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  Compositions and methods for modulation of vascular structure and/or functionUSPTO Application #: 20070072826Title: Compositions and methods for modulation of vascular structure and/or function Abstract: The present invention relates to compositions comprising semi-crystalline β-1-4-N-acetylglucosamine polymers (p-GlcNac) and methods utilizing such polymers modulation of vascular structure and/or function. The compositions and methods disclosed are useful for stimulating, in a p-GlcNac concentration-dependent manner, endothelin-1 release, vasoconstriction, and/or reduction in blood flow out of a breached vessel, as well as for contributing to or effecting cessation of bleeding. The methods of the present invention comprise topical administration of materials comprising semi-crystalline p-GlcNac polymers that are free of proteins, and substantially free of single amino acids as well as other organic and inorganic contaminants, and whose constituent monosaccharide sugars are attached in a β-1-4 conformation. (end of abstract) Agent: Jones Day - New York, NY, US Inventors: John N. Vournokis, Sergio Finkielsztein USPTO Applicaton #: 20070072826 - Class: 514054000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, Polysaccharide The Patent Description & Claims data below is from USPTO Patent Application 20070072826. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation of U.S. application Ser. No. 10/194,740, filed Jul. 12, 2000, which is a continuation of U.S. application Ser. No. 09/781,182, filed Feb. 12, 2001, now U.S. Pat. No. 7,041,657, issued May 9, 2006, each of which is incorporated by reference herein in their entireties. 1. INTRODUCTION [0002] The present invention relates to compositions comprising semi-crystalline poly-.beta.-1.fwdarw.4-N-acetylglucosamine (p-GlcNac) polysaccharide polymers and methods utilizing such polymers for stimulating, in a p-GlcNac concentration-dependent manner, transient, localized stimulation of endothelin-1 release, vasoconstriction, and/or reduction in blood flow out of a breached vessel. These effects, individually and/or collectively, contribute or lead to cessation of bleeding. More specifically, the methods of the present invention comprise topical administration of compositions and materials comprising semi-crystalline polymers of N-acetylglucosamine that are free of proteins and substantially free of single amino acids and other organic and inorganic contaminants, and whose constituent monosaccharide sugars are attached in a .beta.-1.fwdarw.4 conformation. 2. BACKGROUND [0003] Vascular homeostasis depends, in part, upon the regulated secretion of biochemical modulators by endothelial cells. Under normal physiological conditions, endothelial cells synthesize and secrete nitric oxide, prostacyclin, PG12, adenosine, hyperpolarizing factor, tissue factor pathway inhibitor, and scuplasminogen activator. Endothelial cells also activate antithrombin III and protein C, which, collectively, mediate vascular dilation, inhibit platelet adhesion, platelet activation, thrombin formation and fibrin deposition. Nitric oxide, in particular, plays a critical role in vascular homeostasis (Pearson, J. D. (2000) Lupus 9 (3): 183-88; Becker et al. (2000) Z Kardiol 89 (3): 160-7; Schinin-Kerth, V. B. (1999) Transfus Clin Biol 6 (6): 355-63). [0004] Production of nitric oxide and prostacyclin, which are powerful vasodilators and inhibitors of platelet aggregation and activation, underlies the antithrombotic activity of the endothelium (Yang et al. (1994) Circulation 89 (5): 2666-72). Nitric oxide is synthesized at a constitutive, basal level from arginine by nitric oxide synthase, and this synthesis is stimulated by the vaso-active agents acetylcholine and bradykinin. It has been shown that inhibition of nitric oxide synthase by the arginine analogues monomethyl-L-arginine (L-NMMA) and nitro-L-arginine methyl ester (L-NAME) reduces nitric oxide levels and leads not only to vasoconstriction, as measured by intravascular ultrasound imaging, but also to an increase in platelet aggregation (Yao et al. (1992) Circulation 86 (4): 1302-9; Emerson et al. (1999) Thromb Haemost 81 (6): 961-66). [0005] Perturbation of the endothelium as the result of atherosclerosis, diabetes, postischemic reperfusion, inflammation or hypertension for example, leads to a prothrombotic state in which the endothelium elaborates a further set of biochemical modulators including TNF-.alpha., IL-8, von Willebrand factor, platelet activating factor, tissue plasminogen activator, and type 1 plasminogen activator inhibitor. (Pearson, J. D. (2000) Lupus 2 (3): 183-88; Becker et al. (2000) Z Kardiol 89 (3): 160-7; Schinin-Kerth, V. B. (1999) Transfus Clin Biol 6 (6): 355-63). In addition, the vascular endothelium synthesizes and elaborates the endothelins, which are the most potent vasoconstrictor peptides known. [0006] The endothelins are a family of 21-amino acid peptides, i. e., endothelin-1, endothelin-2, and endothelin-3, originally characterized by their potent vasoconstricting and angiogenic properties (see, e.g., Luscher et al. (1995), Agents Actions Suppl. (Switzerland) 45: 237-253; Yanagisawa et al. (1988) Nature 332: 411-415). The three isopeptides of the endothelin family, endothelin-1, endothelin-2, and endothelin-3, possess highly conserved amino acid sequences that are encoded by three separate genes (see, e.g., Inoue et al. (1989) Proc Natl Acad Sci USA 86: 2863-67; Saida et al. (1989) J Biol Chem 264: 14613-16). Although the endothelins are synthesized in several tissues including smooth muscle cells, endothelin-1 is exclusively synthesized by the vascular endothelium (Rosendorff, C. (1997) Cardiovasc Drugs 10 (6): 795-802). The endothelins are synthesized as preproendothelins of two hundred and three amino acids. The endothelin signal sequence is cleaved and the protein is then further proteolytically processed to yield the mature, biologically active 21 amino acid form (see, e.g., Kashiwabara et al. (1989) FEBS Lett 247: 337-40). Endothelin synthesis is regulated via autocrine mechanisms including endothelin and non-endothelin converting enzymes as well as by chymases (Baton et al. (1999) Curr Opin Nephrol Hypertens 8 (5): 549-56). Elaboration of endothelin-1 from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, and cyclosporin inter alia (see e.g. Brooks et al. (1991) Eur J Pharm 194: 115-17) and is inhibited by nitric oxide. [0007] Endothelin activity is mediated via binding with preferential affinities to two distinct G protein-coupled receptors, ET.sub.A and ET.sub.B, in an autocrine/paracrine manner (see, e.g., Hocher et al. (1997) Eur. J. Clin. Chem. Clin. Biochem. 35 (3): 175-189; Shichiri et al. (1991) J. Cardiovascular Pharmacol. 17: S76-S78). ET.sub.A receptors are found on vascular smooth muscle linked to vasoconstriction and have been associated with cardiovascular, renal, and central nervous system diseases. ET.sub.B receptors are more complex and display antagonistic actions. ET.sub.B receptors in the endothelium have the dual roles of clearance and vasodilation, while ET.sub.B receptors on smooth muscle cells also mediate vasoconstriction (Dupuis, J. (2000) Can J Cardiol 16 (1): 903-10). The ET.sub.B receptors on the endothelium are linked to the release of nitric oxide and prostacycline (Rosendorff, C. (1997) Cardiovasc Drugs 10 (6): 795-802). There are a variety of agonists and antagonists of endothelin receptors (Webb et al. (1997) Medicinal Research Reviews 17 (1): 17-67), which have been used to study the mechanism of action of the endothelins. Because endothelin is known to have powerful vasoconstrictive activity, endothelin antagonists in particular (also termed "endothelin receptor antagonists" in the art) have been studied with regard to their possible role in treating human disease, most notably, cardiovascular diseases such as hypertension, congestive heart failure, atherosclerosis, restenosis, and myocardial infarction (Mateo et al. (1997) Pharmacological Res. 36 (5): 339-351). [0008] Moreover, endothelin-1 has been shown to be involved in the normal functioning of the menstrual cycle. Menstruation represents a remarkable example of tissue repair and replacement, involving the regulated remodeling and regeneration of a new layer of endometrial tissue lining the uterus. This repair and remodeling process is remarkable in that it is accomplished without scarring, a phenomenon generally not seen in other organs of the body. Defects in that repair process are believed to be the basis of excessive or abnormal endometrial bleeding in women with documented menorrhagia as well as in women carrying subcutaneous levonorgestrel implants (NORPLANT) for contraceptive purposes. In both of these groups of patients, only very low levels of endometrial endothelin-1 have been detected as compared with control populations. Moreover, it has been indicated that endothelin-1 not only may play a role in effecting cessation of menstrual bleeding but endothelin-1 may also have a mitogenic activity required for regenerating and remodeling of endometrial tissue after menstruation (see Salamonsen et al. 1999, Balliere's Clinical Obstetrics and Gynaecology 13 (2): 161-79; Goldie 1999, Clinical and Experimental Pharmacology and Physiology 26: 145-48; Salamonsen et al. 1999, Clin. Exp. Phamaol. Physiol. 26 (2): 154-57). [0009] In summary, vascular homeostasis reflects a dynamic balance between two physiological states mediated by the vascular endothelium. The first, which has been termed antithrombotic, is characterized inter alia by the production of nitric oxide, vasodilation, inhibition of platelet attachment and activation, and by repression of endothelin-1 synthesis. The second or prothrombotic physiological state is characterized inter alia by the production of endothelin-1, vasoconstriction, platelet activation, and hemostasis (Warner (1999), Clinical and Experimental Physiology 26: 347-52; Pearson, (2000), Lupus 9(3): 183-88). [0010] In light of the physiological importance of vascular homeostasis, there is a need for methods and compositions that are capable of modulating one or more aspects of the above processes. More specifically, there is a need for compositions and methods for the modulation of endothelin release, vasoconstriction, and blood flow out of a breached vessel and which would therefore be useful for effecting cessation of bleeding. That is, although such compositions and methods would act in a manner that is not dependent upon physical barrier formation, coagulation, or blood clot formation, such compositions and methods would nevertheless contribute, inter alia, to the achievement of hemostasis. Accordingly, such methods and compositions would be expected to have therapeutic applications for the treatment of diseases or conditions arising as a consequence of the perturbation of vascular homeostasis. Moreover, in view of the systemic effects resulting, e.g., from administration to patients of endothelin-1 antagonists as described supra, there is an even greater need for compositions and methods that produce localized and transient physiological responses, including, but not limited to, stimulation of endothelin-1 release, in such patients. 3. SUMMARY OF THE INVENTION [0011] The present invention relates to methods and compositions for the treatment or amelioration of vascular disorders including bleeding disorders. More specifically, the invention relates to compositions comprising semi-crystalline poly-.beta.-1.fwdarw.4-N-acetylglucosamine (p-GlcNac) polysaccharide polymers, and use of such polymers in methods to effect transient localized, modulation of vascular structure and/or function by, e.g., stimulation of endothelin-1 release, vasoconstriction, and/or reduction in blood flow out of a breached vessel, thereby contributing to or effecting cessation of bleeding. [0012] The present invention is based in part on the Applicants' discovery that topical application of semi-crystalline poly-.beta.-1.fwdarw.4-N-acetylglucosamine (p-GlcNac) polysaccharide polymers to a vascular surface induces not only contraction of that vessel, thereby decreasing the lumen of that vessel, but also induction of a transient, localized stimulation of endothelin-1 release in those tissues contiguous with the applied compositions and materials disclosed herein. [0013] The present invention relates, in one aspect, to a method for achieving transient, localized, modulation of vascular structure and/or function in a patient, comprising topical administration of a material comprising semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymers, which are free of protein, substantially free of other organic contaminants, and substantially free of inorganic contaminants. Administration of these materials induces transient, localized physiological responses including, but not limited to, stimulation of endothelin-1 release, vasoconstriction, and reduction in blood flow out of a breached vessel. [0014] In one embodiment of the present invention, endothelin-1 is released from vascular endothelial cells. In other aspects of this embodiment, endothelin-1 release is stimulated from other endothelial tissues or from platelets. [0015] In one embodiment, the poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 4,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 800,000 daltons. In another embodiment, the poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 10,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 2 million daltons. In yet another embodiment, the poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 50,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 10 million daltons. In another embodiment, the poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 150,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 30 million daltons. [0016] In preferred embodiments of the invention, the disclosed method is used for the treatment of a mammalian patient, and in more preferred embodiments, for the treatment of a human in need of such treatment. More specifically, modulation of vascular structure and/or function is used to effect cessation of bleeding, particularly in a patient afflicted with a coagulopathy. Such a disorder can be the result of a genetic defect, such as hemophilia, or a medical treatment, including for example, administration of systemic anticoagulants, e.g. coumadin, to a dialysis patient, cardiac patient, or other patient with an increased risk of vessel blockage. Similarly, the present method is used to effect a temporary, localized, reduction in blood flow out of a breached vessel during surgical repair of an aneurysm or excision of a tumor or polyp, particularly in a patient having a coagulopahtic condition, thereby minimizing blood loss during such a procedure. In other embodiments, the method of the present invention is used for the treatment of bleeding ulcers or varices, particularly esophageal varices. While not wishing to be bound by a particular theory or mechanism, it is believed that such cessation of bleeding by the methods disclosed herein occurs in a coagulation-independent manner. [0017] In other embodiments of the method of the invention, the p-GlcNac-containing material is topically administered to the skin of the patient or to the surface of another organ, or the material may be applied directly to a vascular structure to be modulated, which may be a capillary, vein, or artery. [0018] In yet another embodiment of the method of the invention, where the vascular structure is a breached blood vessel, topical application of the p-GlcNac-containing materials of the invention is used to achieve cessation of bleeding. [0019] In a further embodiment of the invention, the extent of the transient, localized modulation of vascular structure and/or function is substantially proportional to the amount of semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine applied. [0020] The invention is also directed toward a biodegradable material comprising semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymers which are free of protein, substantially free of other organic contaminants, and are substantially free of inorganic contaminants. In one embodiment, the semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymers comprise about 50 to about 4,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation and have a molecular weight of about 10,000 daltons to about 800,000 daltons. In another embodiment, the semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 10,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 2 million daltons. In yet another embodiment, the poly-.beta.1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 50,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 10 million daltons. In another embodiment, the poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymer comprises about 50 to about 150,000 N-acetylglucosamine monosaccharides covalently attached in a .beta.-1.fwdarw.4 conformation, and has a molecular weight of about 10,000 daltons to about 30 million daltons. [0021] In another embodiment, the biodegradable material comprising semi-crystalline poly-.beta.-1.fwdarw.4 N-acetylglucosamine polymers is a non-barrier-forming material. Continue reading... Full patent description for Compositions and methods for modulation of vascular structure and/or function Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Compositions and methods for modulation of vascular structure and/or function patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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