Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer

• US 8,236,346 B2
• Filed: 10/03/2008
• Issued: 08/07/2012
• Est. Priority Date: 10/05/2007
• Status: Active Grant

• Current Assignee: Alzheimer's Institute Of America
• Original Assignee: Alzheimer's Institute Of America
• Inventors: Mullan, Michael J., Paris, Daniel, Ivey, Robert A. III
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Palenik, Jeffrey T
• Application Number:
  US12/245,354
• Publication Number:
  US 20090092667A1
• Time in Patent Office: 1,404 Days
• Field of Search: None
• US Class Current: 424/456
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Abstract

The present invention provides methods for reducing Aβ deposition, Aβ neurotoxicity and microgliosis in an animal or human afflicted with a cerebral amyloidogenic disease, such as Alzheimer'"'"'s disease (AD), by administering therapeutically effective amounts of the (R)-enantiomer of the dihydropyridine compound nilvadipine, also known as (−)-nilvadipine, to the animal or human. Further provided are methods for reducing the risk of Aβ deposition, Aβ neurotoxicity and microgliosis in animals or humans suffering from traumatic brain injury by administering (−)-nilvadipine after the traumatic brain injury and continuing treatment for a prescribed period of time thereafter.

Claims

1. A method for reducing Aβ

deposition, Aβ

neurotoxicity and microgliosis in an animal or human afflicted with a cerebral amyloidogenic disease or condition, comprising administering to the animal or human a therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine.

4. The method of any one of claims 1 to 3, wherein the cerebral amyloidogenic disease or condition is selected from the group consisting of Alzheimer'"'"'s disease, traumatic brain injury, and cerebral amyloid angiopathy.

5. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine is selected from the group consisting of between about 0.05-20 mg per day, about 2-15 mg per day, about 4-12 mg per day, and about 8 mg per day.

6. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine is selected from the group consisting of between 16 to the maximum tolerated dose, 16 to 50, about 16, about 20, about 30, about 40, about 50, about 100, about 300, and about 500 mg per day.

7. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine reduces blood pressure by an amount selected from the group consisting of less than about 20%, less than about 10%, less than about 5%, and less than about 1%, of the pretreatment blood pressure following administration of enantiomerically-enriched (−

)-nilvadipine, where blood pressure is calculated by continuous monitoring and integration over time for an area under the curve and where post-treatment blood pressure is determined after a period of treatment sufficient to achieve a steady-state result.

8. The method of any one of claims 1 to 3, wherein the enantiomerically-enriched (−

)-nilvadipine is administered to a human or animal with blood pressure in a normal or hypotensive range.

9. The method of any one of claims 1 to 3, wherein the enantiomerically-enriched (−

)-nilvadipine is administered to a human or animal with blood pressure in a hypertensive range.

10. The method of any one of claims 1 to 3, wherein the enantiomeric enrichment is selected from the group consisting of greater than about 95%, greater than about 98%, and about 100% up to the limit of detection.

11. The method of any one of claims 1 to 3, wherein the duration of treatment with the therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine is selected from the group consisting of up to the lifetime of the animal or human, between one hour and 5 years, between one day and twelve months, between one week and six months, between two weeks and four weeks, between two weeks to three years, and between six months and twelve months.

12. The method of any one of claims 1 to 3, wherein the enantiomerically-enriched (−

)-nilvadipine is administered in a unit dosage form which 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.

13. The method of any one of claims 1 to 3, wherein the administration is via parenteral, oral, or intraperitoneal administration, and optionally wherein the parenteral route of administration selected from the group consisting of intravenous;

intramuscular;

interstitial;

intra-arterial;

subcutaneous;

intraocular;

intracranial;

intrathecal;

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, optionally selected from the group consisting of aerosols, atomizers, and nebulizers.

2. A method for reducing the risk of cerebral amyloidogenic disease or condition resulting from Aβ

deposition, Aβ

neurotoxicity and microgliosis in an animal or human suffering from traumatic brain injury comprising administering to the animal or human a therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine, wherein the enantiomerically-enriched (−

)-nilvadipine administration begins following the acute head injury.

3. A method for reducing the risk of developing cerebral amyloidogenic disease or condition in an animal or human diagnosed with a risk for developing cerebral amyloidogenic disease or condition, comprising administering to the animal or human a therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine.

14. A method for treating cerebral amyloidogenic disease or condition in an animal or human afflicted with a cerebral amyloidogenic disease or condition, comprising administering to the animal or human a composition consisting essentially of a therapeutically effective amount of enantiomerically-enriched (−

)-nilvadipine, and a pharmaceutically acceptable carrier.