Method of treating neurodegenerative diseases

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S408000, C514S438000, C514S461000

Reexamination Certificate

active

06531488

ABSTRACT:

BACKGROUND TO THE INVENTION
ARICEPT ((±)-2,3-dihydro-5,6-diomethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-indene-1-one hydrochloride), is currently prescribed for the partial relief of congitive sytmptoms associated with Alzheimer's disease. See, for example, pages 2161 to 2164 of the 1998 Pysician's Desk Reference (PDR). As stated therein, there is no evidence that donepezil (ARICEPT) or other cholinesterase inhibitors marketed for the treatment of Alzheimers Disease (e.g. EXELON, COGNEX) alter the course of the underlying dementing process.
The use of selective Cyclooxygenase-2 (COX-2) inhibitors have been disclosed for the treatment of Alzheimer's disease. See, for example, U.S. Pat. No. 5,474,995, U.S. Pat. No. 5,643,960, U.S. Pat. No. 5,604,260 and U.S. Pat. No. 5,436,265.
The present invention provides a method of treating a neurodegenerative disease and in particular Mild Cognitive Impairment and Alzheimer's disease which comprises the co-adminsitration of ARICEPT, or other cholinesterase inhibitors, and a selective COX-2 inhibitor.
In sharp contrast with ARICEPT administered alone, the co-administration of ARICEPT and a selective COX-2 inhibitor provides symptomatic relief of cognitive impairment and prevents future decline.
SUMMARY OF INVENTION
The present invention provides a method of treating a neurodegenerative disease, and in particular Alzheimer's disease, which comprises the co-administration of ARICEPT and a selective COX-2 inhibitor. Although a wide range of COX-2 inhibitors may be employed in combination with ARICEPT, there are preferred choices which are specifically set forth below.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the invention encompasses a method of treating a Mild Cognitive Impairment in a human which comprises co-administering to said human an effective amount of a cholinesterase inhibitor such as ARICEPT, or other cholinesterase inhibitors; or a cholenergic receptor agonist and an effective amount of a selective COX-2 inhibitor.
In a second aspect the invention encompasses a method of treating an objective memory impairment in a human which comprises co-administering to said human an effective amount of a cholinesterase inhibitor such as ARICEPT, or other cholinesterase inhibitors, or a cholenergic receptor agonist and an effective amount of a selective COX-2 inhibitor.
In a third aspect the invention encompasses a method of treating a Alzheimer's disease in a human which comprises co-administering to said human an effective amount of a cholinesterase inhibitor such as ARICEPT, or other cholinesterase inhibitor, or a cholenergic agonist and an effective amount of a selective COX-2 inhibitor.
For purposes of this specification a compound is said to be a selective COX-2 inhibitor if it possesses an IC50 for inhibiting COX-1 that is at least 200 greater than it's IC50 for inhibiting COX-2 in the assay set forth below.
For purposes of this specification, Mild Cognitive Impairment is defined as objective memory impairment below an age-appropriate norm on the Reye Auditory Verbal Learning Test, Selective Reminding Test, the Weschler Logical Memory Test or other objective memory test.
For purposes of this specification, Alzheimer's disease is defined in accordance with the NINLDS/ADRDA criteria or DSM-IV criteria.
ARICEPT, an example of a cholinesterase inhibitor administered alone, has been shown to be effective for the treatment of the symptoms Alzheimer's disease by the results of double blind, placebo-controlled clinical investigations in patients with Alzheimer's disease (diagnosed by NINCDS and DMS III-R criteria, Mini-Mental State Examination≧10 and ≦26 and Clinical Demintia Rating 1 or 2). The effectiveness of ARICEPT in improving cognitive performance was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the CIBIC (Clinical Interview Blinded Investigation of Change). The ADAS-Cog examines selected cognitive performance including elements of memory, orientation, attention, language, and praxis. The ADAS-cog scoring is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0, but it is not unusual for non-demented pateints to score slightly higher. The CIBIC is a global assessment of change conducted in a blinded fashion.
The preferred dosage of ARICEPT will be 5 or 10 mg, once or twice a day.
The preferred dosage range for the selective COX-2 inhibitor will be 1 to 400 mg once or twice a day. The preferred dosage may be 1, 5, 10, 12.5, 25, 50, 75, 100, 120, 150, 200, 250, or 400 mg once or twice a day.
The selective COX-2 inhibitors of this invention are most aptly those which are brain penetrant so that the concentration of COX-2 inhibitor, after administration of an effective dose for Alzheimer's disease, is at least the binding IC50 value and preferably at least 10 times that value, for example at least 100 times the binding IC50 value.
Among the selective COX-2 inhibitors, the following are preferred:
For Compound 1, the preferred dosage will be 12.5 or 25 mg total daily dose.
For Compound 5, the preferred dosage will be 10, 25, 50, 75, 100, 120 or 150 mg total daily dose.
ARICEPT or other cholinesterase inhibitor or cholenergic receptor agonist and the selective COX-2 inhibitor may be administered at the same time, or together in a single dosage, or at separate times during the day.
These compounds and their method of preparation are disclosed in the following patent documents, which are hereby incorporated by reference: U.S. Pat. No. 4,895,841, issued Jan. 23, 1990; U.S. Pat. No. 5,474,995, issued Dec. 12, 1995; U.S. Pat. No. 5,633,272, issued May 27, 1997; U.S. Pat. No. 5,521,207, issued May 28, 1996; 2183645 published Jun. 6, 1996 and WO 98/03484, published Jan. 29, 1998.
Oral administration (such as by tablet or capsule) is a preferred mode of administration
In a fourth aspect, the invention encompasses pharmaceutical compositions for treating an objective memory impairment, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of ARICEPT or other cholinesterase inhibitor or cholinergic agonist and an effective amount of a selective COX-2 inhibitor compound as defined herein.
In a fifth aspect, the invention encompasses pharmaceutical compositions for treating Mild Cognitive Impairment, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of ARICEPT or other cholinesterase inhibitor or cholenergic agonist and an effective amount of a selective COX-2 inhibitor compound as defined herein.
In a sixth aspect, the invention encompasses pharmaceutical compositions for treating Alzheimer's Disease, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of ARICEPT cholinesterase inhibitor or cholenergic agonist and an effective amount of a selective COX-2 inhibitor compound as defined herein.
The pharmaceutical compositions of the present invention comprise ARICEPT, or other cholinesterase inhibitors, and a selective COX-2 inhibitor as the active ingredients and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
COX-2 selectivity is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E
2
(PGE
2
) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a putative selective COX-2 inhibitor. The IC
50
values represent the concentration of inhibitor required to return PGE
2
synthesis to 50% of that obtained as compared to the uninhibited control.
For the treatment of Mild Cognitive impairment or other objectives memory impairment, or Alzheimer's Disease, ARICEPT and the selective COX-2 inhi

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