. 5 Mice fatty acid metabolism.
  • FIG. 6 Mice glycerol metabolism.
  • (b) Relative mRNA levels of Aqp9 (ANOVA p 0.4).
  • (c) Relative mRNA levels of Gk (ANOVA p 0.04).
  • Gene expression data are expressed normalized to Rn18s gene expression and as a fold change of the mean of the lean healthy controls.
  • FIG. 7 Mice muscle force. Ex vivo force measurements of the m. extensor digitorum longus (EDL).
  • EDL Dry weight
  • ANOVA p ⁇ 0.01 Peak tetanic muscle tensions
  • CLP cecal ligation and puncture
  • ctrl healthy control animals, PF, pair-fed, fed: parenterally fed
  • FIG. 8 Muscle cross-sectional area in prolonged critically ill patients.
  • Cross-sectional area is categorized in blocks of 1000 pixels.
  • the graph displays smoothed curves of the percentage myofibers in each category, split up for critically ill patients (black line) and healthy controls (gray dotted line).
  • Statistical difference reflects a change in proportion of small ( ⁇ 2000) myofibers.
  • FIG. 9 Effect of 3-hydroxybutyrate administration on muscle weakness in prolonged critically ill mice.
  • EDL extensor digitorum longus
  • FIG. 10 Effect of 3-hydroxybutyrate injections on 5-day mortality in prolonged critically ill mice.
  • Black line healthy control mice (15/15 survivors); gray line, parenterally fed critically ill mice (17/20 survivors); dash dot line; parenterally fed critically ill mice receiving 3-hydroxybutyrate (17/21 survivors); dotted line, fasted critically ill mice receiving 3-hydroxybutyrate (14/22 survivors).
  • FIG. 11 Effect of 3-hydroxybutyrate administration on muscle wasting in prolonged critically ill mice.
  • EDL extensor digitorum longus
  • FIG. 11 Dry weight of the tibialis anterior muscle.
  • PN parenteral nutrition
  • 3HB 3-hydroxybutyrate
  • FIG. 12 Effect of a ketogenic diet on muscle weakness in prolonged critically ill mice.
  • EDL extensor digitorum longus
  • FIG. 13 Effect of a ketogenic diet on muscle wasting in prolonged critically ill mice.
  • EDL extensor digitorum longus
  • FIG. 14 Circulating 3-hydroxybutyrate in prolonged critically ill mice.
  • light gray parenterally fed critically ill mice
  • PN parenteral nutrition;
  • Lipid lipid-rich, ketogenic diet].
  • FIG. 15 Effect of a ketogenic diet on liver steatosis in prolonged critically ill mice.
  • Liver steatosis presented as the hepatic triglyceride content.
  • light gray parenterally fed critically ill mice
  • PN parenteral nutrition;
  • Lipid lipid-rich, ketogenic diet].
  • FIG. 16 Effect of ketone supplementation with different compositions of parenteral nutrition on muscle wasting in prolonged critically ill mice.
  • A Wet weight of the extensor digitorum longus (EDL) muscle.
  • B Ex vivo absolute force measurements of the EDL muscle.
  • C Ex vivo specific force measurements of the EDL muscle.
  • the caloric target in the meaning of this application is a caloric target calculated as the caloric need times the Corrected Ideal Body Weight.
  • the formula for calculating Ideal Body Weight for a female patient is 45.5+[0.91 ⁇ (height in cm ⁇ 152.4)] and for a male patient 50+[0.91 ⁇ (height in cm ⁇ 152.4)]. If BMI ⁇ 18.5, the Corrected Ideal Body Weight is (Ideal Body Weight+Actual Body Weight)/2, if 27 ⁇ BMI ⁇ 18.5, the Corrected Ideal Body Weight is the Ideal Body Weight, if BMI>27, the Corrected Ideal Body Weight is the Ideal Body Weight ⁇ 1.2.
  • the caloric need for a female patient>60 years is 24 kcal/kg/day
  • the caloric need for a male patient>60 years is 30 kcal/kg/day
  • the caloric need for a female patient ⁇ 60 years is 30 kcal/kg/day
  • the caloric need for a male patient ⁇ 60 years it is 36 kcal/kg/day.
  • caloric calories required for pediatric ICU patients differ from adults, for instance caloric calories required for pediatric ICU patients is 100 Cal/kg/day for a body weight 0-10 kg, 1000+(50/kg over 10 kg) for a body weight of 10-20 kg, and 1500+(20/kg over 20 kg) for a body weight>20 kg. It has to be understood that likewise the claimed ratio chemical energy providing macronutrient or caloric organic compounds in the medical compositions are adaptable for pediatric ICU patients.
  • subject refers to any animal, including, without limitation, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like, and transgenic animals.
  • the methods of the invention find use in experimental animals, in veterinary applications, and in the development of animal models for disease.
  • the patient is a human.
  • parenterally or “parenteral administration” as used herein means administration of a product by means of injection, such as injection into a vein (intravenous administration), into a muscle (intramuscular administration), under the skin (subcutaneous administration) or intraperitoneal injection.
  • enteral administration refers to the introduction of a product into the stomach or intestines, such as by tube feeding or by peroral administration (such as eating).
  • enteral administration refers to the introduction of a product into the stomach or intestines via a tube.
  • Critical illness myopathy and Critical illness polyneuropathy refers to a syndrome of diffuse, symmetric, flaccid muscle weakness occurring in critically ill patients and involving all extremities and the diaphragm with relative sparing of the cranial nerves.
  • Critical illness myopathy and Critical illness polyneuropathy have similar symptoms and presentations and are often distinguished largely on the basis of specialized electrophysiological testing or muscle and nerve biopsy.
  • a “critically ill patient”, as used herein refers to a patient who has sustained or are at risk of sustaining acutely life-threatening single or multiple organ system failure due to disease or injury, a patient who is being operated and where complications supervene, and a patient who has been operated in a vital organ within the last week or has been subject to major surgery within the last week.
  • the term a “critically ill patient”, as used herein refers to a patient who has sustained or are at risk of sustaining acutely life-threatening single or multiple organ system failure due to disease or injury, or a patient who is being operated and where complications supervene.
  • a “critically ill patient”, as used herein refers to a patient who has sustained or are at risk of sustaining acutely life-threatening single or multiple organ system failure due to disease or injury.
  • these definitions apply to similar expressions such as “critical illness in a patient” and a “patient is critically ill”.
  • ICU Intensive Care Unit
  • ICU Intensive Care Unit
  • ICU refers to the part of a hospital where critically ill patients are treated. Of course, this might vary from country to country and even from hospital to hospital and said part of the hospital may not necessary, officially, bear the name “Intensive Care Unit” or a translation or derivation thereof. Of course, the term “Intensive Care Unit” also covers a nursing home, a clinic, for example, a private clinic, or the like if the same or similar activities are performed there.
  • lipid refers to a fat or fat-like substance that is insoluble in polar solvents such as water.
  • lipid is intended to include true fats (e.g. esters of fatty acids and glycerol); lipids (phospholipids, cerebrosides, waxes); sterols (cholesterol, ergosterol) and lipoproteins (e.g. HDL, LDL and VLDL).
  • BMI body mass index
  • body mass index refers to the ratio of weight (kg)/height (m2) and can be used to define whether a subject is underweight, normal, overweight, obese or severely obese.
  • a subject is underweight if he has a BMI ⁇ 18.5; normal if he has a BMI of 18.5-24.9, overweight if he has a BMI of 25-29.9, class I obese if he has a BMI of 30-34.9, class II obese if he has a BMI of 35-39.9 and class Ill or severely obese if he has a BMI>40.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) increasing survival time; (b) decreasing the risk of death due to the disease; (c) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (d) inhibiting the disease, i.e., arresting its development (e.g., reducing the rate of disease progression); and (e) relieving the disease, i.e., causing regression of the disease, (f) improving the condition of the patient (e.g., in one or more symptoms), etc.
  • administration refers to delivery of at least one therapeutic agent to a patient.
  • “Pharmaceutically acceptable or under food law acceptable salt” includes, but is not limited to, amino acid salts, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate salts, or salts prepared from the corresponding inorganic acid form of any of the preceding, e.g., hydrochloride, etc., or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts.
  • salts containing pharmaceutically acceptable or under food law acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted
  • prodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith by reference. Such pharmaceutically acceptable or under food law acceptable esters are usually hydrolyzed in vivo when injected in a mammal and transformed into the acid form of the carboxylic acid.
  • a pharmaceutically acceptable or under food law acceptable carrier medium includes any and all solvents, diluents, other liquid vehicles, dispersion or suspension aids, surface active ingredients, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton Pa. 1975) discloses various vehicles or carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, (such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition), its use is within the scope of the invention.
  • a device comprising means A and B should not be limited to the devices consisting only of components A and B. It means that with respect to the present invention, the only relevant components of the device are A and B.
  • the invention is broadly drawn to provide for an enteral or parenteral composition
  • an enteral or parenteral composition comprising 1) a carboxylic acid and 2) a chemical energy providing macronutrient or caloric organic compound of the group consisting of amino acid, peptide, protein, fatty acid, glycerol, glyceride, triglyceride, monosaccharide, disaccharide, oligosaccharide and polysaccharide or combination thereof for use in the treatment of the physical condition of patient with a disorder of the group consisting of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy.
  • Exemplary carboxylic acids are acetoacetic acid, lactic acid, propionic acid, 3-hydroxypropanoic acid, malonic acid, hydroxypentanoic acid, butyric acid, ⁇ -methylbutyric acid, ⁇ -hydroxy 3-methylbutyric acid, erythrose, threose, 1,2-butanediol,1,3-butanediol, 2,3-butanediol, 1,4-butanediol, hydroxybutyric acid, 3-hydroxybutyric acid, L- ⁇ -hydroxybutyric acid, D- ⁇ -hydroxybutyric acid, DL- ⁇ -hydroxybutyric acid or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • the carboxylic acid is selected from the group consisting of acetoacetic acid, hydroxybutyric acid, 3-hydroxybutyric acid and L- ⁇ -hydroxybutyric acid or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • the carboxylic acid is acetoacetic acid (also diacetic acid); the organic compound with the formula CH3COCH2COOH. It is the simplest beta-keto acid group, and like other members of this class it is unstable. The methyl and ethyl esters, which are quite stable, are produced on a large scale industrially as precursors to dyes.
  • Acetoacetic acid is a weak acid. It is of biochemical importance in various animals, including humans, as one of the endogenous ketone bodies produced by the liver when it breaks down fatty acids into Acetyl-CoA and TCA cycle intermediates are depleted (particularly oxaloacetate, which is formed from pyruvate derived from glycolysis).
  • the carboxylic acid is ⁇ -Hydroxybutyric acid, also known as 3-hydroxybutyric acid, an organic compound and a beta hydroxy acid with the formula CH3CH(OH)CH2CO2H; its conjugate base is beta-hydroxybutyrate, also known as 3-hydroxybutyrate.
  • ⁇ -Hydroxybutyric acid is a chiral compound having two enantiomers, D- ⁇ -hydroxybutyric acid and L- ⁇ -hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature.
  • the enteral or parenteral composition is intended for use in the treatment for preventing or improving muscle weakness of patient with a disorder of the group consisting of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy.
  • the enteral or parenteral composition is intended for use in the treatment for preventing or improving muscle weakness, despite muscle wasting of a patient with a disorder of the group consisting of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy.
  • the composition is used without causing or without aggravating a hepato-pancreato-biliary disorder.
  • the composition is used without causing or without aggravating fatty liver.
  • the enteral or parenteral composition further comprises a pharmaceutically acceptable or under food law acceptable carrier.
  • the enteral or parenteral composition has a total calorie content between 16-106% of the calculated caloric target for intensive care (ICU) patients.
  • the enteral or parenteral composition has a total calorie content between 200 to 2000 kcal/l, yet more preferable between 900 to 1400 kcal/l, yet more preferable 900 to 1300 kcal/I, 1100 to 1200 kcal/l.
  • the composition has a calorie content of monosaccharide, disaccharide, oligosaccharide, polysaccharide, fatty acid, glycerol, glyceride and/or triglyceride between 600 to 1300 kcal/l, yet more preferable between 700 to 1200 kcal/l, yet more preferable 800 to 1100 kcal/l, 900 to 1000 kcal/l.
  • the composition has a calorie content of amino acid, peptide and/or protein between 20 to 330 kcal/l, yet more preferable between 50 to 300 kcal/l, yet more preferable 100 to 250 kcal/I and most preferable 150 to 200 kcal/l.
  • the composition has a calorie content of monosaccharide, disaccharide, oligosaccharide and/or polysaccharide between 200 to 800 kcal/l, yet more preferable between 300 to 800 kcal/l, yet more preferable 400 to 700 kcal/I and most preferable 500 to 600 kcal/l.
  • the composition has a calorie content of fatty acid, glycerol, glyceride and/or triglyceride between 200 to 600 kcal/l, yet more preferable between 250 to 550 kcal/l, yet more preferable 300 to 500 kcal/I and most preferable 350 to 450 kcal/l.
  • the fatty acid, glycerol, glyceride and/or triglyceride provide between 20 to 80%, yet more preferable 25 to 45% and most preferable 30 to 40% of the total calorie content of said composition.
  • the carboxylic acid or carboxylate thereof or pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof is administered to a patient at a daily dose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg and the additional chemical energy providing macronutrient or caloric organic compound is administered to a patient at a dose of 10-100% of the calculated caloric target for ICU patients.
  • this administration is enteral or parenteral, once to several times for one day to several days and in 84% of the patients less than 14 days.
  • the composition is used in a treatment of a patient with a BMI under 24.9, more particularly in a treatment of a normal weight patient with a BMI between 18.5 and 24.9 or in the treatment of an underweight patient with a BMI under 18.5.
  • the present invention provides a method for preventing and treating sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy.
  • the method comprises administering the enteric or parenteral composition comprising 1) a carboxylic acid and 2) a chemical energy providing macronutrient or caloric organic compound of the group consisting of amino acid, peptide, protein, fatty acid, glycerol, glyceride, triglyceride, monosaccharide, disaccharide, oligosaccharide and polysaccharide or combination thereof.
  • the carboxylic acid can be selected from the group consisting of acetoacetic acid, lactic acid, propionic acid, 3-hydroxypropanoic acid, malonic acid, hydroxypentanoic acid, butyric acid, ⁇ -methylbutyric acid, ⁇ -hydroxy 3-methylbutyric acid, erythrose, threose, 1,2-butanediol,1,3-butanediol, 2,3-butanediol, 1,4-butanediol, hydroxybutyric acid, 3-hydroxybutyric acid and L- ⁇ -hydroxybutyric acid or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • the carboxylic acid is selected from the group consisting of acetoacetic acid, hydroxybutyric acid, 3-hydroxybutyric acid and L- ⁇ -hydroxybutyric acid or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically acceptable or under food law acceptable ester thereof.
  • the caloric target can be calculated as the caloric need times the Corrected Ideal Body Weight.
  • the formula for calculating Ideal Body Weight for a female patient is 45.5+[0.91 ⁇ (height in cm ⁇ 152.4)] and for a male patient 50+[0.91 ⁇ (height in cm ⁇ 152.4)]. If BMI ⁇ 18.5, the Corrected Ideal Body Weight is (Ideal Body Weight+Actual Body Weight)/2, if 27 ⁇ BMI ⁇ 18.5, the Corrected Ideal Body Weight is the Ideal Body Weight, if BMI>27, the Corrected Ideal Body Weight is the Ideal Body Weight ⁇ 1.2.
  • the caloric need for a female patient>60 years is 24 kcal/kg/day
  • the caloric need for a male patient>60 years is 30 kcal/kg/day
  • the caloric need for a female patient ⁇ 60 years is 30 kcal/kg/day
  • the caloric need for a male patient ⁇ 60 years it is 36 kcal/kg/day.
  • the invention includes method for the treatment for preventing or improving muscle weakness of patient with a disorder of the group consisting of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy, comprising administering an enteric or parenteral composition.
  • the invention includes method for the treatment for preventing or improving muscle weakness of patient despite muscle wasting with a disorder of the group consisting of sepsis, severe sepsis, severe sepsis with septic shock, critical illness myopathy and critical illness polyneuropathy, comprising administering an enteric or parenteral composition.
  • the method is used in a treatment of a patient with a BMI under 24.9, more particularly in a treatment of a normal weight patient with a BMI between 18.5 and 24.9 or in the treatment of an underweight patient with a BMI under 18.5.
  • the method further comprises one or more pharmaceutically acceptable or under food law acceptable adjuvants, carriers, excipients, and/or diluents.
  • Diet-induced obesity Male, 12-week old C57BL/6J mice (Janvier SAS Chassal, France) received ad libitum standard chow (10% fat, E15745-04, ssniff, Soest, Germany), or ad libitum high-fat diet (45% fat, E15744-34, ssniff) for 12 weeks. Body weight was quantified weekly. Only animals placed on the high-fat diet that reached a body weight above 30 g but below 45 g (to avoid morbid obesity-associated metabolic alterations) within the 12 weeks of diet were included in the study. Tail blood glucose measurements indicated that all mice remained normoglycemic during the obesity-inducing diet (Accu-check, Roche, Basel, Switzerland).
  • mice After 5 days of critical illness, animals were sacrificed by decapitation, vital organs were removed, snap frozen in liquid nitrogen and stored at ⁇ 80° C., or preserved in paraformaldehyde. In lean CLP animals, 9/15 fasted and 7/11 fed mice survived until day 5. In obese CLP animals, 9/10 fasted and 10/18 fed mice survived until day 5.
  • EDL extensor digitorum longus
  • Serum concentrations of free fatty acids, glycerol and 3-hydroxybutyrate (3-HB) were determined with commercially available assay kits (free fatty acid fluorometric assay kit, Cayman Chemical Company, Ann Arbor, Mich., USA; glycerol assay kit, Sigma-Aldrich, Saint Louis, Mo., USA; EnzyChrom ketone body assay kit, BioAssay Systems, Hayward, Calif., USA).
  • RNA of skeletal muscle and liver was isolated and cDNA was quantified in realtime as previously described with commercial TaqMan® Assays (Applied Biosystems, Carlsbad, Calif., USA). Data were normalized to ribosomal 18S (Rn18s) gene expression and expressed as fold change of the mean of the controls.
  • Microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, LC3-II (Ab from Sigma-Aldrich) and p62 protein (Ab from Novus, Littleton, Colo., USA) levels were quantified in m. gastrocnemius with Western blots. Data were expressed relative to the means of the controls.
  • Muscle weakness In fully cooperative patients, who were still in the ICU on day 8 ⁇ 1, muscle strength was quantified with the MRC sum score (Hermans et al, 2013 Lancet Respir Med 1(8):621-9). To correct for a possible bias by an effect of the randomized intervention on ICU stay, a random sample of patients discharged from the ICU was assessed in the regular hospital ward on post-randomization day 8 ⁇ 1. Clinically relevant weakness was diagnosed when the MRC sum score was lower than 48. Of the 352 patients that were tested on post-admission-day 8 ⁇ 1, 139 lean and 139 overweight/obese patients were propensity score matched, similarly as the first sets. Of the 139 lean patients, 74 patients were tested on the regular hospital ward, 65 in the ICU. Of the 139 overweight/obese patients, 76 patients were tested on the ward, 63 in the ICU.
  • Example 2 Mice Study—Markers of Skeletal Muscle Atrophy and Autophagy
  • cathepsin activity was increased in lean CLP mice, whereas this increase tended to be attenuated in obese CLP mice ( FIG. 3 d ).
  • fasting further increased the cathepsin activity both in lean and obese CLP mice ( FIG. 3 d ).
  • Atg7 was elevated in both lean and obese CLP mice, but most pronounced in fasted lean CLP mice ( FIG. 3 e ). In contrast, Atg5 gene expression was only increased in fasted lean CLP mice ( FIG. 3 f ).
  • Hepatic gene expression of Cd36 was markedly increased in obese (healthy, fasted-CLP and fed-CLP) mice compared to lean (healthy, fasted-CLP and fed-CLP) mice ( FIG. 5 b ).
  • Hepatic gene expression of Acadl, the first enzyme of ⁇ -oxidation was comparable in lean, obese, healthy, and CLP mice (data not shown).
  • hepatic gene expression of Hmgcs2, encoding for the mitochondrial enzyme that catalyzes the first step of ketogenesis decreased in lean CLP animals (lean healthy control mice 1.0 ⁇ 0.1 vs.
  • lean CLP mice demonstrated a lower peaktetanic tension and a lower recovery from fatigue than lean control mice
  • obese CLP mice maintained peak tetanic tensions and the recovery from fatigue was comparable to obese healthy control mice ( FIG. 7 b - c ).
  • obese CLP mice tended to have higher peak tetanic tensions and displayed better recovery from fatigue ( FIG. 7 b - c ).
  • Example 6 Patient Study—Muscle Wasting and Weakness
  • mice and humans that being obese prior to becoming critically ill protected against muscle wasting and weakness.
  • obese mice showed better preservation of muscle mass and myofiber size, irrespective of whether they were fasted or received parenteral nutrition.
  • obese CLP mice preserved their muscle strength.
  • Obesity, but not nutrition during critical illness attenuated the loss of lipids and myofibrillary proteins, and increased mobilization and metabolization of fat from adipose tissue.
  • myofiber size appeared more preserved than in lean patients.
  • Insufficient autophagy activation is characterized by elevated p62 protein levels and an inadequate rise in LC3-II/LC3-1 ratio.
  • LC3-II/LC3-1 ratio increased expression of autophagy-related genes Atg5 and Atg7 in muscle of lean and obese CLP mice.
  • ubiquitin-proteasome pathway only lean but not obese critically ill animals displayed an additional upregulation in autophagy genes in response to fasting. Histological analysis indicated presence of muscle abnormalities (such as myocyte necrosis, fibrosis and fasciitis) in our mice model consistent with earlier human and rodent observations.
  • Glycerol and fatty acid metabolism can indeed generate vital energy through the production of glucose and ketone bodies.
  • ketone bodies may also directly be involved in the attenuation of muscle wasting, comparable to what has been observed in pancreatic cancer cachexia (Shukla S K et al, 2014 Cancer&Metabolism 2:18).
  • Muscle wasting was evaluated by quantification of the dry weight of isolated skeletal muscles. Muscle weight of the EDL muscle decreased in all critically ill mice, irrespective of hydroxybutyrate treatment or nutritional regime (1.9 ⁇ 0.3 mg for PN, 2.1 ⁇ 0.3 mg for PN+3HB, and 2.0 ⁇ 0.4 mg for fasting+3HB as compared with 2.7 ⁇ 0.3 mg in healthy control mice; p ⁇ 0.0001) ( FIG. 11A ).
  • Muscle dry weight of the EDL muscle decreased in all critically ill mice, irrespective of nutritional regime (2.9 ⁇ 0.6 mg for PN, 2.9 ⁇ 0.6 mg for Lipid, as compared with 4.3 ⁇ 1 mg for healthy controls; p ⁇ 0.0001) ( FIG. 13A ). Also tibialis anterior dry weight decreased similarly in all critically ill mice (9.6 ⁇ mg for PN and 10.2 ⁇ 1.8 mg for Lipid versus 12.7 ⁇ 3.4 mg in healthy controls; p ⁇ 0.001) ( FIG. 13B ). The lipid-rich diet increased circulating 3-hydroxybutyrate to 0.8 ⁇ 0.6 mM (p ⁇ 0.0001 compared to PN critically ill mice and healthy controls) ( FIG. 14 ).
  • livers of Lipid critically ill mice contained 7-times more triglycerides than PN critically ill mice and healthy controls (p ⁇ 0.0001) ( FIG. 15 ). This unfavorable liver steatosis limits the therapeutic potential of a lipid-rich, ketogenic diet during critical illness.
  • mice received twice daily a bolus injection of 75 mg of 3HB combined either with standard total parenteral nutrition (3HB+TPN, mixture of glucose, lipids and amino acids), a glucose infusion (3HB+GLUC), a lipid-low-glucose infusion (3HB+LIP), or an amino-acids-low-glucose infusion (3HB+AA) [Table 1 for composition].
  • standard total parenteral nutrition (3HB+TPN, mixture of glucose, lipids and amino acids)
  • a glucose infusion 3HB+GLUC
  • a lipid-low-glucose infusion 3HB+LIP
  • amino-acids-low-glucose infusion 3HB+AA
  • EDL extensor digitorum longus
  • the maximal force reached by the GLUC+3HB, LIPID+3HB and AA+3HB groups was significantly lower than the TPN+3HB group (p ⁇ 0.05) with respectively 62% (173 ⁇ 13 mN), 57% (158 ⁇ 16 mN) and 56% (155 ⁇ 15 mN) of the maximal muscle force of the healthy controls (p ⁇ 0.0001).
  • Specific maximal muscle force, corrected for the total EDL weight, was comparable between TPN+3HB and healthy controls, whereas it was lower than controls similarly in the GLUC+3HB, LIPID+3HB and AA+3HB groups ( FIG. 16C ).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Nutrition Science (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US16/472,600 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment Abandoned US20190314307A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/472,600 US20190314307A1 (en) 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201662438771P 2016-12-23 2016-12-23
LU100353 2017-08-01
LU100353 2017-08-01
PCT/EP2017/081394 WO2018114309A1 (en) 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment
US16/472,600 US20190314307A1 (en) 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/081394 A-371-Of-International WO2018114309A1 (en) 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/135,847 Continuation US20230310353A1 (en) 2016-12-23 2023-04-18 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Publications (1)

Publication Number Publication Date
US20190314307A1 true US20190314307A1 (en) 2019-10-17

Family

ID=60582587

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/472,600 Abandoned US20190314307A1 (en) 2016-12-23 2017-12-04 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment
US18/135,847 Pending US20230310353A1 (en) 2016-12-23 2023-04-18 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Family Applications After (1)

Application Number Title Priority Date Filing Date
US18/135,847 Pending US20230310353A1 (en) 2016-12-23 2023-04-18 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

Country Status (10)

Country Link
US (2) US20190314307A1 (ja)
EP (1) EP3558291A1 (ja)
JP (1) JP7174428B2 (ja)
KR (1) KR20190099469A (ja)
CN (1) CN110248652B (ja)
AU (1) AU2017381059B2 (ja)
BR (1) BR112019012899A2 (ja)
CA (1) CA3047362A1 (ja)
CO (1) CO2019007531A2 (ja)
MX (1) MX2019007597A (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021247360A1 (en) * 2020-06-05 2021-12-09 Baxter International Inc. Parenteral nutrition formulation
CN117243939A (zh) * 2023-11-14 2023-12-19 南京今冉生物新材料科技有限公司 一种酮体缓释物及其应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1098655B1 (en) * 1998-07-22 2004-11-24 Metabolix, Inc. Nutritional and therapeutic uses of 3-hydroxyalkanoate oligomers
JP2002524506A (ja) * 1998-09-15 2002-08-06 ビーティージー・インターナショナル・リミテッド 治療用組成物（ｉｉ）
AU2004245567B2 (en) * 2003-06-03 2011-06-23 Oxford University Innovation Limited Nutritional supplements and therapeutic compositions comprising (R)-3-hydroxybutyrate derivatives
CN100344280C (zh) * 2005-08-01 2007-10-24 清华大学 3－羟基丁酸及其衍生物的新用途
CN102164884B (zh) * 2008-08-21 2015-03-11 伊希斯创新有限公司 羟基丁酸酯及其医学用途
GB201206192D0 (en) 2012-04-05 2012-05-23 Tdeltas Ltd Ketone bodies and ketone body esters and for maintaining or improving muscle power output
GB201314127D0 (en) 2013-08-07 2013-09-18 Tdeltas Ltd Ketone body and ketone body ester for reducing muscle breakdown

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021247360A1 (en) * 2020-06-05 2021-12-09 Baxter International Inc. Parenteral nutrition formulation
US11666548B2 (en) 2020-06-05 2023-06-06 Baxter International Inc. Parenteral nutrition formulation
CN117243939A (zh) * 2023-11-14 2023-12-19 南京今冉生物新材料科技有限公司 一种酮体缓释物及其应用

Also Published As

Publication number Publication date
MX2019007597A (es) 2019-12-19
KR20190099469A (ko) 2019-08-27
CO2019007531A2 (es) 2020-01-17
AU2017381059A1 (en) 2019-07-25
EP3558291A1 (en) 2019-10-30
BR112019012899A2 (pt) 2019-12-03
CA3047362A1 (en) 2018-06-28
CN110248652A (zh) 2019-09-17
AU2017381059B2 (en) 2023-11-30
US20230310353A1 (en) 2023-10-05
JP7174428B2 (ja) 2022-11-17
JP2020502202A (ja) 2020-01-23
CN110248652B (zh) 2023-05-26

Similar Documents

Publication Publication Date Title
WO2018114309A1 (en) 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment
US20230310353A1 (en) 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment
US20210100766A1 (en) Methods of sustaining dietary ketosis and its effects on lipid profile
Fucho et al. ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis
Zhu et al. Expression patterns of hepatic genes involved in lipid metabolism in cows with subclinical or clinical ketosis
Wilson et al. Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review
US20190388379A1 (en) Anaplerotic therapy for alzheimer's disease and the aging brain
Derde et al. Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits
Greiwe et al. Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle
US20100062090A1 (en) Pharmaceutical Composition Comprising Metadoxine and Garlic Oil For Preventing and Treating Alcohol-Induced Fatty Liver and Steatohepatitis
US20130197084A1 (en) Nutrient sensor
Horii et al. Effects of Eucommia leaf extracts on autonomic nerves, body temperature, lipolysis, food intake, and body weight
US20110306663A1 (en) Triheptanoin diet for adult polyglucosan body disease (apbd) treatment
Myette-Côté et al. Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing
KR20180015126A (ko) 자폐증을 치료하기 위한 조성물 및 방법
Brunt et al. Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice
Poffé et al. Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload
Tecos et al. Disruption of enterohepatic circulation of bile acids ameliorates small bowel resection associated hepatic injury
JP2008184429A (ja) 肝臓トリグリセリド濃度低下剤
US20140155442A1 (en) Anti-obesity agent comprising high-purity epa
US20020197301A1 (en) Animal body fat control
Pathak Modifying Acetylation in Skeletal Muscle to Improve Health-and Life-Span
신채영 Effects of Aerobic Exercise and Diet Control on Myonectin and Fatty Acid Transporters in Skeletal Muscle and Liver Obese Mice
Juby Addressing the knowledge gaps in two common age-related conditions, both associated with nutrition and physical activity: Alzheimer’s Dementia and Sarcopenia

Legal Events

Date Code Title Description
AS Assignment

Owner name: KATHOLIEKE UNIVERSITEIT LEUVEN, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GOOSSENS, CHLOE;LANGOUCHE, LIES;VAN DEN BERGHE, GREET;AND OTHERS;SIGNING DATES FROM 20200330 TO 20200331;REEL/FRAME:052275/0039

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE AFTER FINAL ACTION FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: ADVISORY ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION