Treatment of cognitive disorders

• US 9,364,497 B2
• Filed: 09/17/2010
• Issued: 06/14/2016
• Est. Priority Date: 07/01/2010
• Status: Active Grant

• Current Assignee: Oxford University Innovation Limited (University of Oxford)
• Original Assignee: Isis Innovation Limited
• Inventors: Smith, Anthony David, Refsum, Helga Margareta
• Primary Examiner(s): Long, Scott
• Assistant Examiner(s): Barron, Sean C
• Application Number:
  US13/807,917
• Publication Number:
  US 20130142769A1
• Time in Patent Office: 2,097 Days
• Field of Search: 424/94.1, 514/52
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/14 Quaternary ammonium compounds, e.g. edrophonium, choline betaines A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/4415 Pyridoxine, i.e. Vitamin B6 pyridoxal phosphate A61K31/675
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/714 Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The invention relates to treatments of cognitive disorders e.g. Mild Cognitive Disorder comprising the use of agents which are capable of lowering homocysteine levels in a subject, preferably a human subject. Aspects of the invention relate to a method of treating such disorders comprising administering one or more B vitamins e.g. folic acid, Vitamin B₆ and/or Vitamin B₁₂ or derivatives thereof.

Claims

1. A method for treating mild cognitive impairment (MCI) in a subject, the method comprising administering to the subject a therapeutically effective amount of folic acid, vitamin B₆ and vitamin B₁₂, wherein:

the folic acid is administered in a daily amount of approximately 0.1 mg to approximately 1.5 mg;

the vitamin B₆ is administered in a daily amount of approximately 1 mg to approximately 30 mg; and

the vitamin B₁₂ is administered in a daily amount of approximately 0.01 mg to approximately 1.0 mg,

wherein the method provides a reduction in brain atrophy by a factor of at least 2 per year compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B₁₂.

4. The method of claim 1, wherein the subject is at least 60 years old.

5. The method of claim 4, wherein the subject is at least 70 years old.

8. The method of claim 1, wherein the subject is at least 50 years old.

9. The method of claim 1, which comprises administering a composition comprising the folic acid, the vitamin B₆ and the vitamin B₁₂.

12. The method of claim 1, wherein:

the folic acid is administered in an amount of from approximately 0.5 mg to approximately 1.5 mg.

15. The method of claim 9, wherein:

the folic acid is in an amount of approximately 0.5 mg to approximately 1.5 mg;

the vitamin B₆ is in an amount of approximately 15 mg to approximately 30 mg;

the vitamin B₁₂ is in an amount of approximately 0.4 mg to approximately 1.0 mg.

18. The method of claim 1, wherein:

attention is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

executive function is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

learning or memory is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂.

21. The method of claim 1, wherein the subject has a baseline tHcy exceeding approximately 9.5 μ

mol/L.

22. The method of claim 1, wherein the vitamin B₁₂ is as cyanocobalamin, methylcobalamin, hydroxocobalamin or adenosylcobalamin or a salt thereof;

and/or wherein the folic acid is as 5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, 5,10-methenyltetrahydrofolate, 5,10-formiminotetrahydrofolate, 5-formyltetrahydrofolate (leucovorin) or 10-formyltetrahydrofolate or a salt thereof or is as a salt of folic acid; and

/or wherein the vitamin B₆ is as pyridoxine or a salt thereof.

26. The method of claim 1, wherein the subject is at least 50 years old.

27. The method of claim 1 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months.

38. The method of claim 1 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months and has a baseline tHcy exceeding about 13 μ

mol/L.

41. The method of claim 1, wherein the folic acid is administered in a daily amount of approximately 0.8 mg, the vitamin B₆ is administered in a daily amount of approximately 20 mg and the vitamin B₁₂ is administered in a daily amount of approximately 0.5 mg.

2. A method for retarding the onset and/or development of MCI in a subject, the method comprising administering to the subject a therapeutically effective amount of folic acid, vitamin B₆ and vitamin B₁₂, wherein:

the folic acid is administered in a daily amount of approximately 0.1 mg to 6 approximately 1.5 mg;

the vitamin B₆ is administered in a daily amount of approximately 1 mg to approximately 30 mg; and

the vitamin B₁₂ is administered in a daily amount of approximately 0.01 mg to approximately 1.0 mg,

wherein the method provides a reduction in brain atrophy by a factor of at least 2 per year compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B₁₂.

6. The method of claim 2, wherein the subject is at least 50 years old.

10. The method of claim 2, which comprises administering a composition comprising the folic acid, the vitamin B₆ and the vitamin B₁₂.

13. The method of claim 2, wherein:

the vitamin B₆ is administered in an amount of approximately 15 mg to approximately 30 mg.

16. The method of claim 10:

the folic acid is in an amount of approximately 0.5 mg to approximately 1.5 mg;

the vitamin B₆ is in an amount of approximately 15 mg to approximately 30 mg;

the vitamin B₁₂ is in an amount of approximately 0.4 mg to approximately 1.0 mg.

19. The method of claim 2, wherein:

attention is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

executive function is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

learning or memory is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂.

28. The method of claim 2 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months.

30. The method of claim 2 wherein the subject has a baseline tHcy exceeding above about 9.5 μ

mol/L.

39. The method of claim 2 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months and has a baseline tHcy exceeding about 13 μ

mol/L.

3. A method for improving cognitive function in a subject with MCI, the method comprising administering to the subject a therapeutically effective amount of folic acid, vitamin B₆ and vitamin B₁₂, wherein:

the folic acid is administered in a daily amount of approximately 0.1 mg to approximately 1.5 mg;

the vitamin B₆ is administered in a daily amount of approximately 1 mg to approximately 30 mg; and

the vitamin B₁₂ is administered in a daily amount of approximately 0.01 mg to approximately 1.0 mg,

wherein the method provides a reduction in brain atrophy by a factor of at least 2 per year compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B_12.

7. The method of claim 3, wherein the subject is at least 50 years old.

11. The method of claim 3, which comprises administering a composition comprising the folic acid, the vitamin B₆ and the vitamin B₁₂.

14. The method of claim 3, wherein:

the vitamin B₁₂ is administered in an amount of approximately 4.0 mg to approximately 1.0 mg.

17. The method of claim 11, wherein the folic acid is in an amount of approximately 0.5 mg to approximately 1.5 mg;

the vitamin B₆ is in an amount of approximately 15 mg to approximately 30 mg;

the vitamin B₁₂ is in an amount of approximately 0.4 mg to approximately 1.0 mg.

20. The method of claim 3, wherein:

attention is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

executive function is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

learning or memory is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂ memory is improved in the subject following administration of the at least one agent.

29. The method of claim 3 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months.

31. The method of claim 3 wherein the subject has a baseline tHcy exceeding above about 9.5 μ

mol/L.

40. The method of claim 3 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months and has a baseline tHey exceeding about 13 μ

mol/L.

23. A method which comprises administering to a subject a therapeutically effective amount of at least one agent which reduces brain atrophy, the method being selected from:

(i) a method for treating mild cognitive impairment (MCI) in the subject;

(ii) a method for retarding the onset and/or development of MCI in the subject;

(iii) a method for improving cognitive function in the subject, wherein the subject has MCI,

wherein the method comprises administering a dosage form which comprises approximately 0.1 mg to approximately 1.5 mg of folic acid, approximately 1 mg to approximately 30 mg vitamin B₆ and approximately 0.01 mg to approximately 1.0 mg of vitamin B₁₂, and wherein the method provides a reduction in brain atrophy by a factor of at least 2 per year compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B₁₂.

24. The method of claim 23, wherein the subject'"'"'s level of baseline tHcy exceeds 9.5 μ

mol/L.

25. The method of claim 23 wherein the vitamin B₁₂ is as cyanocobalamin, methylcobalamin, hydroxocobalamin or adenosylcobalamin or a salt thereof, and/or wherein the folic acid is as 5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, 5,10-methenyltetrahydrofolate, 5,10-formiminotetrahydrofolate, 5-formyltetrahydrofolate (leucovorin) or 10-formyltetrahydrofolate or a salt thereof.

32. A method for retarding the onset and/or development of MCI in a subject or for improving cognitive function in a subject with MCI, the method comprising administering to the subject for a minimum of 18 months a therapeutically effective amount of folic acid, vitamin B₆ and vitamin B₁₂, wherein:

the folic acid is in an amount of approximately 0.5 mg to approximately 1.5 mg;

the vitamin B₆ is in an amount of approximately 15 mg to approximately 30 mg; and

the vitamin B₁₂ is in an amount of approximately 0.4 mg to approximately 1.0 mg,

wherein the method provides a reduction in brain atrophy by a factor of at least 2 per year compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B₁₂.

33. The method of claim 32, wherein the folic acid, vitamin B₆ and vitamin B₁₂ are administered at least once a day for the minimum period of at least 18 months.

34. The method of claim 32, wherein the folic acid, vitamin B₆ and vitamin B₁₂ are administered at least once a day for a minimum period of at least 24 months.

35. The method of claim 32, wherein the vitamin B₁₂ is as cyanocobalamin, methylcobalamin, hydroxocobalamin or adenosylcobalamin or a salt thereof;

and/or wherein the folic acid is as 5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, 5,10-methenyltetrahydrofolate, 5,10-formiminotetrahydrofolate, 5-formyltetrahydrofolate (leucovorin) or 10-formyltetrahydrofolate or a salt thereof or is as a salt of folic acid; and

/or wherein the vitamin B₆ is as pyridoxine or a salt thereof.

36. The method of claim 32, wherein:

attention is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

executive function is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂; and

/or

learning or memory is improved in the subject following administration of the folic acid, vitamin B₆ and vitamin B₁₂.

37. The method of claim 33 wherein the subject is administered the folic acid, vitamin B₆ and vitamin B₁₂ for a minimum of 18 months and has a baseline tHey exceeding about 13 μ

mol/L.

42. A method of reducing brain atrophy, wherein the method consists essentially of administering to a subject a therapeutically effective amount of the following:

(a) folic acid in an amount of approximately 0.1 mg to approximately 1.5 mg;

(b) vitamin B₆ in an amount of approximately 1 mg to approximately 30 mg; and

(c) vitamin B₁₂ in an amount of approximately 0.01 mg to approximately 1.0 mg, wherein the method provides a reduction in brain atrophy by a factor of at least 2 compared to the absence of administration of the folic acid, vitamin B₆ and vitamin B₁₂.