Glyceryl 3-hydroxybutyrates for migraine symptom management

Abstract

A method of management of migraine symptom reduction and/or management and/or prophylaxis is disclosed using 3-hydroxybutyate glycerides is disclosed.

1 . A method of use of a glyceryl (3-hydroxybutyrate) ester in the management of migraine symptomology comprising:
 administering an amount of a glyceryl (3-hydroxybutyrate) compound   (a) to a subject presenting with at least one migraine symptom, wherein said amount is sufficient to eliminate, control, limit, or reduce said at least one symptom or   (b) to a subject so as to prevent the onset of at least one of said symptoms from a previously established pattern of migraine symptom onset   wherein said glyceryl (3-hydroxybutyrate) compound is selected from compounds which are mono, di, or triesters of glycerol with 3-hydroxybutyric acid with any remaining glycerol hydroxyl groups independently either free OH or esterified with an omega fatty acid selected from 3-omega fatty acids, 6-omega fatty acids, and 3,6-omega fatty acids   said amount of said glyceryl (3-hydroxybutyrate) compound which is administered is to deliver a total ketone body blood level comprising the sum of 3-hydroxybutyroyl moiety and acetoacetate selected from a range having a lower and upper limit selected from about 5.5 mM, 6 mM, 6.5 mM, 7 mM and about 7.5 mM within the first 24 hours of administration of said glyceryl (3-hydroxybutyrate) compound, provided said upper limit of the range is larger than the lower limit of the range.   
     
     
         2 . The method of  claim 1  wherein said glyceryl (3-hydroxybutyrate) compound is selected from the group consisting of a glyceryl tris (3-hydroxybutyrate), a glyceryl bis (3-hydroxybutyrate), a glyceryl mono(3-hydroxybutyrate), a glyceryl bis(3-hydroxybutyrate)-mono(3-omega fatty acyl ester), a glyceryl bis(3-hydroxybutyrate)-mono(6-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-di(6-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-mono(3-omega fatty acyl ester)-mono(6-omega fatty acyl ester), a glyceryl bis(3-hydroxybutyrate)-mono(3,6-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-di(3-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-di(3,6-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-mono(3-omega fatty acyl ester)-mono(3,6-omega fatty acyl ester), a glyceryl mono(3-hydroxybutyrate)-mono(6-omega fatty acyl ester)-mono(3,6-omega fatty acyl ester) any of the foregoing having one or more of the omega fatty acyl or unesterified hydroxyl groups replaced by a mid-chain fatty acyl ester group, and mixtures thereof, wherein multiple omega fatty acyl groups in a single molecule may be the same or different, and wherein multiple mid chain fatty acyl groups in a single molecule may be the same or different; and each 3-hydroxybutyrate group is independently selected from D and L forms thereof. 
     
     
         3 . The method of  claim 1  wherein said glyceryl (3-hydroxybutyrate) compound is glyceryl tris (3-hydroxybutyrate) wherein each 3-hydroxybutyrate group is independently in the D or L form and mixtures thereof. 
     
     
         4 . The method of  claim 3  wherein glyceryl tris (3-hydroxybutyrate) compound is selected from the group consisting of glyceryl tris(D-3-hydroxybutyrate), glyceryl tris (L-3-hydroxybutyrate), glyceryl tris (DL-3-hydroxybutyrate), and mixtures thereof, wherein the designation “DL” refers to the overall bulk of hydroxybutyrate groups and not any specific molecule. 
     
     
         5 . The method of  claim 4  wherein the glyceryl tris (3-hydroxybutyrate) compound is glyceryl tris (DL-3-hydroxybutyrate). 
     
     
         6 . The method of  claim 5  wherein the glyceryl tris (DL-3-hydroxybutyrate) compound has an approximate ratio of D-3-hydroxybutyrate groups to L-3-hydroxybutyrate groups of 96:4. 
     
     
         7 . The method of  claim 1  wherein said amount is an oral amount of about 0.5 g/kg of body weight/day to about 2.0 g/kg of body weight/day based on glyceryl tris (3-hydroxybutyrate) and the corresponding amounts that provide the same amount of the 3-hydroxybutyroyl group for the other esters assuming complete hydrolysis of the esters, taken as a single dose or divided doses. 
     
     
         8 . The method of  claim 7  wherein said administration is continued (a) for 2-4 days for a subject presenting with episodic migraine or (b) for a subject presenting with a chronic repetitive migraine history for at least 2 to 4 days beyond the historic chronic repetitive cycle as determined from said subjects medical history or where such history is unknown or unreliable, for about 1 month. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1  wherein said total ketone body blood level is achieved within the first 6 hours of administration of said glyceryl (3-hydroxybutyrate) compound. 
     
     
         11 . The method of  claim 1  wherein said total ketone body blood level is achieved within the first 2 hours of administration of said glyceryl (3-hydroxybutyrate) compound. 
     
     
         12 . The method of  claim 1  wherein said total ketone body blood level is achieved within the first hour of administration of said glyceryl (3-hydroxybutyrate) compound. 
     
     
         13 . The method of  claim 1  wherein administration is begun due to the appearance of one or more prodromal symptoms of migraine. 
     
     
         14 . The method of  claim 1  wherein administration is begun upon presentation of headache. 
     
     
         15 . A method of use of a glyceryl tris(3-hydroxybutyrate) ester in the management of migraine symptomology comprising:
 administering an amount of said glyceryl tris (3-hydroxybutyrate) ester   (a) to a subject presenting with at least one migraine symptom, wherein said amount is sufficient to eliminate, control, limit, or reduce said at least one symptom or   (b) to a subject so as to prevent the onset of at least one of said symptoms from a previously established pattern of migraine symptom onset   wherein each of the 3-hydroxybutyrate groups in said glyceryl tris (3-hydroxybutyrate) ester is independently selected from the D and L form and mixtures thereof;   said amount of said glyceryl (3-hydroxybutyrate) compound which is administered is to deliver a total ketone body blood level comprising the sum of 3-hydroxybutyroyl moiety and acetoacetate selected from a range having a lower and upper limit selected from about 5.5 mM, 6 mM, 6.5 mM, 7 mM and about 7.5 mM within the first 24 hours of administration of said glyceryl (3-hydroxybutyrate) compound, provided said upper limit of the range is larger than the lower limit of the range.