Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-12
1999-06-29
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514351, 514353, C07D21379, A01N 4340, A61K 3160
Patent
active
059169060
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to methods and compositions useful for reducing cellular toxicity, in vitro and/or in vivo, associated with increases of poly-(ADP)-ribosylation reactions. This invention also relates to pharmaceutical compositions useful for treating diseases for which increasing endogenous concentrations of nicotinamide provide a therapeutic benefit, and methods of treating disease using these compositions. Specifically, this invention relates to compositions comprising nicotinylalanine, and/or related analogues, and an inhibitor, such as aspirin, of glycine conjugation, a metabolic process leading to the metabolism of nicotinamide and optionally B6. In other useful compositions of this invention B6 may be substituted for the glycine conjugate inhibitor. The diseases for which the compositions and methods of this invention provide a therapeutic benefit involve poly (ADP)-ribosylation reactions which contribute to pathogenesis. Such diseases include neurodegenerative diseases, infectious diseases, cancer and certain forms of diabetes.
BACKGROUND OF THE INVENTION
Cellular toxicity associated with poly (ADP)-ribosylation reactions resulting from DNA damage contributes to pathogenesis of several types of diseases. Poly (ADP)-ribosylation reactions have been shown to be associated with the cellular damage occurring in neurodegenerative diseases, autoimmune diseases, infections and cancer.
Several mechanisms, including increases in nitric oxide may contribute to activation of poly (ADP-ribose) synthetase which catalyzes the poly (ADP)-ribosylation reaction. Cleaver J. E. & Morgan W. F., Mutat. Res. 257:1-18, 1991; Snyder S. H., Science, U.S.A., 265: 723, 1994; Zhang J. & Snyder S. H., Proc. Natl. Acad. Sci., U.S.A., 89:9382-9385, 1992; DeMurcia G., et al., Bio Essays, 13:455-462, 1991. Nitric oxide is produced in a variety of cell types including neurons and blood endothelial cells. Kandel E. R., Schwartz J. H, Jessell T. M., Principles of Neural Science. Third Edition, 1991, p191. Nitric oxide is also significant as a possible pathogenic agent for multiple populations of cells because, besides being toxic to the cells in which nitric oxide is produced, nitric oxide is also released into blood where it acts as a "local hormone". Id. In addition, nitric oxide is capable of readily passing across cell membranes into adjacent cells. Id.
Activation of poly (ADP-ribose) synthetase is reported to be associated with the pathogenesis of a variety of neurodegenerative disorders in response to the generation of toxic quantities of nitric oxide. Zhang J. et al., Science. U.S.A., 263:687-689, 1994. Generation of nitric oxide in neurons occurs in response to over-stimulation of NMDA receptors by naturally occurring excitotoxic agents present in the brain including, for example, glutamic and quinolinic acids. Inhibitors of nitric oxide production provide protection against the pathogenic effects of the excitatory agents. Dawson V. L., et al., Proc. Natl. Acad. Sci., U.S.A., 88:6368-6371, 1991.
Inhibition of poly (ADP-ribose) synthetase activity has also been associated with the action of anti-viral agents inhibiting gene expression in HIV-1, the virus causing AIDS. Yamagoe S., et al., Molec. Cell. Biol., 11:3522-3527, 1991. For example, both nicotinamide and benzamide, known inhibitors of poly (ADP-ribose) synthetase, when added to cultures of HIV-1 infected cells demonstrated significant antiviral activity. Id. Further support for such a mechanism mediating antiviral activity of nicotinamide comes from recent studies linking cellular HIV-1 infection with decreased levels of nicotinamide adenine dinucleotide (NAD) and a significant antiviral effect of nicotinamide treatment of HIV-infected cells in culture (Murray MF et al., Biochem. Biophys. Res. Commun., 210:954-959, 1995; and, Murray MF et al., Biochem. Biophys. Res. Commun., 212:126-131, 1995). In addition, relevant to HIV-1 associated encephalopathy, it has been reported that the HIV-1 coat protein, gP120, kills neurons in cell culture
REFERENCES:
Chemical Abstracts AN 1977:118750, Yeh et al., Jan. 1977.
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