Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Nitrates or nitrites or nitric acid or nitrogen oxides
Reexamination Certificate
1999-10-21
2001-05-15
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Nitrates or nitrites or nitric acid or nitrogen oxides
C514S340000, C514S610000
Reexamination Certificate
active
06231894
ABSTRACT:
TECHNICAL FIELD
The invention is directed to treating disorders in which reactive oxygen contributes to the pathology (e.g., paraquat-induced injury, stoke, adriamycin toxicity), to treating disorders characterized by pathologically proliferating cells containing a diaphorase, to inhibiting nitric oxide synthase, to constricting blood vessels, and for treating for NO depletion.
BACKGROUND OF THE INVENTION
Paraquat is a herbicide which damages the lungs, liver and kidneys, and produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide (O
2
−
). Nitric oxide synthase (NOS) has been shown to participate in paraquat-induced lung injury. Current theory holds that nitric oxide (NO) generated by NOS reacts with O
2
−
generated by paraquat to produce the toxic peroxynitrite.
SUMMARY OF THE INVENTION
It has now been discovered that the “current theory” is incorrect and that rather NOS functions as a paraquat diaphorase. In other words, paraquat accepts electrons from nitric oxide synthase whereupon the reduced paraquat generates toxic O
2
−
and prevents NOS from giving electrons to arginine and thereby inhibits NO production thereby resulting in NO depletion. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds cause generation of O
2
−
and inhibit nitric oxide synthase and kill cells including NOS, by the combination of the increased O
2
−
and of depriving the cells of the NO which they need.
A first embodiment of the invention is directed to a method for treating paraquat-induced injury in a patient having such injury or preventing paraquat-induced injury in a patient at risk for such comprising administering to said patient a therapeutically effective amount of a nitric oxide synthase inhibitor that blocks electron transfer reactions of nitric oxide synthase.
A second embodiment of the invention is directed to a method of treating paraquat-induced injury or preventing paraquat-induced injury in a patient at risk for such comprising administering to said patient a therapeutically effective amount of NO providing compound.
A third embodiment of the invention is directed at a method for treating a patient having a disease in which nitric oxide synthase contributes to reactive oxygen production which causes tissue injury, comprising administering to said patient a therapeutically effective amount of nitric oxide synthase inhibitor that blocks electron transfer reactions of nitric oxide synthase and of NO providing compound.
A fourth embodiment of the invention is directed to a method for treating a patient having a disease where treatment with nitric oxide synthase inhibitor ameliorates symptoms of the disease but lowers the NO level to a cytotoxic level or where it is beneficial to supplement nitric oxide synthase inhibitor treatment with treatment with NO providing compound, comprising administering to said patient the nitric oxide synthase inhibitor in therapeutically effective amount, and also a therapeutically effective amount of NO providing compound.
A fifth embodiment of the invention is directed to a method of treating a patient with a disease characterized by pathologically proliferating cells containing nitric oxide synthase, comprising administering to said patient a therapeutically effective amount of a dipyridinum compound. In one aspect of this embodiment, agent that induces expression of nitric oxide synthase is also administered.
A sixth embodiment of the invention is directed to a method of treating a patient affected with a disorder in which reactive oxygen contributes to pathology, comprising administering to said patient a therapeutically effective amount of a nitric oxide synthase inhibitor which blocks generation of reactive oxygen from NOS. This embodiment is generic to the first embodiment.
A seventh embodiment of the invention is directed to a method of inhibiting nitric oxide synthase in a patient in need thereof, comprising administering to said patient a therapeutic amount of agent with a redox potential greater than nitric oxide synthase and an LD
50
greater than 1 &mgr;M or 100 times the effective dose for systemic non-liposome or other non-local administration to inhibit nitric oxide synthase, and optionally to provide therapeutic effect except required in those cases necessary for novelty therapeutic amount of NO providing compound.
An eighth embodiment of the invention is the seventh embodiment where the patient is affected with a disorder characterized by pathologically proliferating cells containing nitric oxide synthase and the agent in inhibiting nitric oxide synthase accepts electrons from it to generate reactive oxygen to kill the pathologically proliferating cells.
A ninth embodiment of the invention is directed to a method of treating a patient affected with pathologically proliferating cells containing a diaphorase or a disease producing a diaphorase, comprising administering to said patient agent with a redox potential greater than the diaphorase and an LD
50
greater than 1 &mgr;M or 100 times the effective dose for systemic non-liposome or other non-local administration to generate reactive oxygen and kill the pathologically proliferating cells, and optionally to provide therapeutic effect except required in those cases where necessary for novelty therapeutic amount of NO providing compound. This embodiment is generic to the eighth embodiment.
A tenth embodiment of the invention is directed to a method of treating a patient affected with pathologically proliferating cells, comprising causing overexpression of nitric oxide synthase in said patient, and administering to said patient a therapeutic amount of agent with redox potential greater than nitric oxide synthase and an LD
50
greater than 1 &mgr;M or 100 times the effective dose for systemic non-liposome or other non-local administration. This embodiment is generic to the case of the fifth embodiment where agent that induces expression of nitric oxide synthase is also administered.
An eleventh embodiment of the invention is directed to treating a patient in need of constricting of blood vessels, said method comprising administering to said patient a therapeutically effective amount of agent with redox potential greater than nitric oxide synthase and an LD
50
greater than 1 &mgr;M or 100 times the effective dose for systemic non-liposome or other non-local administration, and optionally to provide therapeutic effect except required in those cases where necessary for novelty therapeutic amount of NO providing compound.
A twelfth embodiment of the invention is directed to a method of treating patients for disorders where generation of O
2
−
provides benefit, comprising administering to said patient a amount of agent with a redox potential greater than nitric oxide synthase and an LD
50
greater than 1 &mgr;M or 100 times the effective dose for systemic non-liposome or other non-local administration to generate O
2
−
from nitric oxide synthase or other agents which otherwise generate O
2
−
in the patient and optionally to provide therapeutic effect except required in those cases where necessary for novelty NO providing compound. This embodiment is generic to all or portion of the fifth embodiment, the eighth embodiment and the ninth embodiment.
A thirteenth embodiment of the invention is directed to a method of determining nitric oxide synthase containing cells comprising the steps of adding a superoxide generating sufficient amount of paraquat to a suspension of cells and assaying for superoxide, with detecting of superoxide in the assay indicating the presence of nitric oxide synthase-containing cells.
A fourteenth embodiment of the invention is directed to a method for determining nitric oxide synthase deficient cells and thereby selecting for them, comprising adding paraquat to a suspension of cells in an amount to provide a concentration of paraquat ranging from 25 &mgr;M to 8 mM, thereby to kill nitric oxide synthase-cont
Day Brian J.
Griffith Owen W.
Gross Steven S.
Stamler Jonathan S.
Duke University
Henley III Raymond
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