Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Utility Patent
1999-05-21
2001-01-02
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Utility Patent
active
06169115
ABSTRACT:
BACKGROUND OF THE INVENTION
The nervous system is an unresting assembly of cells that continually receives information, analyzes and perceives it and makes decisions. The principle cells of the nervous system are neurons and neuroglial cells. Neurons are the basic communicating units of the nervous system and possess dendrites, axons and synapses required for this role. Neuroglial cells consist of astrocytes, oligodendrocytes, ependymal cells, and microglial cells. Collectively, they are involved in the shelter and maintenance of neurons. The functions of astrocytes are incompletely understood but probably include the provision of biochemical and physical support and aid in insulation of the receptive surfaces of neurons. In addition to their activities in normal brain, they also react to CNS injury by glial scar formation. The principle function of the oligodendrocytes is the production and maintenance of CNS myelin. They contribute segments of myelin sheath to multiple axons.
The ependyma cells react to injury mainly by cell loss. Microglial cells become activated and assume the shape of a macrophage in response to injury or destruction of the brain. These cells can also proliferate and adopt a rod-like form which could surround a tiny focus of necrosis or a dead neuron forming a glial nodule. Microglial degradation of dead neurons is called neuronophagia.
The creatine kinase/creatine phosphate energy system is only one component of an elaborate energy-generating system found in nervous system cells such as, for example, neurons, oligodendrocytes and astrocytes. The components of the creatine energy system include the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the transporter of creatine. The reaction catalyzed by creatine kinase is: MgADP
±
PCr
=
+H
+
MgATP
=
+Cr. Some of the functions associated with this system include efficient regeneration of energy in cells with fluctuating and high energy demands, energy transport to different parts of the cell, phosphoryl transfer activity, ion transport regulation, and involvement in signal transduction pathways.
The creatine kinase/phosphocreatine system has been shown to be active in neurons, astrocytes, oligodendrocytes and Schwann cells. Manos et al.,
J. Neurochem.
56:2101-2107 (1991); Molloy et al.,
J. Neurochem.
59:1925-1932. The activity of the enzyme has been shown to be up-regulated during regeneration and down-regulated in degenerative states (see, e.g.,
Annals Neurology
35(3):331340 (1994); DeLeon et al.,
J. Neurnosci. Res.
29:437-448 (1991); Orlovskaia et al.
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk.
8:34-39 (1992). Burbaeva et al.
Shurnal Neuropathologll Psikhiatrii Imeni S
-
S
-
Korsakova
90(7):85-87 (1990); Mitochondrial creatine kinase was recently found to be the major constituent of pathological inclusions seen in mitochondrial myopathies. Stadhouders et al.,
PNAS,
91, pp 5080-5093 (1994).
It is an object of the present invention to provide methods for treatment of diseases that affect cells of the nervous system that utilize the creatine kinase/phosphocreatine system using compounds which modulate the system.
SUMMARY OF THE INVENTION
The present invention pertains to methods of treating diseases of the nervous systems in an individual afflicted with such a disease by administering to the afflicted individual an amount of a compound or compounds which modulate one or more of the structural or functional components of the creatine kinase/phosphocreatine system sufficient to prevent, reduce or ameliorate the symptoms of the disease. Compounds which are effective for this purpose include aminoguanidines, e.g., aminoguanidine, diaminoguanidine, and analogs thereof.
The present invention also provides compositions containing aminoguanidino compounds, e.g., aminoguanidines or diaminoguandines, in combination with a pharmaceutically acceptable carrier, and effective amounts of other agents which act on the nervous system, to prophylactically and/or therapeutically treat a subject with a disease of the nervous system. The present invention further pertains to methods of use of aminoguanidino compounds in combination with other agents which act on the nervous system for treating diseases of the nervous system.
Packaged drugs for treating subjects having a disease of the nervous system or one who is predisposed to such diseases also are the subject of the present invention. The packaged drugs include a container holding the aminoguanidino compound, e.g., an aminoguanidine or diaminoguanidine, in combination with a pharmaceutically 15 acceptable carrier, along with instructions for administering the same for the purpose of preventing, ameliorating, arresting or eliminating a disease of the nervous system.
Some of the diseases susceptible to treatment with aminoguanidino compounds, e.g., aminoguanidines or diaminoguanidines, according to the present invention include, but are not limited to Alzheimer disease, Parkinson's disease, Huntington's disease, motor neuron disease, diabetic and toxic neuropathies, traumatic nerve injury, multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, diseases of dysmyelination, mitochondrial diseases, fungal and bacterial infections, migrainous disorders, stroke, aging, dementia, and mental disorders such as depression and schizophrenia.
REFERENCES:
patent: WO 96/16031 (1996-05-01), None
Brady, S. and Lasek, R., “Nerve-Specific Enolase and Creatine Phosphokinase in Axonal Transport: Soluble Proteins and the Axoplasmic Matrix,”Cell, vol. 23, 515-23 (1981).
Burbaeva, GSh et al., “Decreased Level of Immunoreactive Phosphokinase BB Isoenzymes in the Brain of Patients with Schizophrenia and Senile Dementia of the Alzheimer Type,”Zh. Nevropatol. Psikhiatr Im S S Korsakova, vol. 90, No. 7, 85-7 (1990)—abstract attached.
Cadoux-Hudson, T. et al., “Imaging of Human Brain Creatine Kinase Activity in Vivo,”FASEB J., vol. 3, 2660-6 (1989).
Chandler, W. et al., “Regional Creatine Kinase, Adenylate Kinase, and Lactate Dehydrogenase in Normal Canine Brain,”Stroke, vol. 19, 251-5 (1988).
De Leon, M. et al., “Identification of Transcriptionally Regulated Genes After Sciatic Nerve Injury,”J. Neurosci. Res., vol. 29, 437-48 (1991).
Erecinska, M. and Silver, I., “ATP and Brain Function,”J. Cerebr. Blood Flow and Metabolism, vol. 9, 2-19 (1989).
Friedhoff, A. and Lerner, M., “Creatine Kinase Isoenzyme Associated with Synaptosomal Membrane and Synaptic Vesicles,”Life Sci., vol. 20, 867-74 (1977).
Hemmer, W. and Wallimann, T., “Functional Aspects of Creatine Kinase in Brain,”Dev. Neuroscience, vol. 15, 249-260 (1993).
Hemmer, W. et al., “Creatine Kinase Isoenzymes in Chicken Cerebellum: Specific Localization of Brain-type Creatine Kinase in Bergmann Glial Cells and Muscle-type Creatine Kinase in Purkinje Neurons,”Eur. J. Neuroscience, vol. 6, 538-49 (1994).
Hertz, L. and Peng, L., “Energy Metabolism at the Cellular Level of the CNS,”Can. J. Physiol. Pharmacol., vol. 70, S145-57 (1992).
Ito, M., “The Cellular Basis of Cerebellar Plasticity,”Curr. Opin. Neurobiol., vol. 1, 616-20 (1991).
Khan, M.A., “Effect of Calcium on Creatine Kinase Activity of Cerebellum,”Histochem., vol. 48, 29-32 (1976).
Lim, L. et al., “Neurone-Specific Enolase and Creatine Phosphokinase are Protein Components of Rat Brain Synaptic Plasma Membranes,”J. Neurochem., vol. 41, 1177-82 (1983).
Maker, H.S. et al., “Regional Changes in Cerebellar Creatine Phosphate Metabolism During Late Maturation,”Exp. Neurol., vol. 38, 295-300 (1973).
Manos, P. et al., “Creatine Kinase Activity in Postnatal Rat Brain Development and in Cultured Neurons, Astrocytes, and Oligodendrocytes,”J. Neurochem., vol. 56, 2101-7 (1991).
Molloy, G. et al., “Rat Brain Creatine Kinase Messenger RNA Levels are High in Primary Cultures of Brain Astrocytes and Oligodendrocytes and Low in Neurons,”J. Neurochem., vol. 59, 1925-32 (1992).
Newman, E., “Regulation of Potassium Levels by Glial Cells in the Retina,”Trends in Neuroscience,
Hanley, Esq. Elizabeth A.
Jarvis William R. A.
Lahive & Cockfield LLP
LandOfFree
Use of aminoguanidine analogs for the treatment of diseases... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of aminoguanidine analogs for the treatment of diseases..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of aminoguanidine analogs for the treatment of diseases... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2498751