Therapeutic mixture useful in inhibiting lesion formation...

Details Therapeutic mixture useful in inhibiting lesion formation... Therapeutic mixture useful in inhibiting lesion formation...

1999-04-16

2002-07-30

Jones, Dwayne C. (Department: 1614)

Surgery

Means for introducing or removing material from body for...

Treating material introduced into or removed from body...

C514S053000, C514S094000, C514S269000

Reexamination Certificate

active

06425881

ABSTRACT:

BACKGROUND OF THE INVENTION
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, 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, 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 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.
It is known that administration of drugs consisting of nitric oxide, or releasing nitric oxide, can inhibit restenosis after angioplasty. Chronic inhalation of nitric oxide inhibits restenosis following balloon-induced vascular injury of the rat carotid artery. Oral administration of NO donors (drugs which release nitric oxide) inhibits restenosis in rat and pig models of balloon angioplasty-induced vascular injury.
The long term benefit of coronary balloon angioplasty and atherectomy is limited by the considerably high occurrence of symptomatic restenosis (40-50%) 3 to 6 months following the procedure. Restenosis is in part due to myointimal hyperplasia, a process that narrows the vessel lumen and which is characterized by vascular smooth muscle cell migration and proliferation. Medical therapies to prevent restenosis have been uniformly unsuccessful. Intravascular stents have been successfully used to achieve optimal lumen gain, and to prevent significant remodeling. However, intimal thickening still plays a significant role in stent restenosis.
The vascular architecture is maintained or remodeled in response to the changes in the balance of paracrine factors. One of the substances that participates in vascular homeostasis is endothelium derived nitric oxide (NO). NO is synthesized from the amino acid L-arginine by NO synthase. NO relaxes vascular smooth muscle and inhibits its proliferation. In addition, NO inhibits the interaction of circulating blood elements with the vessel wall. NO activity is reduced in hypercholesterolemia and after vascular injury. The administration of L-arginine alone has been shown to restore vascular NO activity in animals and in humans with endothelial vasodilator dysfunction.
SUMMARY OF THE INVENTION
We have developed an approach to diminish the incidence of restenosis resulting from angioplasty and atherectomy, using an arginine based mixture to enhance NO activity in the vessel wall.
The term “subject” as used herein means any mammal, including humans, where nitric oxide (“NO”) formation from arginine occurs. The methods described herein 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 in 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-lysine may be considered a biological equivalent of L-arginine. Other bioequivalents of L-arginine may be arginase inhibitors, citrulline, ornithine, and hydralazine.
“To mix”, “mixing”, or “mixture(s)” as used herein means mixing a substrate (i.e., L-arginine) and another therapeutic agent agonist (e.g., nitroglycerin or an Hmg-CoA reductase inhibitor): 1) prior to administration (“in vitro mixing”); 2) mixing by simultaneous and/or consecutive, but separate (e.g., 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 (e.g., 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 pre-determined amounts of a NOS agonist and a NOS substrate.
“Agonist” refers to an agent which stimulates the bio-transformation of a NO precursor, such as L-arginine or L-lysine to EDNO or EDRF either through enzymatic activation, regulation or increasing gene expression (i.e., increased protein levels of c-NOS). Of course, either or both of these mechanisms may be acting simultaneously.
As used herein, the term “pharmaceutically acceptable carrier” refers to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredients and which is not toxic to the hosts to which it is administered.
Methods and devices are provided for inhibiting the pathology associated with vascular injury, particularly during angioplasty and atherectomy. A NO producing mixture, preferably L-arginine and a NOS agonist, is introduced either intraluminally or more preferably intramurally (for example by a stent) to into the walls of the injured vessel in proximity to the injury in an amount to inhibit the pathology, e.g, restenosis, associated with the vascular injury. Various conventional deliv

Affiliated with

Also associated with

Rating

Therapeutic mixture useful in inhibiting lesion formation... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Therapeutic mixture useful in inhibiting lesion formation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic mixture useful in inhibiting lesion formation... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2844368