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US5545625.Pdf ||||||||| US005545625A United States Patent 19 11 Patent Number: 5,545,625 Gross et al. (45. Date of Patent: Aug. 13, 1996 54). PREVENTING CONVERSION OF Schmidt, H. H. H. W., et al, Eur. J. Pharmacol. 154, CITRULLINE TO ARGINNOSUCCNATE TO 213–216 (1988). LIMIT PATHOLOGICAL NITRIC OXDE Sessa, W. C., et al. Proc. Natl. Acad. Sci. USA, OVERPRODUCTION 87.8607-8611 (Nov. 1990). Corbett, J. A., et al, Biochemistry 32, 13767-13770 (1993). 75 Inventors: Steven S. Gross, New York, N.Y.: Cross, A. H., et al., J. Clin. Invest. 93, 2684-2690 (1994). Owen W. Griffith, Milwaukee, Wis. McCartney-Francis, N., et al, J. Exp. Med. 178, 749–754 (1993). (73) Assignee: The Medical College of Wisconsin Misko, T. P., et al, Eur. J. Pharmacol. 233, 119-125 (1993). Research Foundation, Inc., Suarez-Pinzon, W. L., et al, Endocrinology, 134, 1006-1010 Milwaukee, Wis. (1994). Takada, S., et al., J. Biochem. 85, 1309-1314 (1979). 21 Appl. No.: 354,585 Freytag, S. O., Medline Abstract of J. Biol. Chem..., 259, 22 Filed: Dec. 12, 1994 3160-6 (1984). Grisolia, S., et al, The Urea Cycle, John Wiley & Sons, p. (51 Int. Cl." ......................... A61K 31/70; A61 K 31/195 191 (1976). 52 U.S. Cl. ............................ 514/33; 514/561; 514/564; Mitchell, J. A., et al, Eur, J. Pharmacol., 182, 573-576 514/930 (1990). 58 Field of Search .............................. 514/33, 561,564, Mulligan, M. S., et al. Proc. Natl. Acad. Sci. USA, 88, 514/930 6338-6342 (Jul 1991). Weinberg, J. B., et al., J. Exp. Med. 148, 651–660 (Feb. 56 References Cited 1994). U.S. PATENT DOCUMENTS Wu, G., et al. Biochem. J., 281, 45-48 (1992). 4,775,623 10/1988 Katsumata et al. ..................... 435/114 Hattori, Y., et al., J. Biol. Chem. 269,9405-9408 (1994). 5,028,627 7/1991 Kilbourn et al. .... ... 514/565 Ialenti, A., ct al., Eur, J. Pharmacol. 211, 177-182 (1992). 5,059,712 10/1991 Griffith ............ ... 562/560 Mulligan, M. S., et al, Br. J. Pharmacol., 107, 1159–1162 5, 196,195 3/1993 Griffith et al. ... ... 424/94.6 (1992). 5,216,025 6/1993 Gross et al. ..... ... 514/565 Nathan, C. F., et al, Current Opinion in Immunology, 3, 5,364,881 11/1994 Griffith et al. ... ... 54/508 65–70 (1991). 5,424,447 6/1995 Griffith et al. ............................ 594/74. 5,464,858 11/1995 Griffith et al. .......................... 514/399 Yang, X., et al, J. Clin. Invest., 94, 714-721 (1994). FOREIGN PATENT DOCUMENTS Primary Examiner-Kimberly Jordan WO95/O1972 1/1995 WIPO 57 ABSTRACT OTHER PUBLICATIONS Administration of argininosuccinate synthetase activity Carignan, J. A., et al, Hosp. Formul. 21, 1025-1030 and reducing agents, e.g., argininosuccinate synthetase induction 1033 (1986). blocking agents (e.g., antibiotics that bind to DNA Corbett, J. A., et al., J. Clin. Invest. 90, 2384-2391 (1992). Sequences present in the upstream regulatory region of the Jinno, Y., et al, EMBL Database, Sequence from J. Biochem. argininosuccinate synthetase gene, such as mithramycin) 98, 1395-1403 (1985). and argininosuccinate synthetase inhibitors (e.g., L-citrul Kleeman, R., et al, FEBS, 328, 9–12 (Aug. 1993). line antagonists such as methyl citrulline and L-aspartatic Nussler, A. K. etal, J. Biol. Chem., 269, 1257–1261 (1994). antagonists such as D-aspartate) is useful to prevent or treat Schmidt, H. H. H. W., et al, Eur, J. Pharmacol., 148, sepsis or cytokine-induced systemic hypotension, is useful 293-295 (1988). in the treatment of sepsis or cytokine-induced systemic Corbett, J. A., et al, Proc. Natl. Acad. Sci. USA, 90, hypotension to restore vascular sensitivity to the effects of 1731-1735 (Mar. 1993). O-adrenergic agonists, and is useful to suppress an immune Corbett, J. A., et al., Proc. Natl. Acad. Sci. USA, 90, response, e.g., in treating inflammation. In one embodiment, 8992-8995 (Oct. 1993). certain argininosuccinate synthetase activity reducing agents Kroncke, K-D, et al, Biochem. Biophys. Res. Commun. are used together with arginine antagonists to treat sepsis or 175, 752–758 (1991). cytokine induced hypotension. Lukic, M. L., et al, Biochem. Biophys. Res. Commun. 178, 913–920 (1991). 35 Claims, 5 Drawing Sheets U.S. Patent Aug. 13, 1996 Sheet 1 of 5 5,545,625 O-O (uyeo.Id fu/ugu/OUId) KLIAILOW SON a 3 3 c 9 s a s Y. I. 8 53 O O s 3 (ueoud su/uyuu/loud) LIAILow Sw U.S. Patent Aug. 13, 1996 Sheet 2 of 5 5,545,625 U.S. Patent Aug. 13, 1996 Sheet 3 of 5 5,545,625 U.S. Patent Aug. 13, 1996 Sheet 4 of 5 5,545,625 D 9 ED O ver D 2. E r vau N 2) c s m 2. 5 n s 2 R s LO O LO C O O S. g S CN N qme vase (W) NOLLOndoald LLIHLIN I U.S. Patent Aug. 13, 1996 Sheet S of 5 5,545,625 1°0|0° (WUI)[GINITIn?LIO] ± |00"0 07 9| Z! (Wil) NOLLOnCIOld ELIA LIN 5,545,625 1. 2 PREVENTING CONVERSION OF To date, pathological overproduction of nitric oxide has CITRULLINE TO ARGINNOSUCCINATE TO been controlled by administration of nitric oxide synthase LIMIT PATHOLOGICAL, NTRIC OXDE inhibiting arginine antagonists, plasma arginine depleting OVERPRODUCTION enzymes and tetrahydrobiopterin induction or utilization blocking agents. This invention was made at least in part with Govern ment support under National Institutes of Health Grant HL46403 and under National Institutes of Health Grant SUMMARY OF THE INVENTION DK371 16. It has been discovered herein that administration of O argininosuccinate synthetase activity reducing agents is use TECHNICAL FIELD ful to prevent or treat sepsis or cytokine-induced systemic hypotension, is useful in the treatment of sepsis or cytokine This invention is directed to a novel approach for inhib induced systemic hypotension to restore vascular sensitivity iting biological nitric oxide production. to the effects of O-adrenergic agonists, is useful to suppress 15 an immune response, e.g., in treating inflammation, and is BACKGROUND OF THE INVENTION useful to prevent or treat a subject for a stroke. One embodiment herein is directed to a method of pro For several decades nitroglycerin has been administered phylaxis or treatment of a subject for systemic hypotension to humans as a vasodilating agent in the treatment of caused by pathological overproduction of nitric oxide from cardiovascular disease. It has been shown that nitroglycerin 20 arginine in vascular cells in said subject induced by therapy so administered is converted in the body to nitric oxide with a cytokine or by exposure to a bacterial endotoxin, said which is the pharmacologically active metabolite. Recently, method comprising administering to a subject expected to nitric oxide has been shown to be formed enzymatically as develop or having such systemic hypotension a therapeuti a normal metabolite from arginine in vascular endothelium cally effective amount of an argininosuccinate synthetase to provide an important component of endothelium-derived 25 activity reducing agent. The agent can be either an argini relaxing factors (EDRFs) which are currently being inten nosuccinate synthetase induction blocking agent or an sively studied as participating in regulation of blood flow argininosuccinate synthetase inhibitor. A therapeutically and vascular resistance. Macrophages have also been shown effective amount of an argininosuccinate synthetase activity to produce nitric oxide in the body as a component of their reducing agent in this method is one that causes reduction in cell killing and/or cytostatic function. 30 induced nitric oxide production to the extent of causing an More recently it has been established that the enzyme increase in blood pressure. forming nitric oxide from arginine, i.e., nitric oxide syn Another embodiment herein is directed to a method for thase, occurs in at least two distinct types, namely the treatment of a subject for systemic hypotension caused by constitutive forms and an inducible form. Constitutive forms 35 pathological overproduction of nitric oxide from arginine in are present in normal endothelial cells, neurons and some vascular cells in said subject induced by therapy with a other tissues. Formation of nitric oxide by a constitutive cytokine or by exposure to a bacterial endotoxin, said form in endothelial cells is thought to play a role in normal method comprising administering to a subject having such blood pressure regulation. The inducible form of nitric oxide systemic hypotension a therapeutically effective amount of synthase has been found to be present in activated macroph 40 an O-adrenergic agonist, and an amount of argininosucci ages and is induced in endothelial cells and vascular smooth nate Synthetase activity reducing agent to restore vascular muscle cells, for example, by various cytokines and/or contractile sensitivity to the effects of said O-adrenergic microbial products. It is thought that in sepsis or cytokine agonist. The argininosuccinate synthetase activity reducing induced shock, overproduction of nitric oxide by the induc agent can be either an argininosuccinate synthetase induc ible form of nitric oxide synthase plays an important role in 45 tion blocking agent or an argininosuccinate synthetase the observed life-threatening hypotension. Furthermore, it is inhibitor. A therapeutically effective amount of O-adrener thought that overproduction of nitric oxide by the inducible gic agonist is one that causes increase in blood pressure. form of nitric oxide synthase is a basis for insensitivity to Still another embodiment herein is directed to a method clinically used pressor agents such as O-adrenergic agonists for treating a subject for systemic hypotension caused by in the treatment of septic or cytokine-induced shock 50 pathological overproduction of nitric oxide from arginine in patients. Moreover, it is thought that overproduction of nitric vascular cells in said subject induced by therapy with a oxide by inducible form of nitric oxide synthase is involved cytokine or by exposure to a bacterial endotoxin, said in inflammation incident to an immune response.
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