Gh secretagogues and uses thereof

Abstract

The invention relates to use of a GH secretagogue (e.g. GRF or an analog thereof) for (1) altering a lipid parameter in a subject; (2) altering a body composition parameter in a subject, (3) treating a condition characterized by deficient or decreased bone formation in a subject (4) improving daytime vigilance and/or cognitive function in a subject, (5) improving a metabolic condition in a subject, (6) improving anabolism in a catabolic condition in a subject, and/or (7) improving and/or reconstituting immune function in a subject.

1 - 17 . (canceled) 
     
     
         18 . A method of altering a first body composition parameter of a subject having abnormal fat accumulation and a waist circumference of 95 cm or more if said subject is male or a waist circumference of 94 cm or more if said subject is female, wherein said method results in no or substantially no decrease in a second body composition parameter of said subject, wherein said second body composition parameter is:
 (i) subcutaneous fat;   (ii) subcutaneous abdominal tissue (SAT); or   (iii) both (i) and (ii);   said method comprising administering to said subject an agent wherein said agent is:   (a) a growth hormone (GH) secretagogue; or   (b) a composition comprising a GH secretagogue and a pharmaceutically acceptable carrier.   
     
     
         19 . The method of  claim 18 , wherein said GH secretagogue is GH-releasing factor (GRF) or a GRF analog. 
     
     
         20 . The method of  claim 19  wherein said GRF analog is a GRF analog of formula A:
   X-GRF Peptide  (A)
 
 wherein; 
 the GRF peptide is a peptide of formula B (SEQ ID NO: 1); 
 
       
         
           
                 
               
                   A1-A2-Asp-Ala-Ile-Phe-Thr-A8-Ser-Tyr-Arg-Lys-A13- 
                 
                     
                 
                   Leu-A15-Gln-Leu-A18-Ala-Arg-Lys-Leu-Leu-A24-A25- 
                 
                     
                 
                   Ile-A27-A28-Arg-A30-R0 (B) 
                 
             
                
                
                
                
                
               
            
           
         
         wherein,
 A1 is Tyr or His; 
 A2 is Val or Ala; 
 A8 is Asn or Ser; 
 A13 is Val or Ile; 
 A15 is Ala or Gly; 
 A18 is Ser or Tyr; 
 A24 is Gln or His; 
 A25 is Asp or Glu; 
 A27 is Met, Ile or Nle; 
 A28 is Ser or Asn; 
 A30 is a bond or amino acid sequence of 1 up to 15 residues; and 
 R0 is NH 2  or NH—(CH 2 )n-CONH 2 , with n=1 to 12; and 
 
         X is a hydrophobic tail anchored via an amide bond to the N-terminus of the peptide and the hydrophobic tail defining a backbone of 5 to 7 atoms; 
         wherein the backbone can be substituted by C 1-6  alkyl, C 3-6  cycloalkyl, or C 6-12  aryl and the backbone comprises at least one rigidifying moiety connected to at least two atoms of the backbone; and 
         said moiety is a double bond, triple bond, saturated or unsaturated C 3-9  cycloalkyl, or C 6-12  aryl. 
       
     
     
         21 . The method of  claim 20 , wherein X is: 
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , and the double bond is cis or trans; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , and wherein when R is CH 3  or CH 2 CH 3 , X is in a cis or trans configuration; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein when R is CH 3  or CH 2 CH 3 , X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein when R is CH 3  or CH 2 CH 3 , X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , and wherein when R is CH 3  or CH 2 CH 3 , X is in a cis or trans configuration; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 ; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 ; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 ; 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 ; or 
       
       
         
           
           
               
               
           
         
         wherein R is H, CH 3  or CH 2 CH 3 , wherein X is in a cis or trans configuration, and wherein said GRF analog is a racemic mixture or a pure enantiomer. 
       
     
     
         22 . The method of  claim 20 , wherein A30 is:
 (a) a bond;   (b) an amino acid sequence corresponding to positions 30-44 of a natural GRF peptide, or   (c) said amino acid sequence of (b) having a 1-14 amino acid deletion from its C-terminal.   
     
     
         23 . The method of  claim 20 , wherein said GRF peptide is:
 (a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 3;   (b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 5; or   (c) the polypeptide of (a) having a 1 to 14 amino acid deletion from its C-terminus.   
     
     
         24 . The method of  claim 20 , wherein said GRF analog is (hexenoyl trans-3)hGRF(1-44)NH 2 . 
     
     
         25 . The method of  claim 18 , wherein said alteration of a first body composition parameter is:
 (a) an increase in lean body mass;   (b) a decrease in trunk fat;   (c) a decrease in visceral fat;   (d) a decrease in abdominal girth;   (e) a decrease in visceral abdominal tissue (VAT);   (f) a decrease in VAT:SAT ratio; or and   (g) any combination of (a) to (f).   
     
     
         26 . The method of  claim 18 , wherein said abnormal fat distribution is associated with lipodystrophy, lipohypertrophy, obesity, dyslipidemia, hypertriglyceridemia or syndrome X. 
     
     
         27 . The method of  claim 26 , wherein said lipodystrophy is HIV-related lipodystrophy. 
     
     
         28 . The method of  claim 18 , wherein said subject is HIV positive. 
     
     
         29 . The method of  claim 28 , wherein said subject is receiving antiviral therapy. 
     
     
         30 . The method of  claim 18 , wherein said subject suffers from diabetes, glucose intolerance or insulin resistance. 
     
     
         31 . The method of  claim 20 , wherein said GRF analog is administered at a dose of about 0.0001 to 2 mg. 
     
     
         32 . The method of  claim 31 , wherein said GRF analog is administered at a dose of about 1 mg or about 2 mg. 
     
     
         33 . The method of  claim 18 , wherein said GH secretagogue or said composition is administered by an intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal or topical route. 
     
     
         34 . The method of  claim 33 , wherein said GH secretagogue or said composition is administered by a subcutaneous route. 
     
     
         35 . The method of  claim 18 , wherein said alteration of a first body composition parameter results in an improvement in quality of life of said subject. 
     
     
         36 - 88 . (canceled) 
     
     
         89 . The method of  claim 32 , wherein said GRF analog is administered at a dose of about 2 mg. 
     
     
         90 . The method of  claim 18 , wherein said subject has a body mass index (BMI) of 20 kg/m 2  or more.