ZA200608239B

ZA200608239B - Therapeutic combination for treatment of Alzheimers disease

Info

Publication number: ZA200608239B
Application number: ZA200608239A
Authority: ZA
Inventors: Gregg H Larson
Original assignee: Warner Lambert Co
Priority date: 2004-04-14
Filing date: 2006-10-03
Publication date: 2008-06-25
Also published as: CN1960781A; WO2005099823A1; JP2007532624A; RU2006136361A; AU2005232447A1; MXPA06011969A; EP1737539A1; BRPI0509881A; NO20065196L; CA2562069A1; TW200533341A; KR20060133008A; IL178120A0

Description

THERAPEUTIC COMBINATION FOR TREATMENT OF ALZHEIMER'S

DISEASE

The present application claims priority under 35 U.S.C. section 119(e) to

United States Provisional Application Serial Numbers 60,562,141 filed April 16,

S 2004.

FIELD OF THE INVENTION

The present invention relates to compositions useful for the treatment of

Alzheimer’s Disease. The inveution further relates to methods of using such compositions to treat subjects, including humans, suffering from Alzheimer’s

Disease.

B ACKGROUND OF THE INVENTION

Alois Alzheimer in 1906 was the first to describe the unique neuropathologic features of what we now call Alzheimer’s disease (AD), in the brain of a patient with progressive dementia (Alzheimer A. Ueber eine eigenartige erkrankung der hirnrinde. Z Gesamte Neurol Psychiat. 18:177; 1907). Over 5% of individuals over the age of 65 are estimated to be affected by dementia (Hofman

A, Rocca WA, Brayne C, Breteler MM, Clarke M, Cooper B, et al. The prevalence of dementia in Europe: A collaborative study of 1980-1990 findings.

EURODEM Prevalence Research Group. Int J Epidemiol, 20(3): 736-748; 1991).

Between 60 and 70% of dementias are attributed to Alzheimer’s disease (“AD”).

According to the Alzheimer’s Association, one in ten people over 65 years of age, and nearly half of those over 85 years of age suffer from AD. Currently, over 4 million Americans suffer from this disease. It is estimated that this number will increase to 14 million in the year 2050 (Brookmeyer R and Gray S. Methods for projecting the incidence and prevalence of chronic diseases in aging populations:

Application to Alzheimer’s disease. Stat Med, 19(11-12): 1481-1493; 2000).

Alzheimer’s disease is a chronic neurodegenerative disorder that is manifested by cognitive declines in learning and memory. It is accompanied by diffuse structural abnormalities in the brain. A growing body of evidence suggests that beta amyloid (AB) plays an important role in this multifactorial degenerative process (De Strooper B and Annaert W. Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci, 113:1857-1870; 2000).

However, in a review by Emmerling and co-workers (Emmerling MR, Spiegel K,

Hall ED, LeVine H, Walker LC, Schwarz RD and Gracon S. Emerging strategies for the treatment of Alzheimer’s disease at the Millennium. Emerging Drugs, 4:35-86; 1999), they described AD as “...no longer viewed solely as a disease of neurotransmitter deficits or amyloid deposition. Rather, it is a combination of events (amyloidosis, neurofibrillary pathology, inflammation, oxidative stress and cerebral vascular insufficiency) that conspire to produce this dementia.”

Acetylcholine esterase inhibitors are known to be useful in the treatment of

AD. Examples of known acetylcholine esterase inhibitors include donepezil (Aricept®), tacrine (Cognex®), rivastigmine (Exelon®) and galantamine (Reminyl).

Aricept® is disclosed in the following U.S. patents, all of which are fully incorporated herein by reference: 4,895,841, 5,985,364, 6,140,321, 6,245,911 and 6,372,760. Exelon® is disclosed in U.S. Patent Nos. 4,948,807 and 5,602,176 which are fully incorporated herein by reference.

Cognex® is disclosed in U.S. Patent Nos. 4,631,286 and 4,816,456 (fully incorporated herein by reference). Remynil® is disclosed in U.S. Patent Nos. 4,663,318 and 6,099,863 which are fully incorporated herein by reference.

Cholesterol may play an important role in the development and progression of AD. The synthesis and secretion of various lipid particles occurs differentially in the periphery and the brain. Importantly, further research is needed to understand the potentially critical role of transport and metahnlism of lipid particles both in the periphery and the brain in AD (Beisiegel U and Spector

AA. Lipids and lipoproteins in the brain. Current Opinion in Lipidology, 12:243- 244; 2001).

Cholesterol modulates the processing of amyloid precursor protein (APP) and associated Ap production as demonstrated through in vitro and animal mode] studies (Emmerling MR, Spiegel K, Hall ED, LeVine H, Walker LC, Schwarz RD and Gracon S. Emerging strategies for the treatment of Alzheimer’s disease at the

Millennium. Emerging Drugs, 4:35-86; 1999). Excess cholesterol in culture or animal diet results in an increase in processing of amyloid precursor protein (APP) and production of AB. Removing cholesterol from culture or animal diets results in a reduction in the processing of APP and production of Ap (Bergmann C, Runz

H, Jakala P and Hartmann T. Diversification of gamma secretase versus beta- secretase inhibition by cholesterol depletion. Neurobiol Aging, 21:5278; 2000).

Statins inhibit de novo synthesis by blocking a critical step in the pathway, conversion of HMG-CoA to mevalonate. Lowering cholesterol through HMG-

CoA-reductase inhibitors, known as statins, has a similar effect on the processing of APP and the production of AB (Austen BM, Frears ER and Davies H.

Cholesterol upregulatr es production of Abeta 1-40 and 1-42 in transfected cells.

Neurobiol Aging, 21:5254; 2000).

In normal human subjects treated with, for example, lovastatin, serum Af concentrations are reduced in a dose-dependent manner (Friedhoff LT, Cullen EI,

Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A) peptide. Int J

Neuropsychopharmacol., 4(2):127-30; June 2001). These data suggest that a lowering of serum cholesterol is correlated with a reduction in APP and B amyloid. Such reduction could result in a modification of disease progression and an improvement in cognitive and behavioral function.

It has been suggested that the role of serum ApoE in the development of

AD may not be through cholesterol, but more directly on Ap aggregation (Golde

TE and Eckman CB. Cholesterol modulation as an emerging strategy for the treatment of Alzheimer’s disease. Drug Discovery Today, 6(2): 1049-1055; 2001).

Advancing age, female gender and family history are clear risk factors for AD.

Additional risk factors include smoking, body mass, blood pressure, and lipid values. However, as the disease progresses, the relative importance of these risk factors may change (Corti MC, Guralnik JM, Salive ME, Harris T, Ferrucci L,

Glynn RJ, Havlik RJ. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med, 126:753- 760; 1997). In general, the diagnosis of AD is associated with raised serum cholesterol several decades earlier (Kivipelto M, Helkala EL, Heanninen T and others. Midlife vascular risk factors and late-life mild cognitive impairment — A population-based study. Neurology, 322:1447-1451; 2001).

Early work by Sparks and co-workers (Sparks, DL, Hunsaker JC and others. Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiology of Aging, 11(6): 601-607; 1990) demonstrated AD-like neuropathologic lesions in non-demented CAD patients. Epidemiological work has demonstrated an association between high fat diets and the risk of AD (Desmond DW, Tatemichi TK, Paik M, Stern Y. Risk factors for cerebrovascular disease as correlates of cognitive function in a stroke-free cohort. Arch Neurol, 50:162-166; 1993). Diet that are so-called cardinprotective have been shown to reduce the risk of developing AD (Forette F, Seux ML, Staessen JA and others.

Prevention of dementia in randomized double-blind placebo-controlled Systolic

Hypertension in Europe (Syst-Eur) trial. Lancet, 352:1347-1351; 1998). * Recent retrospective studies point to a positive relationship between the use of cholesterol-lowering agents, namely statins, and a reduction in cholesterol and risk of developing AD (Jick H, Zomberg GL, Jick SS, Seshadri S and

Drachman DA. Statins and the risk of dementia. The Lancet, 356:1627-1631; 2000).

Atorvastatin is 2 member of the statin class of lipid regulators for use in the treatment of hypercholesterolemia. United States Patent No. 4,681,893 (fully incorporated herein by reference) and United States Patent No. 5,273,995 (fully incorporated herein by reference) disclose atorvastatin (Lipitor®). Other statins include lovastatin, fluvastatin, cerivastatin, pravastatin, simvastatin and rosuvastatin.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable 5 salt thereof; an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent. :

The present invention further provides a method for treating a mammal suffering from Alzheimer’s Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's

Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating or preventing Alzheimer's

Disease in a mammalwhich has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's

Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in 2 mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.

Further provided is a first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer’s Disease- modifying effect in a mammal suffering from Alzheimer’s Disease, which

Alzheimer’s Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.

Further provided is a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; . an amount of a statin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating a mammal suffering from

Alzheimer’s Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.

Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.

Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof: and an amount of a second active ingredient (b), said second active ingredient (b) being a statin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating or preventing Alzheimer's

Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's

Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being a statin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of a statin or 2 pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.

Further provided is a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an Alzheimer’s Disease- modifying effect in a mammal suffering from Alzheimer’s Disease, which

Alzheimer’s Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.

The present invention further provides a pharmaceutical composition comprising an amount of donepezil or a pharmaceutically acceptable salt thereof; an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating a mammal suffering from

Alzheimer’s Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed, an amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (2) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating Alzheimer’s Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof and a pharmacentically acceptable carrier or diluent in a first unit dosage form;a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.

Alzheimer’s Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of donepezil or a pharmaceutically acceptable carrier or diluent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof, an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Further provided is the above composition comprising the hemicalcium salt of atorvastatin.

Further provided is the above cornposition comprising from about 0.2 mg. to about 20 mg. of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and about 5 mg. to about 80 mg. of atorvastatin or a pharmaceutically acceptable salt thereof.

Further provided is the pharmaceutical composition comprising a fixed combination selected from the group consisting of: atorvastatin calcium, 5 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and atorvastatin calcium, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.

Further provided is a method for treating a mammal suffering from

Alzheimer’s Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amonnt of a first active ingredient ( a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating or preventing Alzheimer's

Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and di agnosed as in need of therapy for said Alzheimer's

Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmacentically acceptable salt thereof; wherein said first active in gredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.

Alzheimer’s Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately’ wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.

Further provided is a method for stabilizing symptoms of Alzheimer’s

Disease in a mammal requiring stabilization comprising administering to said mammal a stabilizing amount of the above-described pharmaceutical composition.

Further provided is the method wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Further provided is the method wherein said stabilization is assessed by the

Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale (ADCS-CGIC).

Still further, the present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; an amount of a statin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Further provided is the above pharmaceutical composition comprising from about 0.2 mg. to about 20 mg. of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and about 5 mg. to about 80 mg. of a statin or a pharmaceutically acceptable salt thereof.

Further provided is the above pharmaceutical composition comprising a fixed combination selected from the group consisting of: a statin, 5 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and a statin, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.

Further provided is a method for treating a mammal suffering from

Alzheimer’s Disease comprising administering to said mammal:a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.

Further provided. is a method for preventing Alzheimer's Disease in. a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.

Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being a statin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a method for treating or preventing Alzheimer's

Disease by the joint adiministration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (2) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being a statin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of a statin ora pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.

Further provided is a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an Alzheimer’s Disease- modifying effect in armammal suffering from Alzheimer’s Disease, which

Alzheimer’s Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmacentical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.

Further provided is a method for stabilizing symptoms of Alzheimer’s

Further provided is the above method wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Claims

PCT/1B2005/000923 CLAIMS:

1. A pharmaceutical composition comprising a fixed combination selected from the group consisting of: a statin, 5S mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, mg active; a statin, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active; 10 a statin, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and a statin, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.

2. The pharmaceutical composition of Claim 1 comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of Claim 2 comprising an amount of donepezil or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising from about 0.20 mg. to about 20 mg. of donepezil or a pharmaceutically acceptable salt thereof; about 5 mg. to about 80mg. of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

3. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Discase, which Alzheimer's Disease- modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptabie carrier or diluent, and wherein said second AMENDED SHEET

) PCT/1B2005/000923 pharmaceutical composition comprises and an amount of donepezil or a pharmaceutically acceptable carrier or diluent.

6. The use of the pharmaceutical composition as defined in any one of claims 1-5 3) respectively, for the manufacture of a medicament to treat Alzheimer's Disease.

7. The use of the pharmaceutical composition as defined in any one of claims 1-5 respectively, for the manufacture of a medicament for stabilizing symptoms of Alzheimer's Disease in a mammal requiring stabilization.

8. The use as defined in claim 7 wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, (ADAS-Cog), or by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale, (ADCS-CGIC).

9. A composition of any one of claims 1 to 5, substantially as herein described with reference to and as illustrated in any of the examples.

10. Use of any one of claims 6 to 8, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET