Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-02-23
2003-06-10
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S183000, C514S255030, C424S078170
Reexamination Certificate
active
06576672
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of neurological disorders in mammalian subjects, and more specifically to the diagnosis and therapy of Parkinson's Disease, Olivopontine Cerebellar Atrophy, Alzheimer's Disease and Lou Gehrig's Disease.
BACKGROUND OF THE INVENTION
Parkinson's Disease is a degenerative disease of the nervous system which affects one person in fifty over fifty years of age and one person in twenty over seventy years of age, without gender or social bias. Described by James Parkinson in 1817, the shaking palsy is comprised of a triad of tremor at rest, muscular rigidity and slowness of movement. Accurate description of the disease during the period of the Industrial Revolution has prompted people to speculate that environmental exposure to toxic chemicals precipitates the disease. Exposure to manganese precipitated a Parkinsonian syndrome in miners which also includes schizophreniform behaviors. Some epidemiologic studies have found association between industrial exposure to copper, manganese and copper simultaneously with iron and the incidence of Parkinson's disease (Gorell J. M et al), between incidence of Parkinson's disease and blood mercury levels (Ngim C. H. et al) and with death rates from Parkinson's Disease and proximity to iron and copper related industrial processes (Rybicki B. A. et al). Xenobiotics, natural and man made insecticides have also been suggested as candidate agents because they precipitate on occasion motor disturbances in animals and man somewhat akin to Parkinsonism. Thus both inorganic and organic chemicals may contribute to the toxicity mechanism. Other types of Parkinsonism include post encephalitic, Wilson's Disease and Parkinsonism secondary to cerebrovascular accidents, space occupying lesions and drug induced. The disease is progressive though not in all cases. Dementia with Alzheimer type pathological changes follows but does not precede the development of Parkinson's Disease in about one quarter of diagnosed cases.
Generalized wasting and anorexia also occur, metabolic components of the disease not attributable to hypothalamic (tuberoinfundibular) dopaminergic dysfunction.
PROGRESSION
Parkinson's Disease progresses to differing extents in different patients, most commonly over a seven to ten year timeframe from the time of diagnosis. Some patients experience generalized wasting and anorexia, depression and mental changes frequently occur and approximately one quarter develop Alzheimer type clinical changes in cognitive functioning and measurable Alzheimer pathological changes in up to forty percent of cases.
PHENOMENOLOGY
A. Iron Deposition and Copper Displacement
Iron is deposited as haemosiderin granules in the cytoplasm, and mitochondria filled with ferritin granules have been observed in the neuronal and glial cells of the ventrolateral thalamus, caudate and lenticular nuclei and substantia nigra of Parkinsonian brains (Earle K. M., Asenjo A. et. al., Riederer P. et. al.), and copper, though not detectable in excess in the brain, does overflow into the cerebrospinal fluid. The level of copper overflow correlates with the clinical severity of Parkinson's Disease and the level of Alzheimer type damage present in the patients (Pall H. S. et al).
Though Parkinsonian syndromes can be induced by other metals such as chronic manganese poisoning which causes Parkinsonian like and psychotic symptoms in miners and hepatolenticular degeneration due to copper deposition in Wilson's Disease, excessive levels of metals other than iron have not been observed in idiopathic or post encephalitic Parkinsonism.
B. Mitochondrial Morphology
Mitochondria are morphologically distorted and iron is deposited in large quantities, without evidence of deposition of other metals (Earle K. M., Asenjo A. et. al., Riederer P. et. al). Iron and copper may be released from neuromelanin and from damaged mitochondria. Elevated free iron in mitochondria and cytosol and apparent overflow of copper from a storage site through cytosol to cerebrospinal fluid occurs. Inhibition of complex 1 of the mitochondrial electron transport chain depressing mitochondrial respiration occurs in Parkinson's Disease.
C. Thiol Methyltransferase
Thiol methyltransferase activity is reduced in Parkinson's disease and increased in motor neurone disease (Waring et al 1989). Glutathione S transferase activity is present in oligodendrocytes, astrocyte end feet, choroid plexus and ependymal cells. Neither isoform of the enzyme is present in neurons. The enzyme activity is present in white and gray matter oligodendrocytes as the yp form. The yb form is present in astrocytes, ependymal cells and tanycytes. The distribution of the enzyme suggests that it is a first line of defence against toxic substances (Cammer W. et al 1989).
D. Copper Zinc Superoxide Dismutase
High levels of CuZn SOD were demonstrated immunohistochemically in the large pyramidal cells of control and Alzheimer's disease patients brains (Delacourte A. et al 1988). The localization of the superoxide dismutase gene on chromosome twenty one and the early occurrence of Alzheimer's Disease in Down's syndrome suggest that superoxide dismutase activity and hydrogen peroxide formation may contribute to Alzheimer's pathogenesis. Also the neurons containing high levels of NADPH diaphorase are relatively spared in neonatal hypoxia and hypoglycemia but are affected in Alzheimer's disease. The increase in platelet membrane fluidity, noted in a subgroup of Alzheimer's disease patients, possibly due to dysregulation of platelet membrane biosynthesis is not associated with a higher erythrocyte level of superoxide dismutase (Zubenko G. S. et al 1989).
E. Monoamine Oxidase and NADPH Diaphorase
The capacity to produce Parkinsonian damage is correlated with the level of melanization of the substantia nigra of the species, and the activities of monoamine oxidase B and NADPH diaphorase in the basal ganglia.
Monoamine Oxidase
Astrogliosis associated with aging leads to increased MAO B activity and increased susceptibility to the toxin MPTP as do differences in MAO B activity between various mouse strains (Zimmer J. et al 1987). MAO B increases with age in humans and MAO A activity does not (Oreland L. et al 1986). MAO B activity increases more in white matter than in grey matter. MAO B is increased in Alzheimer's disease patients compared with age matched controls, more so in white matter than in gray matter, a thirty two percent per decade increase compared to a twelve percent increase. Monoamine oxidase activity in the brains of alcoholics who committed suicide was lower than that in brains of non alcoholic suicides and controls (Gottfries C. G. et al 1975).
Nicotinamide Adenine Dinucleotide Phosphate Diaphorase
In human brain NADPH diaphorase activity was greater in gray matter than in white matter, and likewise for malic dehydrogenase, succinic dehydrogenase and cytochrome oxidase. In monkey brain NADPH diaphorase has greater activity in nuclei containing much neuropil than in nuclei which were predominantly perikaryal and with lesser activity again in white matter (Friede R. L. et al 1963b). A similar pattern of distribution for NADPH diaphorase, succinic dehydrogenase and cytochrome oxidase was observed in random sections of human brain (Friede R. L. et al 1962).
In the human brainstem NADPH diaphorase containing neurones are located in the vicinity of melanin containing neurones such as the dorsal motor nucleus of the vagus, locus coeruleus and substantia nigra, suggesting a role in the processing of melanin and lipofuscin (Kowall N. W. et al 1988, Friede R. L. et al 1962).
Formation of lipofuscin is correlated with oxidative enzyme activity, but it is readily removed from the neuropil by glial cells whereas it accumulates in perikarya (Friede R. L. 1961). In Alzheimer's disease a subset of non pyramidal neurones, in layers II and III, V and VI of the cerebral cortex and subcortical white matter conta
Buchaca John D.
Charmasson Henri J. A.
Nguyen Helen
Webman Edward J.
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