Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-07
2001-05-29
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06239172
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to therapeutic formulation comprised of a combination of angiogenic growth factors and substrates of Nitric Oxide Synthase (“NOS”), preferably arginine, as well as a method of treating, preventing and/or ameliorating cardiocerebrorenovascular disease and the symptoms thereof. More particularly, the present invention is directed to the administration of a biological equivalent of arginine and an agonist of NOS (e.g., vascular endothelium growth factor (“VEGF”)) to produce a beneficial effect.
DESCRIPTION OF RELATED ART
One approach to treating cardiac disease is to effect the dilation of vascular conduits in the body. In this regard, nitric oxide has been shown to be formed enzymatically as a normal metabolite from arginine in the vascular endothelium and provides an important component to the formation of endothelium-derived relaxing factor (EDRF). EDRF appears to be equivalent to Endothelium Derived Nitric Oxide (EDNO) and as used herein EDRF and EDNO are used interchangeably unless otherwise indicated.
It has also been established that a family of enzymes called Nitric Oxide Synthase (“NOS”) form nitric oxide from L-arginine, and the nitric oxide produced is responsible for the endothelium dependent relaxation and activation of soluble guanylate cyclase, neurotransmission in the central and peripheral nervous systems, and activated macrophage cytotoxicity. Nitric Oxide Synthase occurs in many distinct isoforms which include a constitutive form (“cNOS”) and an inducible form (iNOS). The constitutive form is present in normal endothelial cells, brain, neurons and some other tissues. Formation of nitric oxide by the constitutive form in endothelial cells is thought to play an important role in normal blood pressure regulation, prevention of endothelial dysfunction such as hyperlipodemia, arteriosclerosis, thrombosis, and restenosis. The by-product of the conversion of L-arginine is L-citrulline. Brain, endothelium, and macrophage isoforms of NOS appear to be products of a variety of genes that have approximately 50% amino acid identity. NOS in brain and in endothelium have very similar properties, the major differences being that brain NOS is cytosolic and the endothelial enzyme is mainly a membrane-associated protein.
Functionally, the constitutive form of Nitric Oxide Synthase, which is the predominant synthase present in brain and endothelium, may be active under basal conditions and can be further stimulated by increases in intracellular calcium that occur in response to receptor-mediated agonists or calcium ionophores. cNOS appears to be the “physiological” form of the enzyme and plays a role in a diverse group of biologic processes. In vitro studies suggest that the activity of NOS can be regulated in a negative feedback manner by nitric oxide itself. In cardiocerebrorenovascular circulation, the primary target for constitutively produced nitric oxide is believed to be soluble guanylate cyclase located in vascular smooth muscle, the myocardium (myocytes) and coronary vascular smooth muscle.
In contrast to the cNOS, the inducible, calcium-independent form, iNOS was initially only described in macrophages. It is now known that induction of nitric oxide synthase can occur in response to appropriate stimuli in many other cell types. This includes both cells that normally do not express a constitutive form of nitric oxide synthase, such as vascular smooth muscle cells, as well as cells such as those of the myocardium that express considerable levels of the constitutive isoform. The inducible form of nitric oxide synthase has been found to be induced in vascular smooth muscle cells, for example, by various cytokines and/or microbial products.
iNOS exhibits negligible activity under basal conditions, but in response to factors such as lipopolysaccharide and certain cytokines, expression occurs over a period of hours. The induced form of the enzyme produces much greater amounts of NO than the constitutive form, and induced NOS appears to be the “pathophysiological” form of the enzyme because high concentrations of NO produced by iNOS can be toxic to cells. Induction of iNOS can be inhibited-by glucocorticoids and some cytokines.
SUMMARY OF THE INVENTION
The term “subject” as used herein to mean any mammal, including humans, where nitric oxide formation from arginine occurs. The methods herein for use on subjects contemplate prophylactic use as well as curative use.
The term endpoints as used herein refers to clinical events encountered in the course of treating cardiovascular disease, up to and including death (mortality).
L-arginine as used herein includes all biochemical equivalents (i.e. salts, precursors, and its basic form). “To mix”, “mixing”, or “mixture(s)” as used herein means mixing a substrate (i.e. L-arginine) and an agonist (i.e. angiogenic growth factors ): 1) prior to administration (“in vitro mixing”); 2) mixing by simultaneous and/or consecutive, but separate (i.e. separate intravenous lines) administration of substrate (L-arginine) and agonist (angiogenic growth factor) to cause “in vivo mixing”); and 3) the administration of a NOS agonist after saturation with a NOS substrate (i.e. L-arginine is administered to build up a supply in the body prior to administering the NOS agonist (nitroglycerin or angiogenic growth factors)); or any combination of the above which results in the delivery of therapeutic amounts of a NOS agonist and a NOS substrate in an additive or synergistic way with regard to the treatment of disease, preferably cardiocerebrorenovascular disease.
Agonist refers to an agent which stimulates the bio-transformation of a substrate such as L-arginine either through enzymatic activation or increasing gene expression (i.e. increased levels of NOS). Of course, either or both of these mechanisms may be acting simultaneously.
The present invention is preferably useful in preventing, treating, arresting, or ameliorating disease conditions which are benefited by the bio-transformation of a substrate into nitric oxide or “native” nitric oxide. The present invention preferably promotes therapeutic angiogenesis.
The present invention may also be useful in preventing, treating, arresting, or ameliorating disease conditions which are benefited by the bio-transformation of L-arginine into “native” nitric oxide through enzyme activation of NOS.
The present invention may also be useful in achieving a beneficial effect when treating disease conditions by increasing or maximizing the production of EDRF or EDNO, and reducing clinical endpoints to include mortality.
The present invention may also be useful in preventing, treating, or avoiding tachycardia and ischemia.
The present invention may also be useful in preventing, treating, arresting, or ameliorating reperfusion injury in subjects who have had abrupt restoration of blood flow.
In one embodiment of the present invention, a mixture of NOS agonists, preferably angiogenic growth factors, and biological equivalents of L-arginine are used for the treatment of hypertension, hypertensive heart disease, coronary heart disease, including arteriosclerosis, angina, myocardial infarction, coronary thrombosis, restenosis post angioplasty, and sudden death, as well as a wide range of cardiovascular disease (heart failure, stroke, and peripheral vascular diseases), and renovascular ischemia/hypertension.
In an alternative embodiment of the invention, therapeutically effective amounts of a precursor of EDNO and an agonist of NOS (preferably one of those cited in Table I herein) are combined prior to administration to a patient. In another embodiment of the invention, therapeutically effective amounts of a precursor of EDNO and an angiogenic growth factor are combined and administered.
In a preferred embodiment of the present invention, therapeutically effective amounts of L-arginine and therapeutically effective amounts of a macrophage secretory product are mixed at a physiologically acceptable pH.
Another embodiment of the present invention is a method for treatin
Benesch Friedlander Coplan & Aronoff LLP
Jones Dwayne C.
Miller Raymond A.
NitroSystems, Inc.
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