Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-08
2001-07-17
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S297000, C514S317000, C514S333000
Reexamination Certificate
active
06262081
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of treating neurological disorders associated with neurotransmitter deficit in a mammal comprising administering to the mammal a therapeutically effective amount of a combination of: (i) at least one neurotransmitter release enhancer and (ii) at least one acetylcholinesterase inhibitor. This invention also relates to compositions and kit containing the same.
BACKGROUND OF THE INVENTION
The hypothesis that the symptoms of neurodegenerative diseases such as Alzheimer's Disease are the result of reduced neuronal function has led to the development of therapies aimed at reversing these deficits. In an attempt at neurotransmitter replacement, neurotransmitter precursor supplementation has been used to treat neurodegenerative diseases. Cotzias, et al.
New Engl. J. Med
. 276:374-379 (1967).
Another means of enhancing neurotransmission is to increase stimulated, but not basal, release of neurotransmitters, thereby specifically increasing normal synaptic activity. Substituted oxindoles such as 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one are agents under investigation as a palliative treatment for the dementia associated with Alzheimer's disease. Compounds of this structural type have been shown to enhance potassium(K
+
)-stimulated release of tritium from rat brain slices preloaded with [
3
H]choline, [
3
H]dopamine, and [
3
H]serotonin without affecting basal efflux. Nickolson et al.,
Drug Dev. Res
. 19:285-300 (1990); Zaczek et al.
Neurosci. Lett
. (1993); Zaczek et al.,
Drug Dev. Res
. 29:203-208 (1993).
The present invention is based on a synergy found with a combination therapy involving neurotransmitter release enhancers, and acetylcholinesterase inhibitors. Such a therapy provides higher extracellular levels of acetylcholine and a greater improvement for the treatment of neurological disorders such as Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides a method of treating neurological disorders associated with neurotransmitter deficit in a mammal comprising administering to the mammal a therapeutically effective amount of a combination of: (i) at least one neurotransmitter release enhancer, such as a compound of Formula (I) (shown below); and (ii) at least one acetylcholinesterase inhibitor. The present invention is also directed to pharmaceutical compositions and pharmaceutical kits containing the same.
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Earl, Richard A. et al., “2-Fluoro-4-pyridinylmethyl Analogs of Linopirdine . . . ”, J. Med. Chem. (1998), 41(23), 4615-4622, XP002145541.
Zaczek, R. et al., “Two new potent neurotransmitter release enhancers . . . ”, J. Pharmacol. Exp. Ther. (1998), 285(2), 724-730, XP002145542.
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The New England Journal of Medicine, Cotzias et al., vol. 276, pp. 374-379 (1967).
Drug Development Research, Nickolson et al., vol. 19, pp. 285-300 (1990).
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Drug Development Research, Zaczek et al., vol. 29, pp. 203-208 (1993).
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DuPont Pharmaceuticals Company
Fuzail Kalim S.
Jarvis William R. A.
Rubin Kenneth B.
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