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

Abstract

This invention relates generally to methods and compositions for the treatment or prevention of critical illness myopathy and critical illness polyneuropathy and of critical illness myopathy and critical illness polyneuropathy caused by critical illnesses including sepsis, severe sepsis, severe sepsis with septic shock, and particularly to the use of a combination of parenteral or enteral feeding with a 3-hydroxybutyrate.

1 : A method of treatment for ameliorating or preventing 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 patient in need thereof an 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, 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. 
     
     
         2 : The method according to  claim 1 , 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. 
     
     
         3 : The method according to  claim 1 , 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. 
     
     
         4 : The method according to  claim 1 , 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. 
     
     
         5 : The method according to  claim 1 , 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. 
     
     
         6 : The method according to any one  claim 1 , 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. 
     
     
         7 : The method according to any  claim 1 , 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 macro-nutrient 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, oligosaccharide and polysaccharide or combination thereof. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 : The method according to  claim 1 , wherein the patient has a BMI under 24.9. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 : The method according to  claim 1 , further comprising one or more pharmaceutically acceptable or under food law acceptable adjuvants, carriers, excipients, and/or diluents. 
     
     
         14 : A method of treatment for treating or preventing 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 a 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 macro nutrient 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 three macronutrient groups 1) a macro nutrient of the group consisting of amino acid, peptide and protein or combination thereof and 2) a macronutrient of the group consisting of fatty acid, glycerol, glyceride and triglyceride or combination thereof and 3) a macronutrient of the group consisting of monosaccharide, disaccharide, oligosaccharide and polysaccharide or combination thereof. 
     
     
         15 . (canceled) 
     
     
         16 : The method according to  claim 14 , for preventing or ameliorating 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 (2016/17 ICD-10-CM Diagnosis Code G62.81) disorder. 
     
     
         17 : The method according to  claim 14 , whereby the pack or composition 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, 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 macro nutrient groups each or of each of the three macro nutrient 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. 
     
     
         18 : The method according to  claim 14 , wherein said 3-hydroxybutyrate and said macronutrient mixture are formulated together and in individual dosage amounts. 
     
     
         19 : The method according to  claim 14 , wherein said 3-hydroxybutyrate and said macronutrient mixture are formulated separately and in individual dosage amounts. 
     
     
         20 : The method according to  claim 14 , wherein the treatment with 3-hydroxybutyrate is to 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. 
     
     
         21 : The method according to  claim 14 , wherein the treatment with 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. 
     
     
         22 : The method according to  claim 14 , wherein the treatment with 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. 
     
     
         23 : The method according to  claim 14 , wherein the treatment with 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. 
     
     
         24 : The method according to  claim 14 , 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. 
     
     
         25 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 1-70 grams. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is present in said composition in an amount equivalent to 0.05-10 grams. 
     
     
         29 . (canceled) 
     
     
         30 : The method according to  claim 14 , wherein said pack or composition is formulated for systemic administration. 
     
     
         31 : The method according to  claim 14 , without causing or without aggravating an hepato-pancreato-biliary disorder, without causing or without aggravating fatty liver, or without causing or without aggravating nonalcoholic steatohepatitis (NASH) (2017 ICD-10-CM Diagnosis Code K75.81). 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is (R)-3-hydroxybutyric acid or a pharmaceutically acceptable or under food law acceptable ester thereof. 
     
     
         35 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is (S)-3-Hydroxybutyric acid or pharmaceutically acceptable or under food law acceptable ester thereof. 
     
     
         36 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is (R)-3-hydroxybutyric sodium salt. 
     
     
         37 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is sodium (S)-3-hydroxybutyrate. 
     
     
         38 : The method according to  claim 14 , wherein the 3-hydroxybutyrate is the D-β-hydroxybutyrate ester, (R)-3-hydroxybutyl (R)-3-hydroxy-butyrate. 
     
     
         39 : The method according to  claim 14 , further comprising a pharmaceutically acceptable or under food law acceptable carrier. 
     
     
         40 : The method according to  claim 14 , whereby said pack or composition has a total calorie content between 16-106% of the calculated caloric target for intensive care (ICU) patients. 
     
     
         41 : The method according to  claim 14 , whereby said pack or 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. 
     
     
         42 : The method according to  claim 14 , whereby said pack or composition has a calorie content of monosaccharide, disaccharide, oligosaccharide, polysaccharide fatty acid, glycerol, glyceride and/or triglyceride between 0 to 1300 kcal/l, 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. 
     
     
         43 : The method according to  claim 14 , whereby said composition has a calorie content of amino acid, peptide and/or protein between 0 to 330 kcal/l, 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, for instance for a use of delivering between 0 and 2 g/kg/day. 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 : The method according to  claim 14 , whereby 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. 
     
     
         47 : The method according to  claim 14 , for use in a treatment of a patient with a BMI under 24.9. 
     
     
         48 . (canceled) 
     
     
         49 . (canceled)