WO2018114309A1 - 3-hydroxybutyrate seul ou en combinaison pour une utilisation dans le traitement de soins d'urgence - Google Patents

3-hydroxybutyrate seul ou en combinaison pour une utilisation dans le traitement de soins d'urgence Download PDF

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Publication number
WO2018114309A1
WO2018114309A1 PCT/EP2017/081394 EP2017081394W WO2018114309A1 WO 2018114309 A1 WO2018114309 A1 WO 2018114309A1 EP 2017081394 W EP2017081394 W EP 2017081394W WO 2018114309 A1 WO2018114309 A1 WO 2018114309A1
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Prior art keywords
hydroxybutyrate
composition
macronutrient
use according
pack
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PCT/EP2017/081394
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English (en)
Inventor
Chloë GOOSSENS
Lies Langouche
Greet Van Den Berghe
Ilse Vanhorebeek
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Katholieke Universiteit Leuven
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Priority to CA3047362A priority Critical patent/CA3047362A1/fr
Priority to KR1020197021001A priority patent/KR20190099469A/ko
Priority to JP2019533344A priority patent/JP7174428B2/ja
Priority to BR112019012899A priority patent/BR112019012899A2/pt
Priority to EP17809280.5A priority patent/EP3558291A1/fr
Priority to AU2017381059A priority patent/AU2017381059B2/en
Application filed by Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Priority to MX2019007597A priority patent/MX2019007597A/es
Priority to US16/472,600 priority patent/US20190314307A1/en
Priority to CN201780080218.4A priority patent/CN110248652B/zh
Publication of WO2018114309A1 publication Critical patent/WO2018114309A1/fr
Priority to CONC2019/0007531A priority patent/CO2019007531A2/es
Priority to US18/135,847 priority patent/US20230310353A1/en

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    • 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
    • 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
    • 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

  • TECHNICAL FIELD 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 myo- pathy and/or critical illness polyneuropathy, a clinical manifestation referred to as intensive care unit (ICU) acquired weakness (ICUAW) (Kress JP, Hall JB 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.
  • ICU intensive care unit
  • ICUAW intensive care unit acquired weakness
  • ICUAW is associated with impaired weaning from mechanical ventilation, delayed rehabilitation and prolonged hospitali- zation, late death and greater impaired functional outcome of survivors.
  • Parenteral provision of macronutrients during acute critical illness does not prevent muscle weakness and may in fact exert deleterious effects via further suppression of autophagic myofiber quality control (Hermans et a I, 2013 Lancet Respir Med l(8):621-9; Derde S et a I, 2012 Crit Care Med 40(l):79-89).
  • 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 prefer- ably 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 pre- vented, 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 (CI NM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxy- butyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or ena ntiomeric mixture, or a pharmaceutically acceptable or under food law acceptable salt or a pharmaceutically accepta ble 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 dia- phragm 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 sa lt 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-hydroxy- butyl (R)-3-hydroxybutyrate.
  • Examples of a for present invention suita ble 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 (CI NM) comprising administering to a subject in need thereof composition comprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxy- butyric 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 ra nge 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 criti- cal 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 criti- cal 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 ICD- 10-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, oligo- saccharide 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-hydroxy- butyrate, 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 mac- ronutrient group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient group consisting of monosaccharide, disaccharide, oligos
  • 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 polyneu- ropathy (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 com- pound 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, disacchari
  • 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-hydroxy- butyrate 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 macronutri- ent group consisting of monosaccharide, disaccharide, oligos
  • 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 Diagno- sis 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 Diagno- sis 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 critica l illness neuromyopathy (CI NM) 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
  • critica l illness neuromyopathy CI NM
  • these pharmaceutically acceptable or under food law acceptable salts are (R)-3-hydroxy- butyric sodium salt or sodium (S)-3-hydroxybutyrate.
  • the pharmaceutically acceptable or under food law acceptable ester is (R)-3-hydroxybutyl (R)-3-hy- droxybutyrate.
  • 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 (CI NM) 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
  • CI NM 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 Diag- nosis Code G72.81), critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CI N M) 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 Diag- nosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD-10-CM Diagnosis Code G62.81
  • CI N M critical illness neuromyopathy
  • Yet another particular aspect of present invention is that the 3-hydroxy- butyrate 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 (CI N M) 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
  • CI N M 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 (CI NM) 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
  • CI NM 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 (CIN M) 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
  • CIN M 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 critica l illness neuromyopathy (CI NM), wherein the 3-hydroxybutyrate is in com- binational 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 com bination 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, dis
  • 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 ICD- 10-CM Diagnosis Code G62.81) or critical illness neuromyopathy (CI NM), wherein the patient has a BM I under 24.9.
  • critical illness myopathy 2016/17 ICD- 10-CM Diagnosis Code G72.81
  • critical illness polyneuropathy 2016/17 ICD- 10-CM Diagnosis Code G62.81
  • CI NM 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 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 a normal weight patient with a BMI between 18.5 and 24.9.
  • 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 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
  • 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 macronu- trient 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 neu- romyopathy (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 criti- cal 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 amelio- rating 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 amelio- rating 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 pharma- ceutically 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 amelio- rating 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
  • DEXA dual-energy-X-ray-absorptiometry, CLP: cecal ligation and puncture, Ctrl: healthy control animals, fed: parenterally fed, fast: fasted
  • 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-I protein ratio, as detected with western blot (ANOVA p 0.4).
  • Fig. 4 Mice muscle and hepatic triglyceride content, (a) Triglyceride content of skeletal muscle tissue (Mann-Whitney p ⁇ 0.01). (b) Hepatic triglyceride content (Mann-Whitney p ⁇ 0.01).
  • Fig. 5 Mice fatty acid metabolism, (a) Serum fatty acid concentration (ANOVA p ⁇ 0.01). (b) Relative mRNA expression of Cd36 (ANOVA p ⁇ 0.01). (c) Relative Hmgcs2 mRNA expression (ANOVA p ⁇ 0.01). (d) Ketone body serum concentration (ANOVA p ⁇ 0.01). Gene expression data are expressed normalized to Rnl8s 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
  • c Recovery from fatigue after 10 minutes, as percentage of initial muscle force (ANOVA p ⁇ 0.01).
  • CLP cecal ligation and puncture
  • Ctrl healthy control animals, PF, pair-fed, fed: parenterally fed
  • 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- hydroxy- butyrate (17/21 survivors); dotted line, fasted critically ill mice receiving 3- hydroxybutyrate (14/22 survivors).
  • PN parenteral nutrition
  • 3HB 3-hydroxybutyrate
  • Fig. 11 Effect of 3-hydroxybutyrate administration on muscle wasting in prolonged critically ill mice, (a) Dry weight of the extensor digitorum longus (EDL) muscle, (b) Dry weight of the tibialis anterior muscle.
  • EDL extensor digitorum longus
  • 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, (a) Dry weight of the extensor digitorum longus (EDL) muscle, (b) Dry weight of the tibialis anterior muscle.
  • EDL extensor digitorum longus
  • b Dry weight of the tibialis anterior muscle.
  • Fig. 14 Circulating 3-hydroxybutyrate in prolonged 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 + [0.91x (height in cm - 152.4)] and for a male patient 50 + [0.91 x (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 x 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 20kg) 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.
  • parenteral administration 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 syn- drome 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 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 III 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 pro- drugs, 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 underfood 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.
  • first, second, third and the like in the description and in the claims are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. Moreover, the terms top, bottom, over, under and the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions.
  • 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- hydroxypropa- noic acid, malonic acid, hydroxypentanoic acid, butyric acid, ⁇ -methylbutyric acid, ⁇ -hydroxy ⁇ -methylbutyric acid, erythrose, threose, l,2-butanediol,l,3-butanediol, 2,3- butanediol, 1,4- butanediol, hydroxybutyric acid, 3-hydroxybutyric acid, L- -hydroxybutyric acid, ⁇ - ⁇ -hydroxy- butyric 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 aceto- acetic 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.
  • I n the human body a large portion of acetoacetate is converted to beta-hydroxybutyrate, a rich energy source for the brain, which ca nnot run directly on fatty acids themselves due to their poor ability to cross the blood-brain barrier.
  • I n the mammalia n body a large portion of acetoacetate is converted to beta-hydroxybutyrate.
  • 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)CH2C02H; its conjugate base is beta-hydroxybutyrate, also known as 3-hydroxy- butyrate.
  • ⁇ -Hydroxybutyric acid is a chiral compound having two enantiomers, D- ⁇ - hydroxybutyric acid a nd 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 consist- ing 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 with- out 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. In one embodiment of the invention 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/l, 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/l 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/l 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/l 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 pol- yneuropathy.
  • 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 aceto- acetic acid, lactic acid, propionic acid, 3-hydroxypropanoic acid, malonic acid, hydroxypenta- noic acid, butyric acid, ⁇ -methylbutyric acid, ⁇ -hydroxy ⁇ - methylbutyric acid, erythrose, thre- ose, l,2-butanediol,l,3-butanediol, 2,3-butanediol, 1,4- butanediol, hydroxybutyric acid, 3- hydroxybutyric acid and
  • 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 + [0.91x (height in cm - 152.4)] and for a male patient 50 + [0.91 x (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 x 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 a nimals 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).
  • EDL extensor digi- torum longus
  • Serum concentrations of free fatty acids, glycerol and 3-hydroxybutyrate (3-HB) were deter- mined with commercially available assay kits (free fatty acid fluorometric assay kit, Cayman Chemical Company, Ann Arbor, Ml, USA; glycerol assay kit, Sigma-Aldrich, Saint Louis, MO, USA; EnzyChrom ketone body assay kit, BioAssay Systems, Hayward, CA, 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, CA, USA). Data were normalized to ribosomal 18S (Rnl8s) gene expression and expressed as fold change of the mean of the controls.
  • Microtubule-associated protein 1A/1B-Iight chain 3 (LC3)-I, LC3-II (Ab from Sigma-Aldrich) and p62 protein (Ab from Novus, Littleton, CO, 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 l(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-admis- sion-day 8 ⁇ 1, 139 lean and 139 overweight/obese patients were propensity score matched, similarly as the first sets.
  • Example 1 Mice study - body composition
  • Atg7 was elevated in both lean and obese CLP mice, but most pronounced in fasted lean CLP mice (Fig. 3e). I n contrast, Atg5 gene expression was only increased in fasted lean CLP mice (Fig. 3f).
  • Example 3 Mice study - ectopic triglyceride content
  • Example 4 Mice study - markers of fatty acid and glycerol metabolism
  • 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. 5b).
  • Hepatic gene expression of Acad 7, 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 peak tetanic 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. 7b-c).
  • obese CLP mice tended to have higher peak tetanic tensions and displayed better recovery from fatigue (Fig. 7b-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 metaboli- zation 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-I ratio.
  • LC3-II/LC3-I 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.
  • Example 7 Mice study - effect of administration of D,L-3-hydroxybutyrate
  • M uscle wasting was evaluated by quantification of the dry weight of isolated skeletal muscles. M uscle 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, a nd 2.0 ⁇ 0.4 mg for fasting+3HB as compared with 2.7 ⁇ 0.3 mg in healthy control mice; p ⁇ 0.0001) ( Figure 11A).
  • livers of Lipid critically ill mice contained 7-times more triglycerides than PN critically ill mice and healthy con- trols (p ⁇ 0.0001) (Figure 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 ac- ids), a glucose infusion (3HB+GLUC), a lipid-low-glucose infusion (3HB+LI P), 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 ac- ids
  • a glucose infusion 3HB+GLUC
  • HB+LI P lipid-low-glucose infusion
  • 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 ⁇ 13mN), 57% (158 ⁇ 16mN) and 56% (155 ⁇ 15mN) of the maximal muscle force of the healthy controls (p ⁇ 0.0001).
  • Specific maximal muscle force, cor- rected 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 (Figure 16C).
  • Table 1 Composition of the different forms of parenteral nutrition

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Abstract

La présente invention concerne de manière générale des méthodes et des compositions pour le traitement ou la prévention de la myopathie de maladie grave et de la polyneuropathie de maladie grave et de la myopathie de maladie grave et de la polyneuropathie de maladie grave provoquées par des maladies graves comprenant une septicémie, une septicémie aggravée, une sepsie aggravée avec un choc septique, et en particulier l'utilisation d'une combinaison d'alimentation parentérale ou entérale avec un 3-hydroxybutyrate.
PCT/EP2017/081394 2016-12-23 2017-12-04 3-hydroxybutyrate seul ou en combinaison pour une utilisation dans le traitement de soins d'urgence WO2018114309A1 (fr)

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JP2019533344A JP7174428B2 (ja) 2016-12-23 2017-12-04 救命救急処置の処置における使用のための３－ヒドロキシブチレートの単独または併用
BR112019012899A BR112019012899A2 (pt) 2016-12-23 2017-12-04 3-hidroxibutirato sozinho ou em combinação para uso no tratamento de cuidado intensivo
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US11690817B2 (en) 2017-11-22 2023-07-04 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
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US11944598B2 (en) 2017-12-19 2024-04-02 Axcess Global Sciences, Llc Compositions containing s-beta-hydroxybutyrate or non-racemic mixtures enriched with the s-enatiomer
US11806324B2 (en) 2018-04-18 2023-11-07 Axcess Global Sciences, Llc Beta-hydroxybutyric acid compositions and methods for oral delivery of ketone bodies
US11793778B2 (en) 2018-04-18 2023-10-24 Axcess Global Sciences, Llc Compositions and methods for keto stacking with beta-hydroxybutyrate and acetoacetate
GB2575623B (en) * 2018-06-04 2022-10-26 Tdeltas Ltd 3-hydroxybutyrate esters for treating cancer cachexia
GB2575623A (en) * 2018-06-04 2020-01-22 Tdeltas Ltd Compounds for new use
JP2022520205A (ja) * 2019-02-11 2022-03-29 アクセス・グローバル・サイエンシーズ・エルエルシー ラセミベータ－ヒドロキシブチレート混合塩－酸組成物および使用方法
JP2022520204A (ja) * 2019-02-11 2022-03-29 アクセス・グローバル・サイエンシーズ・エルエルシー Ｓ－ベータ－ヒドロキシブチレート化合物およびｓ－エナンチオマー富化組成物
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JP7448554B2 (ja) 2019-02-11 2024-03-12 アクセス・グローバル・サイエンシーズ・エルエルシー Ｓ－ベータ－ヒドロキシブチレート化合物およびｓ－エナンチオマー富化組成物
US11950616B2 (en) 2019-06-21 2024-04-09 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
WO2021245040A1 (fr) 2020-06-01 2021-12-09 Gambro Lundia Ab Système et méthode de traitement du sang extracorporel
WO2023099436A1 (fr) 2021-12-01 2023-06-08 Gambro Lundia Ab Nouveau fluide de dialyse
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