Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-09
2002-03-05
Saoud, Christine J. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S399000
Reexamination Certificate
active
06352975
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods for treating hypertension, using a factor that stimulates angiogenesis and/or promotes vascular permeability.
BACKGROUND OF THE INVENTION
Systemic hypertension is the most prevalent cardiovascular disorder in the United States, affecting over 60 million Americans. In spite of increasing public awareness and a rapidly expanding array of antihypertensive medications, hypertension remains one of the leading causes of cardiovascular morbidity and mortality. Hypertension treatments have focused on stimulating the relaxation of the peripheral vasculature (vasodilation), depressing cardiac function, or by stimulating salt transport by blocking epithelial transport of sodium or chloride (diuresis). “Textbook of Medical Physiology”, Guyton and Hall, eds. p. 234 (1996) W. B. Saunders. In addition, adverse metabolic effects have been observed with treatment using certain classes of antihypertensive treatment in coronary disease prevention. “Cecil Textbook of Medicine” pp. 252-269 (1992) W. B. Saunders. Therefore, there is a need to develop improved methods of treatment of hypertension.
Essential hypertension is the pathological expression of the inability to excrete a dietary sodium load efficiently. The causes for and the mechanism of the development of essentially hypertension are less than clear. According to one of the several possible theories, excreting a sodium load depends on the permeability of the vascular/epithelial barrier in the excreting organs such as the kidney and/or the surface area of the vascular/epithelial structures available for solute flux.
In tissues, the basement membrane serves to separate epithelial cells from blood vessels containing endothelial cells, particularly in the transport or flux of solutes in solution, such as sodium chloride, across basement membranes. Normally, the endothelium is relatively impermeable, limiting the flux of solutes and fluid across the basement membrane against which it is juxtaposed. However, the function of several specialized tissues requires permeable capillary beds to support solute flux. Such functions include the filtration of solutes by the kidney to regulate intravascular volume and maintain normal blood pressure, reabsorption of fluid secretions in the lungs to preserve pulmonary oxygenation, reabsorption of fluids containing solutes in the intestines to provide nutrition, production of cerebrospinal fluid in the choroid plexus of the brain to support and protect the central nervous system, diffusion of nutrients toward non-vascular tissue as occurs in certain portions of the eye or in wound healing, and reabsorption of interstitial fluid from the peritoneum. Impaired transport of solutes across basement membranes contributes to or exacerbates, among other disorders, essential hypertension, kidney disease, acute respiratory disease syndrome, macular ischemia, intestinal inflammatory diseases, meningitis, stroke, ascites, impaired peritoneal dialysis efficiency, and impaired wound healing.
A number of factors may potentially affect solute flux between the endothelial bed and epithelial tissue, including: (1) the metabolic activity of the epithelial cells of a particular tissue; (2) the number of the blood vessels adjacent to the epithelium and its basement membrane; and (3) the porosity or permeability of said blood vessels. Some of the diseases cited above are associated with epithelial cell toxicity, such as acute respiratory distress syndrome and kidney disease or with altered integrity of the capillary blood vessels, as occurs in vasculitis or ischemia. Other disease syndromes, such as essential hypertension have no defined central mechanism. The diseases cited above may be associated with diminished capillary number or altered porosity of the capillary vessel.
Angiogenesis, i.e. the growth of new capillary blood vessels, is a process which is crucial to normal tissue formation and repair. Consequently, factors that are capable of promoting angiogenesis are useful as wound healing agents. Angiogenesis is a multi-step process involving capillary endothelial cell proliferation, migration and tissue penetration. A number of known growth factors, including basic and acidic fibroblast growth factor, transforming growth factor &agr; and epidermal growth factor, are broadly mitogenic for a variety of cell types as well as being angiogenic and are, therefore, potentially useful in promoting tissue repair. Broad spectrum mitogenicity is desirable in many types of tissue repair applications. There are, however, specific types of tissue repair applications in which it would be desirable to have endothelial cell-specific mitogenic activity, since proliferation of other cell types along with endothelial cells could cause blockage and/or reduced blood flow.
Vascular endothelial growth factor (VEGF) is a secreted endothelial cell mitogen that, when delivered in vivo, promotes new blood vessel formation. The VEGF protein consists of two polypeptide chains, linked by two disulfide bonds. Although the protein is generally described as a homodimer, heterodimeric species have also been reported. Through alternative splicing of the VEGF RNA transcript, five different forms of the monomer chain can be generated, extending 121, 145, 165, 189, and 206 amino acid residues in length. Tischer et al. (1991)
J. Biol. Chem
. 266:11947-11954; Houck et al. (1991)
Mol. Endocrinol
. 5:1806-1814; Charnock-Jones et al. (1993)
Biol. Reprod
. 48:1120-1128; and Neufeld et al. (1996)
Cancer Metastasis Rev
. 15:153-158. The 121-residue form of VEGF (VEGF
121
) is unique among the five forms in that it does not bind to heparin-like molecules associated with the extracellular matrix. VEGF
121
and the 165-residue form, VEGF
165
, appear to be the most prevalent forms in vivo.
VEGF is known to stimulate new blood vessel formation by stimulating endothelial cell proliferation and by inducing chemotaxis of endothelial cells. In contrast to other mitogens such as the fibroblast growth factors, VEGF has a much more restricted range of target cell type, and is mitogenic almost exclusively toward endothelial cells. VEGF is also known to enhance vascular permeability and can trigger the relaxation of blood vessels through the release of endothelial nitric oxide. Hariawala et al. (1996)
J Surgical Res
. 63:77-82; and Sellke et al. (1996)
Am. J. Physiol
. 271:H713-H720. In addition, VEGF has been shown to regulate the expression of other growth factors and biological mediators and may participate in a growth factor cascade that promotes tissue remodeling and repair.
The activity of VEGF is mediated by interaction with specific membrane receptors on target tissues, most notably the vascular endothelium. Both VEGF
121
and VEGF
165
are known to interact with two tyrosine kinase receptors: kinase insert domain-containing receptor (KDR; also known as Flk-1), and fms-like tyrosine kinase-1 (Flt-1). deVries et al. (1992)
Science
255:989-991; Terman et al. (1992)
Biochem. Biophys. Res. Commun
. 187:1579-1586; and Millauer et al. (1993)
Cell
72:835-846. Both KDR and Flt-1 consist of extracellular ligand-binding domains and intracellular tyrosine kinase domains, the latter being functionally activated upon engagement of VEGF. KDR is found only on endothelial cells, while Flt-1 is found on endothelial cells and monocytes. The angiogenic properties and other known functions of VEGF appear to be mediated via KDR and Flt-1.
Each human kidney comprises about one million nephrons, each capable of forming urine. Each nephron has two major components: a glomerulus, through which large amounts of fluid are filtered from the blood, and a long tubule, in which the filtered fluid is converted into urine. The glomerular capillary has three major layers: the endothelium, a basement membrane, and a layer of epithelial cells. The capillary endothelium is perforated by thousands of small holes called fenestrae.
VEGF can increase the permeability of blood vessels to solutes on a long-term basis by inducing the formation of fen
Johnson Richard J.
Schreiner George F.
Knobbe Martens Olson & Bear LLP
Saoud Christine J.
Scios Inc.
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