Use of Ketogenic Compounds for Treatment of Age-Associated Memory Impairment

• US 20080287372A1
• Filed: 04/03/2007
• Published: 11/20/2008
• Est. Priority Date: 05/01/2000
• Status: Active Grant

• Current Assignee: Cerecin, Inc.
• Original Assignee: Accela Incorporated (Piksel Incorporated)
• Inventors: Henderson, Samuel T.
• Granted Patent: US 8,124,589 B2
• Time in Patent Office: Days
• US Class Current: 514/23
• CPC Class Codes: A23L 2/52 Adding ingredients adding preservatives A23L2/44
• CPC Class Codes: A23L 33/10 using additives addition of substantially indigestible substances A23L33/21
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/23 of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

This invention relates to the field of therapeutic agents for the treatment of Age-Associated Memory Impairment (AAMI). In particular, the present invention utilizes compositions comprising at least one compound capable of elevating ketone body concentrations in a mammal (e.g., ketogenic compounds), administered in an amount effective for treatment or prevention of loss of cognitive function caused by reduced neuronal metabolism in AAMI. In one embodiment, the composition includes medium chain triglycerides (MCT). In another embodiment, the compositions are administered in the presence of carbohydrate. The present invention also relates to oral dosage forms, in particular, a nutritional drink comprising at least one compound capable of elevating ketone body concentrations in a mammal.

Claims

1. A nutritional drink for oral consumption comprising:

a unit dose sufficient to a) raise blood levels of D-β

-hydroxybutyrate to about 0.1 to about 5 mM or b) raise urinary excretion levels of D-β

-hydroxybutyrate to about 5 mg/dL to about 160 mg/dL;

L-camitine, a plurality of vitamins;

flavoring, and a carbohydrate source and wherein the MCT are of the formula;

wherein the R1, R2, and R3 esterified to the glycerol backbone are each independently fatty acids having carbon chains of 5-12 carbons.

2. The composition of claim 1 wherein greater than about 95% of the R1, R2, and R3 carbon chains are 8 carbons in length.

3. The composition of claim 2 wherein the remaining R1, R2, and R3 are 6-carbon or 10-carbon chains.

4. The composition of claim 1 wherein about 50% of the R1, R2, and R3 carbon chains are 8 carbons in length and about 50% of the R1, R2 and R3 carbon chains are about 10 carbons in length.

5. The composition of claim 1, which is a food composition, further comprising on a dry weight basis about 5-50% protein, about 5-40% fat, about 5-40% carbohydrate, and having a moisture content of about 5-20%.

6. The composition of claim 1, comprising at least about 1% to about 50% MCT on a dry weight basis.

7. A method of treatment for Age-Associated Memory Impairment (AAMI), comprising administration comprising the steps of:

identifying a mammal having, or at risk of AAMI; and

administering to the mammal a composition comprising at least one compound capable of elevating ketone body concentrations in an amount effective for the treatment of or prevention of loss of cognitive function caused by reduced neuronal metabolism in AAMI.

8. The method of claim 7, wherein the compound capable of elevating ketone body concentrations comprises a metabolic precursor to a ketone body.

9. The method of claim 8, wherein the metabolic precursor to a ketone body is selected from the group consisting of:

(a) polyesters of ketone bodies of the formula

wherein n are integers of 0 to 1,000;

(b) esters of polyhydric alcohols of the formula

wherein R is a polyhydric alcohol residue;

n, m and x represent integers; and

m is less than or equal to x;

(c) 3-hydroxyacids of the formula;

wherein, R₁ is selected from hydrogen, methyl, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl, heteroaryl, thiol, disulfide, ether, thiol ether, amine, amide, halogen. R₂ and R₃ are independently selected from hydrogen, methyl, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl; and

(d) glycerol esters of the formula

wherein two or three of the groups R₁, R₂ and R₃ independently of each other, are one or more of the groups acetoacetate, alpha-ketopropionate, beta-hydroxybutyrate and alpha-hydroxypropionate, and when only two of the groups R₁, R₂ and R₃ are any of said groups, the third of them is a hydroxy group or a residue of a saturated or unsaturated fatty acid containing 2 to 24 carbon atoms.

10. The method of claim 7, wherein the compound capable of elevating ketone body concentrations comprises medium chain triglycerides (MCT) of the formula:

wherein the R1, R2, and R3 esterified to the glycerol backbone are each independently fatty acids having 5-12 carbon chains.

11. The method of claim 10 wherein greater than 95% of the R1, R2, and R3 carbon chains are 8 carbons in length.

12. The method of claim 11 wherein the remaining R1, R2, and R3 carbon chains are 6-carbon or 10-carbon chains.

13. The method of claim 10 wherein about 50% of the R1, R2, and R3 carbon chains are 8 carbons in length and about 50% of the R1, R2 and R3 carbon chains are about 10 carbons in length.

14. The method of claim 7, wherein the composition further comprises glucose.

15. The method of claim 7, wherein the compound capable of elevating ketone body concentrations is administered in an amount effective to induce hyperketonemia.

16. The method of claim 15, wherein the hyperketonemia results in ketone bodies being utilized for energy in the brain.

17. The method of claim 7 wherein the composition increases the circulating concentration of at least one type of ketone body in the mammal.

18. The method of claim 17, wherein the amount of β

-hydroxybutyrate is raised in the blood of the mammal.

19. The method of claim 18, wherein the amount of β

-hydroxybutyrate is raised to between about 0.1 millimolar to about 10 millimolar at about two hours post administration.

20. The method of claim 18, wherein the amount of β

-hydroxybutyrate is raised to between about 0.15 millimolar to 0.3 millimolar at about two hours post administration.

21. The method of claim 18 wherein urinary excretion level of β

-hydroxybutyrate is from about 5 to about 160 mg/dL.

22. The method of claim 7 wherein the composition is administered at a dose of about 0.05 g/kg/day to about 10 g/kg/day.

23. The method of claim 7 wherein the composition is administered at a dose of about 0.1 g/kg/day to about 2 g/kg/day.

24. The method of claim 7, wherein the composition is a ready-to-drink beverage, powdered beverage formulation, nutritional or dietary supplement selected from the group consisting of gelatin capsule or tablet, suspension, parenteral solution, or a food product formulated for human consumption.

25. The method of claim 7, wherein the mammal is a human.

26. The method of claim 7, wherein the administering step is on a regular basis comprising at least once daily.

27. The method of claim 26, wherein the composition is administered as part of a daily treatment regimen for at least about one week.

28. The method of claim 26, wherein the composition is administered as part of a daily treatment regimen for at least about three months.

29. The method of claim 7, comprising the further step of determining the ApoE status of the mammal.

30. The method of claim 29, comprising the further step of selecting a mammal for treatment if the mammal is ApoE4(−

).

31. The method of claim 7, wherein efficacy for treatment of or prevention of loss of cognitive function caused by reduced neuronal metabolism in AAMI is determined by results from at least one neuropsychological test.

32. The method of claim 31, wherein the neuropsychological test is selected from the group consisting of Clinical Global Impression of Change (CGIC), Rey Auditory Verbal Learning Test (RAVLT), First-Last Names Association Test (FLN), Telephone Dialing Test (TDT), Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol Digit Coding (SDC), SDC Delayed Recall Task (DRT), Divided Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), and Geriatric Depression Scale (GDS).

34. The method of claim 32, wherein composition comprising at least one compound capable of elevating ketone body concentrations comprises medium chain triglycerides (MCT) wherein the MCT are of the formula:

wherein the R1, R2, and R3 esterified to the glycerol backbone are each independently fatty acids having 5-12 carbons.

33. A method for treatment of Age-Associated Memory Impairment (AAMI) comprising the steps of:

(a) identifying a population of healthy aging mammals having AAMI;

(b) dividing the population into at least a control group and one or more test groups;

(c) formulating at least one delivery system for delivering a composition comprising at least one compound capable of elevating ketone body concentrations in an amount effective for elevating at least one type of ketone body in the blood of an individual mammal;

wherein, on an extended regular basis, each test group receives a formulation delivering a composition comprising at least one compound capable of elevating ketone body concentrations in an amount effective for elevating at least one type of ketone body in the blood of an individual mammal and the control group does not receive any composition comprising at least one compound capable of elevating ketone body concentrations in an amount effective for elevating at least one type of ketone body in the blood of an individual mammal;

(d) comparing at least one neuropsychological test result in the control and test groups;

(e) determining which of the delivery systems for delivering the composition comprising MCT was effective in improving the results of at least one neuropsychological test; and

(f) administering a treatment-based delivery system determined in step (e) to a population of aging mammals, thereby treating AAMI.