United States Patent (19)
Cooke et al.
US 005891459A
(11) Patent Number: 5,891,459
(45) Date of Patent: *Apr. 6, 1999
(54) ENHANCEMENT OF VASCULAR FUNCTION BY MODULATION OF ENDOGENOUS NITRIC OXIDE PRODUCTION OR ACTIVITY
(75) Inventors: John P. Cooke, Palo Alto; Victor J. Dzau, Los Altos Hills; Gary H. Gibbons, Palo Alto, all of Calif.
(73) Assignee: The Board of Trustees of the Leland Stanford Junior University, Stanford Calif.
(*) Notice: The term of this patent shall not exceed beyond the expiration date of Pat. No. 5,428,070.
(21) Appl. No.: 556,035
(22) Filed: Nov. 9, 1995
Related U.S. Application Data
(63) Continuation-in-part of Ser. No. 336,159, Nov. 8, 1994, abandoned, which is a continuation-in-part of Ser. No. 76,312, Jun. 11, 1993, Pat. No. 5,428,070.
(51) Int. Cl.6 ………A23L 1/305; A61K 9/00; A61K 31/195
(52) U.S. Cl. ……………424/439; 424/441; 426/648; 426/656; 514/564; 514;565
(58) Field of Search ……………930/290; 530/358; 426/648, 656, 657; 514/310, 20, 557, 564, 565; 424/439, 441
(56) References Cited
U.S. PATENT DOCUMENTS
3,970,750 7/1976 Brockmeyer et al. 424/679
4,340,592 7/1982 Abidi 514/18
4,920,098 4/1990 Cottes et al. 514/2
5,032,608 7/1991 Dudrick 514/423
5,034,377 7/1991 Abidi et al. 514/18
5,106,836 4,1992 Clemen et al. 514/21
5,157,022 10/1992 Barbul 514/18
5,171,217 12/1992 March et al. 604/53
US 005891459A
(11) Patent Number: 5,891,459
(45) Date of Patent: *Apr. 6, 1999
5,217,997 6/1993 Levere et al. 514/565
5,278,189 1/1994 Rath et al. 514/561
5,364,644 11/1994 Walaszek et al. 514/579
5,428,070 6/1995 Cooke et al. 514/557
5,464,644 11/1995 Wullschleger et al. 426/549
5,543,430 8/1996 Kaesemeyer 514/565
5,576,287 11/1996 Zaloga et al. 514/2
5,576,351 11/1996 Yoshimura et al. 514/565
5,626,883 5/1997 Paul 424/605
5,631,031 5/1997 Mead 426/2
5,650,418 7/1997 Rath et al. 514/356
5.767,160 6/1998 Kaesemeyer 514/565
5,780,039 7/1998 Greenberg et al. 424/400
FOREIGN PATENT DOCUMENTS
546 796 A1 6/1993 European Pat. Off.
55418 4/1983 Japan
321786 11/1994 Japan
OTHER PUBLICATIONS
Ignarro et al. Basic Polyamino Acids Rich in Arginine… Circ. Res. Feb. 1989, vol. 64, No. 2, pp. 315-329.
McNamara et al. L. Arginine Inhibits Balloon Catheter… Biochem. Biophys. Res. Comm. 28 May 1993, vol. 193, No. 1, pp. 291-296.
(List continued on next page.)
Primary Examiner – Jeffrey E. Russel
Attorney, Agent, or Firm – Bertram I. Rowland; Flehr Hohbach Test Albritoon & Herbert
(57) ABSTRACT
Vascular function and structure is maintained or improved by long term administration of physiologically acceptable compounds, namely L. arginine, L-lysine, physiologically acceptable sales thereof, and polypeptide precursors thereof, which enhance the level of endogenous nitric oxide or other intermediates in the NO induced relaxation pathway in the host. In or in combination, other compounds, such as B6, folate, B12, or an antioxidant, which provide for short term enhancement of nitric oxide, either directly or by physiological processes may be employed.
22 Claims, 10 Drawing Sheets
5,891,459
Page 2
OTHER PUBLICATIONS
Rock et al. L-arginyl-L-lysine and L-arginyl-L-arginine…Med.Sci.Res. 1990, vol. 18, pp. 165-166. Andrews et al., “Low-density Lipoproteins inhibit endothelium-dependent Relaxation in Rabbit Aorta”, Nature (1987), 327:327-239.
Bath et al., “Nitric Oxide and Prostacyclin: Divergence of Inhibitory Effects on Monocyte Chemotaxis and Adhesion to Endothelium in Vitro”, Arterioscierosis and Thrombosis (1991), 11:254-260.
Cooke, “Endothelial Dysfunction in Disease States”, Current Opinion in Cardiology (1990), 5:637-644.
Drexler et al., “Correction of Endothelial Dysfunction in Coronary Micocirculation of Hypercholesterolaemic Patients”, The Lancet (1991), 338:1546-1550.
Garg and Hassid, “Nitric Oxide-generating Vasodilators and 8-Bromo-Cyclic Guanosine Monophosphate Inhibit Mitrogenesis and Proliferation of Cultures Rate Vascular Smooth Muscle Cells”, J. Clin. Invest. (1989), 83:1774-1777.
Girerd et al., “L-Arginine Augments Endothelium-Dependent Vasodilation in Cholesterol-Fed Rabbits”, Circultaion Research (1990), 67:1301-1308.
Heistad et al., “Augmented responses to Vasoconstrictor Stimuli in Hypercholesterolemic and Atherosclerotic Monkeys”, Circulation Research (1984), 54:711-718.
Kubes et al., “Nitric Oxide: An Endogenous Modulator of Leukocyte Adhesion”, PNAS USA (1991), 88:4651-4655.
Kugiyama et al., “Impairment of Endothelium-Dependent Arterial Relaxation by Lysolecithin in Modified Low-density Lipoproteins”, Nature (1990), 244:160-162.
Kuo et al., “Pathophysiological Consequences of Atherosclerosis Extend Into the Coronary Microcirculation: Restoration of Endothelium-dependent Responses by L-Arginine”, Circulation Research (19920, 70:465-476.
Lefer et al., “Role of Endothelium-derived Relaxing Factor as a Cardioprotective Agent in Myocardial Ischemia”, Basil, Karger (1990), 190-197.
Minor et al., “Diet-induced Atherosclerosis Increases the Release of Nitrogen Oxides from Rabbit Aorta”, J. Clin. Invest. (1990), 86:2109-2116.
Mitchell et al., “Native LDL Inhibits the Release of Endothelial Derived Relaxing Factors by Reducing the Activity of Endothelial Nitric Oxide Synthase”, (Abstract), J. Vasc. Res. (1992), 29:169.
Pohl and Busse, “EDRF Increases Cyclic GMP in Platelets During Passage Through the Coronary Vascular Bed”, Circulation Research (1989), 65:1798-1803.
Radomski et al., “Comparative Pharmacology of Endothelium-derived Relaxing Factor, Nitric Oxide and Prostacyclin in Platelets”, Br. J. PHarmacol. (1987), 92:181-187.
Ross, “The Pathogenesis of Atherosclerosis – an Update”, The New England Journal of Medicine (1986), 314:488-500.
Rossitch, Jr. et al., “L-Arginine Normalizes Endothelial Function in Cerebral Vessels from Hypercholesterolemic Rabbits”, J. Clin. Invest., 87:1295-1299 (1991).
Stamler et al., “N-Acetylcysteine Potentiates Platelet Inhibition by Endothelium-derived Relaxing Factor”, Circulation Research (1989), 65:789-795.
Tanner et al., “Oxidized Low Density Lipoproteins Inhibit Relaxations of Porcine Coronary Artieries: Role of Scavenger Receptor and Endotheiim- derived Nitric Oxide”, Circulation, 83:2109-2116 (1991).
Tomita et al., “Rapid and Reversible Inhibition by Low Density Lipoprotein of the Endothelium-dependent Relaxation to Hemostatic Substances in Porcine Coronary Arteries”, Circulation (1990), 81:1667-1679.
Yamamoto et al., “Videomicroscopic Demonstration of Defective Cholinergic Arteriolar Vasodilation in Atherosclerotic Rabbit”, J. CLin. Invest. (1988), 81:1752-1758.
Lankin, “Atherosclerosis as a Free Radical Pathology”, Inst. Congr. Ser. Excerpta Med. (1992), 998:385-8.
Zembowicz, “The Biological Role of L-Arginine/Nitric Oxide Pathway”, Folia Med. Cracov. (1992), 33:103-116.
ENHANCEMENT OF VASCULAR FUNCTION BY MODULATION OF ENDOGENOUS NITRIC OXIDE PRODUCTION OR ACTIVITY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application Ser. No. 08/336,159, filed Nov. 8, 1994, now abandoned, which is a continuation-in-part of Ser.No. 08/076,312, filed Jun. 11, 1993, now U.S. Pat. No. 5,428,070.
INTRODUCTION
This invention was supported in part by the United States Government under Grant 1KO7HCO2660 (NHLBI). The U.S. Government may have an interest in this application.
1. Technical Field
The field of this invention is the modulation of NO activity, which finds application in maintaining and improving vascular function and thereby prevention or improving vascular degenerative diseases.
2. Background
Atherosclerosis and vascular thrombosis are a major cause of morbidity and mortality, leading to coronary artery disease, myocardial infarction, and stroke. Atherosclerosis begins with an alteration in the endothelium, which lines the blood vessels. The endothelial alteration results in adherence of monocytes, which penetrate the endothelial lining and take up residence in the subintimal space between the endothelium and the vascular smooth muscle of the blood vessels. The monocytes absorb increasing amounts of cholesterol (largely in the form of oxidized or modified low-density lipoprotein) to form foam cells. Oxidized low-density lipoprotein (LDL) cholesterol alters the endothelium, and the underlying foam cells distort and eventually may even rupture through the endothelium.
Platelets adhere to the area of endothelial disruption and release a number of growth factors, including platelet derived growth factor (PDGF). PDGF, which is also released by foam cells and altered endothelial cells, stimulates migration and proliferation of vascular smooth muscle cells into the lesion. These smooth muscle cells release extracellular matrix (collagen and elastin) and the lesion continues to expand. Macrophages in the lesion elaborate proteases, and the resulting cell damage creates a necrotic core filled with cellular debris and lipid. The lesion is then referred to as a “complex lesion.” Rupture of this lesion can lead to thrombosis and occlusion of the blood vessel. In the case of a coronary artery, rupture of a complex lesion may precipitate a myocardial infarction, whereas in the case of a carotid artery, stroke may ensue.
One of the treatments that cardiologists and other interventionalists employ to reopen a blood vessel which is narrowed by plaque is balloon angioplasty (approximately 300,000 coronary and 100,000 peripheral angioplasties are performed annually). Although balloon angioplasty is successful in a high percentage of the cases in opening the vessel, it unfortunately denudes the endothelium and injures the vessel in the process. This damage causes the migration and proliferation of vascular smooth muscle cells of the blood vessel into the area of injury to form a lesion, known as myointimal hyperplasia or restenosis. This new lesion leads to a recurrence of symptoms within three to six months after the angioplasty in a significant proportion of patients (30-40%).
In atherosclerosis, thrombosis and restenosis there is also a loss of normal vascular function, such that vessels tend to constrict, rather than dilate. The excessive vasoconstriction of the vessel causes further narrowing of the vessel lumen, limiting blood flow. This can cause symptoms such as angina (if a heart artery is involved), or transient cerebral ischemia (i.e. a “small stroke”, if a brain vessel is involved). This abnormal vascular function (excessive vasoconstriction or inadequate vasodilation) occurs in other disease states as well. Hypertension (high blood pressure) is caused by excessive vasoconstriction, as well as thickening, of the vessel wall, particularly in the smaller vessels of the circulation. This process may affect the lung vessels as well causing pulmonary (lung) hypertension. Other disorders known to be associated with excessive vasoconstriction, or inadequate vasodilation include transplant atherosclerosis, congestive heart failure, toxemia of pregnancy, Raynaud’s phenomenon, Prinzmetal’s angina (coronary vasospasm), cerebral vasospasm, hemolytic-uremia and impotence.
Because of their great prevalence and serious consequences, it is critically important to find therapies which can diminish the incidence of atherosclerosis, vascular thrombosis, restenosis, and these other disorders characterized by abnormality of vascular function and structure. Ideally, such therapies would inhibit the pathological vascular processes associated with these disorders, thereby providing prophylaxis, retarding the progression of the degenerative process, and restoring normal vasodilation.
As briefly summarized above, these pathological processes are extremely complex, involving a variety of different cells which undergo changes in their character, composition, and activity, as well as in the nature of the factors which they secrete and the receptors that are up-or down-regulated. A substance released by the endothelium, “endothelium derived relaxing factor” (EDRF), may play an important role in inhibiting these pathologic processes. EDRF is now known to be nitric oxide (NO) or a labile nitroso compound which liberates NO. (For purposes of the subject invention, unless otherwise indicated, nitric oxide (NO) shall intend nitric oxide or the labile nitrosos compound which liberates NO.) This substance relaxes vascular smooth muscle, inhibits platelet aggregation, inhibits mitogenesis and proliferation of cultures vascular smooth muscle, and leukocyte adherence. Because NO is the most potent endogenous vasodilator, and because it is largely responsible for exercise-induced vasodilation in the conduit arteries, enhancement of NO synthesis could also improve exercise capacity in normal individuals and these with vascular disease. NO may have other effects, either direct or indirect, on the various cells associated with vascular walls and degenerative disease of the vessel.
Relevant Literature
Girerd et al. (1990) Circulation Research 67:1301-1308 report that intravenous administration of L-arginine potentiates endothelium-dependent relaxation in the hind limb of cholesterol-fed rabbits. The authors conclude that synthesis of EDRF can be increased by L-arginine in hypercholesterolemia. Rossitch et al. (1991) J. Clin. Invst. 87:1295-1299 report that in vitro administration of L-arginine to basilar arteries of hypercholesterolemic rabbits reverses the impairment of endothelium-dependent vasodilation and reduces vasoconstriction. They conclude that the abnormal vascular responses in hypercholesterolemic animals is due to a reversible reduction in intracellular arginine availability for metabolism to nitric oxide.