Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis

• US 20050009885A1
• Filed: 05/17/2004
• Published: 01/13/2005
• Est. Priority Date: 05/15/2003
• Status: Active Grant

• Current Assignee: Alzheimer's Institute Of America
• Original Assignee: Alzheimer's Institute Of America
• Inventors: Paris, Daniel, Mullan, Michael J.
• Granted Patent: US 7,732,467 B2
• Time in Patent Office: Days
• US Class Current: 514/355
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods for reducing β-amyloid deposition, β-amyloid neurotoxicity and microgliosis in animals or humans afflicted with a cerebral amyloidogenic disease, such as Alzheimer'"'"'s disease (AD), by administering therapeutically effective amounts of the dihydropyridine calcium channel antagonist, nilvadipine. The present invention also provides methods for diagnosing cerebral amyloidogenic diseases in animals or humans. Further provided are methods for reducing the risk of β-amyloid deposition, β-amyloid neurotoxicity and microgliosis in animals or humans suffering from traumatic brain injury by administering nilvadipine immediately after the traumatic brain injury and continuing treatment for a prescribed period of time thereafter. Finally, methods are provided for treating transplantable neuronal stem cells by administering nilvadipine to the neuronal stem cells prior to transplantation in the central nervous system of an animal or human afflicted with a cerebral amyloidogenic disease, such as AD.

Claims

1. A method for reducing β

-amyloid deposition, β

-amyloid neurotoxicity and microgliosis in animals and humans afflicted with a cerebral amyloidogenic disease or condition, comprising administering to the animal or human a therapeutically effective amount of nilvadipine in unit dosage form.

2. The method of claim 1, wherein the cerebral amyloidogenic disease or condition is selected from the group consisting of Alzheimer'"'"'s disease, transmissible spongiform encephalopathy, scrapie, traumatic brain injury, cerebral amyloid angiopathy and Gerstmann-Straussler-Scheinker syndrome.

3. The method of claim 1, wherein the therapeutically effective amount of nilvadipine is between about 0.05-20 mg per day.

4. The method of claim 1, wherein the therapeutically effective amount of nilvadipine is between about 2-15 mg per day.

5. The method of claim 1, wherein the therapeutically effective amount of nilvadipine is between about 4-12 mg per day.

6. The method of claim 1, wherein the therapeutically effective amount of nilvadipine is 8 mg per day.

7. The method of claim 1, wherein the duration of nilvadipine treatment lasts for up to the lifetime of the animal or human.

8. The method of claim 1, wherein the administration of nilvadipine to the animal or human is via parenteral, oral or intraperitoneal administration.

9. The method of claim 8, wherein the unit dosage form of the oral administration is selected from the group consisting of hard or soft shell gelatin capsules, tablets, troches, sachets, lozenges, elixirs, suspensions, syrups, wafers, powders, granules, solutions and emulsions.

10. The method of claim 8, wherein the parenteral route of administration is selected from the group consisting of intravenous;

intramuscular;

interstitial;

intra-arterial;

subcutaneous;

intraocular;

intracranial;

intraventricular;

intrasynovial;

transepithelial, including transdermal, pulmonary via inhalation, ophthalmic, sublingual and buccal;

topical, including ophthalmic, dermal, ocular, rectal, and nasal inhalation via insufflation or nebulization.

11. The method of claim 10, wherein the nasal administration of nilvadipine is selected from the group consisting of aerosols, atomizers and nebulizers.

12. A diagnostic method for a cerebral amyloidogenic disease in an animal or human, comprising:

taking a first measurement of the plasma concentration of β

-amyloid in the peripheral circulation of the animal or human;

administering a therapeutically effective amount of nilvadipine in unit dosage form to the animal or human;

taking a second measurement of the plasma concentration of β

-amyloid in the peripheral circulation of the animal or human; and

calculating the difference between the first measurement and the second measurement, wherein an increase in the plasma concentration of β

-amyloid in the second measurement compared to the first measurement indicates a possible diagnosis of a cerebral amyloidogenic disease in the animal or human.

13. The method of claim 12, wherein the cerebral amyloidogenic disease is selected from the group consisting of Alzheimer'"'"'s disease, transmissible spongiform encephalopathy, scrapie, traumatic brain injury, cerebral amyloid angiopathy, and Gerstmann-Straussler-Scheinker syndrome.

14. The method of claim 12, wherein the therapeutically effective amount of nilvadipine is between about 0.05-20 mg per day.

15. The method of claim 12, wherein the therapeutically effective amount of nilvadipine is between about 2-15 mg per day.

16. The method of claim 12, wherein the therapeutically effective amount of nilvadipine is between about 4-12 mg per day.

17. The method of claim 12, wherein the therapeutically effective amount of nilvadipine is 8 mg per day.

18. The method of claim 12, wherein the duration of nilvadipine treatment lasts for between one day and twelve months.

19. The method of claim 12, wherein the duration of nilvadipine treatment lasts for between one week and six months.

20. The method of claim 12, wherein the duration of nilvadipine treatment lasts for between two weeks and four weeks.

21. The method of claim 12, wherein the administration of nilvadipine to the animal or human is via parenteral, oral or intraperitoneal administration.

22. The method of claim 21, wherein the unit dosage form of the oral administration is selected from the group consisting of hard or soft shell gelatin capsules, tablets, troches, sachets, lozenges, elixirs, suspensions, syrups, wafers, powders, granules, solutions and emulsions.

23. The method of claim 21, wherein the parenteral route of administration is selected from the group consisting of intravenous;

intramuscular;

interstitial;

intra-arterial;

subcutaneous;

intraocular;

intracranial;

intraventricular;

intrasynovial;

transepithelial, including transdermal, pulmonary via inhalation, ophthalmic, sublingual and buccal;

topical, including ophthalmic, dermal, ocular, rectal, and nasal inhalation via insufflation or nebulization.

24. The method of claim 23, wherein the nasal administration of nilvadipine is selected from the group consisting of aerosols, atomizers and nebulizers.

25. A method for reducing the risk of β

-amyloid deposition, β

-amyloid neurotoxicity and microgliosis in animals and humans suffering from traumatic brain injury, comprising administering to the animal or human a therapeutically effective amount of nilvadipine in unit dosage form, wherein the nilvadipine administration begins immediately following the acute head injury.

26. The method of claim 25, wherein the amyloidogenic disease is selected from the group consisting of Alzheimer'"'"'s disease, transmissible spongiform encephalopathy, scrapie, traumatic brain injury, cerebral amyloid angiopathy, and Gerstmann-Straussler-Scheinker syndrome.

27. The method of claim 25, wherein the therapeutically effective amount of nilvadipine is between about 0.05-20 mg per day.

28. The method of claim 25, wherein the therapeutically effective amount of nilvadipine is between about 2-15 mg per day.

29. The method of claim 25, wherein the therapeutically effective amount of nilvadipine is between about 4-12 mg per day.

31. The method of claim 25, wherein the duration of nilvadipine treatment lasts for between one hour to five years.

32. The method of claim 25, wherein the duration of nilvadipine treatment lasts for between two weeks to three years.

33. The method of claim 25, wherein the duration of nilvadipine treatment lasts between six months and twelve months.

34. The method of claim 25, wherein the administration of nilvadipine to the animal or human is via parenteral, oral or intraperitoneal administration.

35. The method of claim 34, wherein the unit dosage form of the oral administration is selected from the group consisting of hard or soft shell gelatin capsules, tablets, troches, sachets, lozenges, elixirs, suspensions, syrups, wafers, powders, granules, solutions and emulsions.

36. The method of claim 34, wherein the parenteral route of administration is selected from the group consisting of intravenous;

intramuscular;

interstitial;

intra-arterial;

subcutaneous;

intraocular;

intracranial;

intraventricular;

intrasynovial;

transepithelial, including transdermal, pulmonary via inhalation, ophthalmic, sublingual and buccal;

topical, including ophthalmic, dermal, ocular, rectal, and nasal inhalation via insufflation or nebulization.

37. The method of claim 36, wherein the nasal administration of nilvadipine is selected from the group consisting of aerosols, atomizers and nebulizers.

30. The method of claim 251, wherein the therapeutically effective amount of nilvadipine is 8 mg per day.

38. A method of treating transplantable neuronal stem cells or fetal cells, comprising administering a therapeutically effective amount of nilvadipine to the neuronal stem cells or fetal cells prior to transplantation of the stem cells or fetal cells in the central nervous system of an animal or human afflicted with a cerebral amyloidogenic disease.

39. The method of claim 38, wherein the cerebral amyloidogenic disease is selected from the group consisting of Alzheimer'"'"'s disease, transmissible spongiform encephalopathy, scrapie, traumatic brain injury, cerebral amyloid angiopathy, and Gerstmann-Straussler-Scheinker syndrome and further wherein the patient is treated with an effective amount of nilvadipine after transplantation of the neuronal stem cells or fetal cells.

40. The method of claim 38, wherein the therapeutically effective amount of nilvadipine is between about 1 nM-3 μ

M.

41. The method of claim 38, wherein the therapeutically effective amount of nilvadipine is between about 10 nM-2 μ

M.

42. The method of claim 38, wherein the therapeutically effective amount of nilvadipine is between about 100 nM-1 μ

M.