Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-09-11
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...
C514S275000
Reexamination Certificate
active
06288089
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for treating neurodegenerative diseases (e.g., Parkinson's disease) involving the use of kinase inhibitors.
BACKGROUND OF THE INVENTION
Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 1 million people in North America. The disease is characterized by symptoms such as muscle rigidity, tremor and bradykinesia.
Early studies of Parkinson's disease showed unusual inclusions in the cytoplasm of neurons (i.e., Lewy bodies), occurring predominantly in the substantia nigra, which innervate the striatal region of the forebrain. Although Lewy bodies were also found in other neurodegenerative conditions, the presence of Lewy bodies in Parkinson's disease is accompanied by cell loss in the substantia nigra. This cell loss is considered to be the defining pathological feature of Parkinson's disease.
Epidemiological studies have reported geographic variation in Parkinson's disease incidence, leading to the search for environmental factors (Olanow and Tatton, Ann. Rev. Neurosci., 22:123-144 [1998]). The recent discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin causes a Parkinson's-like syndrome indistinguishable from the idiopathic disease suggests that Parkinson's disease may be caused by environmental factors (e.g., toxins and causative agents). (See e.g., Langston, Ann. Neurol., 44:S45-S52 [1998]).
Recent research has also identified genes associated with Parkinson's disease (Mizuno et al., Biomed. Pharmacother., 53(3):109-116 [1999]; Dunnett and Bjorklund, Nature 399 (6738 Suppl):A32-A39 [1999]); namely, the &agr;-synuclein gene (Polymeropouos et al., Science 276:2045-2047 [1997]), the parkin gene (Kitada et al., Nature 392:605-608 [1998]), and the UCH-L1 thiol protease gene (Leroy et al., Nature 395:451-452 [1998]). Although additional chromosomal loci associated with the disease state have been identified, these chromosomal loci have not been analyzed at the molecular level. At present, the biochemical roles played by these gene products in both normal cells and in diseased neurons remain ambiguous, and no gene therapy protocols involving their use have been developed.
Furthermore, Parkinson's disease is associated with the progressive loss of dopamine neurons in the ventral mesencephalon of the substantia nigra (Shoulson, Science 282: 1072-1074 [1998]), which innervates the major motor-control center of the forebrain, the striatum. Although a gradual decline in the number of neurons and dopamine content of the basal ganglia is normally associated with increasing age, progressive dopamine loss is pronounced in people suffering from Parkinson's disease, resulting in the appearance of symptoms when about 70-80% of striatal dopamine and 50% of nigral dopamine neurons are lost (Dunnett and Bjorklund, supra). This loss of dopamine-producing neurons resulting in a dopamine deficiency is believed to be responsible for the motor symptoms of Parkinson's disease.
Although the cause of doparninergic cell death remains unknown, it is believed that dopaminergic cell death is affected by a combination of necrotic and apoptotic cell death. Mechanisms and signals responsible for the progressive degeneration of nigral dopamine neurons in Parkinson's disease have been proposed (Olanow et al., Ann. Neurol., 44:S1-S196 [1998]), and include oxidative stress (from the generation of reactive oxygen species), mitochondrial dysfunction, excitotoxicity, calcium imbalance, inflammatory changes and apoptosis as contributory and interdependent factors in Parkinson's disease neuronal cell death.
Apoptosis (i.e., programmed cell death) plays a fundamental role in the development of the nervous system (Oppenheim, Ann. Rev. Neurosci., 14: 453-501 [1991]), and accelerated apoptosis is believed to underlie many neurodegenerative diseases, including Parkinson's disease (Barinaga, Science 281: 1303-1304 [1998]; Mochizuki et al., J. Neurol. Sci., 137: 120-123 [1996]; and Oo et al., Neuroscience 69: 893-901 [1995]). In living systems, apoptotic death can be initiated by a variety of external stimuli, and the biochemical nature of the intracellular apoptosis effectors is at least partially understood.
In light of the selective death of dopamine producing neurons, administration of
L
-dihydroxyphenylalanine (
L
-DOPA) remains the most widely used treatment of Parkinson's disease. However, the administration of therapeutically effective doses of
L
-DOPA is accompanied by disabling side effects. Furthermore, in some cases, treatment with
L
-DOPA requires the coadministration of a peripheral DOPA-decarboxylase inhibitor (e.g., carbidopa), which is also accompanied by adverse side effects.
Newer drug refinements and developments include direct-acting dopamine agonists, slow-release
L
-DOPA formulations, inhibitors of the dopamine degrading enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), and dopamine transport blockers. These treatments enhance central dopaminergic neurotransmission during the early stages of Parkinson's disease, ameliorate symptoms associated with Parkinson's disease, and temporarily improve the quality of life. However, despite improvements in the use of
L
-DOPA for treating Parkinson's disease, the benefits accorded by these dopaminergic therapies are temporary, and their efficacy declines with disease progression. In addition, these treatments are accompanied by severe adverse motor and mental effects, most notably dyskinesias at peak dose and “on-off” fluctuations in drug effectiveness (Poewe and Granata, in
Movement Disorders. Neurological Principles and Practice
(Watts and Koller [eds]) McGraw-Hill, New York [1997]; and Marsden and Parkes, Lancet 1:345-349 [1977]). No drug treatments are currently available that lessen the progressive pace of nigrostriatal degeneration, postpone the onset of illness, or that substantively slow disability (Shoulson, supra).
Other methods for the treatment of Parkinson's disease involve neurosurgical intervention. The thalamic outputs of the basal ganglia are an effective lesion target for the control of tremor (i.e., thalamotomy). Despite the development of modem imaging and surgical techniques to improve the effectiveness of these neurosurgical interventions for the treatment of Parkinson's disease tremor symptoms, the use of neurosurgical therapies is not widely applicable. For example, thalamotomy does not alleviate the akinetic symptoms which are the major functional disability for many people suffering from Parkinson's disease (Marsden et al., Adv. Neurol., 74:143-147 [1997]).
Therapeutic methods aimed at controlling suspected causative factors associated with Parkinson's disease (e.g., therapies which control oxidative stress and excitotoxicity) have also been developed. Clinical trials have shown that administration of antioxidative agents vitamin E and deprenyl provided little or no neuroprotective function (Shoulson et al., Ann. Neurol., 43:318-325 [1998]). Glutamate-receptor blockers and neuronal nitric oxide synthase (NOS) inhibitors have been proposed as therapies for Parkinson's disease, however, no experimental results from human studies have yet been published (Rodriguez, Ann. Neurol., 44:S175-S188 [1998]).
The use of neurotrophic factors to stimulate neuronal repair, survival and growth in Parkinson's disease has also been studied, particularly the use of glial cell line-derived neurotrophic factor (GDNF). Although GDNF protein protects some dopamine neurons from death, it is difficult to supply GDNF protein to the brain. Furthermore, the use of such protein therapies in general is problematic, since protein molecules show rapid in vivo degradation, are unable to penetrate the blood-brain barri
Freed Curt
Heidenreich Kim
Zawada Michael
Jarvis William R. A.
Medlen & Carroll LLP
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