Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-10-18
2002-10-15
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S419000, C514S460000
Reexamination Certificate
active
06465516
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to a method of treating cardio-cerebrorenovascular disease as well as avoiding potential cardiocerebrorenovascular disease, and the symptoms thereof, wherein a substrate of Nitric Oxide Synthase (“NOS”) and an agonist of NOS are combined to produce a beneficial effect.
DESCRIPTION OF RELATED ART
Much focus in the area of cardiac disease has been on the presence of cholesterol in the body. Hypercholesterolemia is known to be a primary risk factor for death from coronary heart disease. It is known that 50% or more of the total body cholesterol in humans is derived from intrinsic biosynthesis. It is also known that a rate-limiting step of major significance in the biosynthesis of cholesterol is at the level of the enzyme known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase or Hmg-CoA reductase. A general class of compounds is known in the art which inhibit and reduce the intrinsic biosynthesis of cholesterol in order to reduce the risk factor of hypercholesterolemia and coronary artery death. This general class of compounds is known as inhibitors of Hmg-CoA reductase.
An alternative 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 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 interchangeable unless otherwise indicated. Macrophages and neurons have also been shown to produce nitric oxide in the body as a component of their cell killing and/or cytosolic function.
Recently it has 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, nuerotransmission 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, 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 inducible form of nitric oxide synthase has been found to be present in activated macrophages and is induced in vascular smooth muscle cells, for example, by various cytokines and/or microbial products.
The conversion of precursor substrates of EDNO such as L-arginine into nitric oxide is enzymatically catalyzed by NOS and the resulting by-product of the conversion of L-arginine is L-citrulline. Although it was initially described in endothelium, NOS activity has now been described in many cell types. Brain, endothelium, and macrophage isoforms 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 (“cNOS”), 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 nitric oxide synthase 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.
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. Relatively little is known about postranscriptional regulation of iNOS. Cytotoxic effects of NO are probably largely independent of guanylate cyclase and cyclic GMP formation. Most of the research in the area has focused on inhibitors of iNOS stimulation using various derivatives of L-arginine.
Research into the area of cNOS activation reveals a number of agonist of cNOS some of which have been described in U.S. Pat. No. 5,543,430, which is hereby incorporated by reference in its entirety. However, until now there was no known research indicating Hmg-CoA reductase inhibitors were capable of functioning as agonist of cNOS.
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 in therapy of an existing condition.
The term “native NO” as used herein refers to nitric oxide that is produced through the bio-transformation of L-arginine or the L-arginine dependent pathway. “EDRF” or “EDNO” may be used interchangeably with “native NO”. 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). L-arginine as defined herein appears to function as a substrate of cNOS.
“To mix”, “mixing”, or “mixture(s)” as used herein means mixing a substrate (i.e. L-arginine) and an agonist (i.e. Hmg-CoA reductase inhibitor): 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 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 Hmg-CoA reductase)); or any combination of the above which results in the combination of therapeutic amounts of a NOS agonist and a (NOS substrate in an additive or synergistic way with regard to the treatment of vascular disease.
Agonist refers to an agent which stimulates the bio-transformation of a substrate such as L-arginine to EDNO or EDRF either through enzymatic activation or increasing gene expression (i.e. increased protein levels of c-NOS). Of course, either or both of these mechanisms may be acting simultaneously.
It is an object of this invention to provide a method of preventing, treating, arresting, or ameliorating disease conditions which are benefited by the bio-transformation of a substrate into endogenous nitric oxide or “native” nitric oxide.
It is another object of this invention to provi
Benesch Friedlander Coplan & Aronoff LLP
Nitrosystems, Inc.
Spivack Phyllis G.
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