Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-12-23
1999-05-04
Fay, Zohreh
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514573, 604 19, 604 20, 604 21, 604 23, 604 26, 604 51, 604 52, 604 53, 604890, 6048911, 128898, A61K 31215, A61K 3119, A61M 3100
Patent
active
059004339
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to methods and devices for the site-specific delivery of bioactive agents in mammals, especially for cardiac and peripheral vascular applications, and more particularly, is directed to a method for treating the heart by intrapericardial access.
A. Vascular Endothelium Function
Normal blood vessels are lined with a layer of endothelial cells. The endothelium releases local factors (endothelium-derived relaxing factor into the vessel wall (intramural release) and into the blood stream (intraluminal release). These factors maintain vascular tone (vessel relaxation), inhibit clot formation on the vessel inner surface (platelet adhesion and aggregation), inhibit monocyte adherence and chemotaxis, and inhibit smooth muscle cell migration and proliferation. Normal endothelium releases both prostacyclin and nitric oxide in response to platelet aggregation. Nitric oxide release inhibits platelet adhesion, prevents further aggregation, and promotes platelet disaggregation. Prostacyclin release, promoted by platelet-derived thromboxane A.sub.2, acts synergistically with nitric oxide to prevent platelet-mediated vasoconstriction. As a result of this process, vasodilation and thrombolysis occurs, and blood flow is maintained. If the endothelium is dysfunctional or damaged, however, nitric oxide and prostacyclin release is impaired. Platelet aggregation and adhesion can occur unopposed, with platelet-derived products acting directly on the smooth muscle cells to cause vasoconstriction. The net result is a blood vessel which is highly susceptible to thrombosis and vasospasm. See, "Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor", Palmer R., et al., NATURE, 327:524, 1987; "Control of coronary vascular tone by nitric oxide", Kelm M., et al., CIRC. RES., 66:1561, 1990; "Regulatory functions of the vascular endothelium", Vane J., et al., N. ENGL. J. MED., 323:27, 1990; "Endothelial modulation of vascular tone: Relevance to coronary angioplasty and restenosis", Harrison D., J. AMER. COL. CARDIOL., 17:71B, 1991; "The antiaggregating properties of vascular endothelium: Interactions between prostacyclin and nitric oxide", Radomski M., et al., BRIT. J. PHARMACOL., 92: 639, 1987; "EDRF increases cyclic GMP in platelets during passage through the coronary vascular bed", Pohl U., et al., CIRC. RES., 65:1798, 1989; "Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cAMP and cGMP", Alheid U., et al., EUROP. J. PHARMACOL., 164:103, 1989; "Nitric oxide: An endogenous modulator of leukocyte adhesion", Kubes P., et al., PROC. NATL. ACAD. SCI., 88:4651, 1991; "Nitric oxide and prostacyclin: Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro", Bath P., et al., ARTERIOSCLER. THROMB., 11:254, 1991; "Nitric oxide generating vasodilators and 8-Br-cGMP inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells", Garg U., et al., J. CLIN. INVEST., 83:1774, 1989; "Role of blood platelets and prostaglandins in coronary artery disease", Mehta J., et al., AMER. J. CARDIOL., 48:366, 1981; and "Prostaglandins and cardiovascular disease: A review", Jacobsen D., SURGERY, 93:564, 1983.
B. Vascular Stenosis
Atherosclerosis can form within a blood vessel over a period of years from a variety of causes. The resulting lesion, or plaque, may progressively occlude the vessel and impede blood flow to vital organs. The stenotic lesions when covered by endothelium are termed stable. See, "Cellular proliferation in atherosclerosis and hypertension", Schwartz S., et al., PROG. CARDIOVASC. DIS., 26:355, 1984; and "The pathogenesis of atherosclerosis: An update", Ross R., N. ENGL. J. MED., 314:488, 1986.
Unstable stenotic lesions are associated with endothelial cell injury at the sites of coronary stenosis. Injury to the endothelium stops the local release of the endothelium-derived factors. Severe injury to the vessel wall exposes the underlying collagen layer, whic
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Igo Stephen R.
Meador James W.
Burgess Tim L.
Cormedics Corp.
Fay Zohreh
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