Method and composition for treating neurodegenerative disorders

• US 20050288375A1
• Filed: 08/05/2005
• Published: 12/29/2005
• Est. Priority Date: 02/05/2003
• Status: Abandoned Application

• Current Assignee: Myriad Genetics
• Original Assignee: Myriad Genetics
• Inventors: Zavitz, Kenton, Hobden, Adrian
• Application Number:
  US11/197,942
• Publication Number:
  US 20050288375A1
• Time in Patent Office: Days
• US Class Current: 514/569
• 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 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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

Abstract

The invention provides compositions and methods for treating neurodegenerative disorders. A method of the invention involves administering to an individual in need of treatment a composition having an R-NSAID and an NMDA antagonist. Another method of the invention involves administering to an individual in need of treatment a composition having at least two compounds that are capable of interacting with CYP2C9, wherein at least one of said compounds is an Aβ₄₂ lowering agent. The methods and compositions of the invention are useful for treating and preventing neurodegenerative disorders like Alzheimer'"'"'s disease, dementia, mild cognitive impairment.

Claims

1. A pharmaceutical composition comprising an R-NSAID and a NMDA antagonist.

2. The composition of claim 1 wherein said R-NSAID is selected from the group consisting of R-flurbiprofen, R-ketoprofen, R-ketorolac, R-naproxen, R-tiaprofenic acid, R-suprofen, R-carprofen, R-pirprofen, R-indoprofen, R-benoxaprofen, and R-etolodac.

3. The composition of claim 2 wherein said NMDA antagonist is selected from the group consisting of memantine, adamantane, amantadine, an adamantane derivative, dextromethorphan, dextrorphan, dizocilpine, ibogaine, ketamine, remacemide, and phencyclidine.

4. The composition of claim 3 wherein said R-NSAID is R-flurbiprofen.

5. The composition of claim 3 wherein said NMDA antagonist is memantine.

6. The composition of claim 4, comprising an amount of R-flurbiprofen or pharmaceutically acceptable salt or ester thereof when administered in a single dose to a fasting individual sufficient to produce a plasma C_max of about 25-150 μ

g per mL per dose.

7. A method of treating Alzheimer'"'"'s disease comprising (a) identifying a patient having Alzheimer'"'"'s disease and (b) administering to said patient an Alzheimer'"'"'s disease treating effective amount of the composition of claim 1.

8. The method of claim 7 wherein said R-NSAID is R-flurbiprofen.

9. The method of claim 7 wherein said NMDA antagonist is memantine.

10. The method of claim 7 further comprising administration of an acetylcholine esterase inhibitor.

11. The method of claim 8 wherein said Alzheimer'"'"'s disease treating effective amount of R-flurbiprofen is from about 50 mg to about 1800 mg per day and the Alzheimer'"'"'s disease treating effective amount of memantine is from about 0.5 mg to about 30 mg per day.

12. A composition comprising two compounds that are capable of interacting with CYP2C9, wherein at least one of said compounds is an Aβ

₄₂ lowering agent.

13. The composition of claim 12, comprising:

flurbiprofen or a derivative of flurbiprofen selected from the group consisting of a nitrosated flurbiprofen, a nitrosylated flurbiprofen, 2-(2′

-fluro-4-biphenylyl)propionic acid, a nitrosated or nitrosylated 2-(2′

-fluro-4-biphenylyl)propionic acid, 2-(2,2′

-difluroro-4-biphenylyl)propionic acid, a nitrosated or nitrosylated 2-(2,2′

-difluroro-4-biphenylyl)propionic acid, and pharmaceutically acceptable salts and ester thereof; and

an interactor of CYP2C9 selected from the group consisting of diclofenac, ibuprofen, meloxicam, naproxen, piroxicam, suprofen, celicoxib, tolbutamide, glipizide, losartan, irbesartan, amitriptyline, fluoxetine, fluvastatin, phenyloin, rosiglitazone, tamoxifen, torsemide, S-warfarin, naphthalene, amiodarone, atorvastatin, cerivastatin, fluconazole, fluvastatin, fluvoxamine, isoniazid, lovastatin, paroxetine, phenylbutazone, probenicid, sertraline, simvastatin, sulfamethoxazole, sulfaphenazole, sulphinpyrazone, teniposide, trimethoprim, zafirlukast, and rosuvastatin, and pharmaceutically acceptable salts or esters thereof.

14. The composition of claim 12 comprising:

R-flurbiprofen or a pharmaceutically acceptable salt or ester thereof; and

a statin that is an interactor of CYP2C9 or a pharmaceutically acceptable salt or ester thereof.

15. The composition of claim 14, wherein said statin is fluvastatin or rosuvastatin, or a pharmaceutically acceptable salt or ester thereof.

16. The composition of claim 15, comprising an amount of from about 1 mg to about 1600 mg of R-flurbiprofen or pharmaceutically acceptable salt or ester thereof.

17. A method of treating Alzheimer'"'"'s disease comprising (a) identifying a patient having Alzheimer'"'"'s disease and (b) administering to said patient an Alzheimer'"'"'s disease treating effective amount of the composition of claim 12.

18. The method of claim 17 wherein said composition comprises an Alzheimer'"'"'s disease treating effective amount of:

R-flurbiprofen or a pharmaceutically acceptable salt or ester thereof, and

a statin that is an interactor of CYP2C9 or a pharmaceutically acceptable salt or ester thereof.

19. The method of claim 17 further comprising administration of an acetylcholine esterase inhibitor.

20. The method of claim 18 wherein said an Alzheimer'"'"'s disease treating effective amount of R-flurbiprofen is from about 1 mg to about 1600 mg per day.