Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-12-09
1998-12-08
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514491, A01N 3718
Patent
active
058470042
ABSTRACT:
In accordance with the present invention, there are provided methods for the in vivo reduction of nitric oxide levels in a mammalian subject. In contrast to the inhibitory approach described in the prior art (i.e., wherein the function of the enzymes responsible for nitric oxide production is inhibited), the present invention employs a scavenging approach whereby overproduced nitric oxide is bound in vivo to a suitable nitric oxide scavenger. The resulting complex renders the nitric oxide harmless, and is eventually excreted in the urine of the host. An exemplary nitric oxide scavenger contemplated for use in the practice of the present invention is a dithiocarbamate-ferrous iron complex. This complex binds to .NO, forming a stable, water-soluble NO-containing complex having a characteristic three-line spectrum (indicative of a mononitrosyl-Fe complex) which can readily be detected at ambient temperatures by electron paramagnetic resonance (EPR) spectroscopy. The present invention relates to methods for reducing in vivo levels of .NO as a means of treating subjects afflicted with inflammatory and/or infectious disease. Nitric oxide scavengers are administered to a host in need of such treatment; these scavengers interact with in vivo produced .NO, forming a stable NO-containing complex. The NO-containing complex is then filtered through the kidneys, concentrated in the urine, and eventually excreted by the subject, thereby reducing in vivo .NO levels.
REFERENCES:
patent: 1863572 (1932-06-01), Lommel et al.
patent: 2876159 (1959-03-01), Sunderman et al.
patent: 4160452 (1979-07-01), Theeuwes
patent: 4166866 (1979-09-01), Wight et al.
patent: 4256108 (1981-03-01), Theeuwes
patent: 4265874 (1981-05-01), Bonsen et al.
patent: 4554108 (1985-11-01), Kimble et al.
patent: 4595538 (1986-06-01), Kimble et al.
patent: 5358703 (1994-10-01), Lai
patent: 5380747 (1995-01-01), Medford et al.
Hambrecht et al., "Inhibition of nitic oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury" J. Leuk. Biol. 52:390-394 (1992).
Aisaka et al., "N.sup.G -Methylarginine, an Inhibitor of Endothelium-Derived Nitric Oxide Synthesis, is a Potent Pressor Agent in the Guinea Pig: Does Nitric Oxide Regulate Blood Pressure in vivo?" Biochem. Biophys. Res. Commun. 160:881-886 (1989).
Aisaka et al., "L-Arginine Availability Determines the Duration of Acetylcholine-Induced Systemic Vasodilation in vivo" Biomed. & Biophys. Res. Commun. 163:710-717 (1989).
Akaike et al., "Therapeutic Effects of Imidazolineoxyl N-Oxide Against Endotoxin Shock Trough its Direct Nitric Oxide-Scavenging Activity" Biochem. & Biophys. Res. Commun. 202:923-930 (1994).
Alving et al., "Increased amount of nitric oxide in exhaled air of asthmatics" Eur. Respir. J. 6:1368-1370 (1993).
Balter, Michael, "Cytokines Move From the Margins Into the Spotlight" Science 268:205-206 (1995).
Barnes and Liew, "Nitric oxides and asthmatic inflammation" Immunology Today 16:128-130 (1995).
Bartholomew, B., "A Rapid Method for the Assay of Nitrate in Urine Using the Nitrate Reductase Enzyme of Escherichia Coli"Food Chem. Toxic. 22:541-543 (1984).
Boughton-Smith et al., "Nitric oxide synthase activity in ulcerative colitis and Crohn's disease" Lancet 342:338-340 (1993).
Bukrinsky et al., "Regulation of Nitric Oside Synthase Activity in Human Immunodificiency Virus Type 1 (HIV-1)-infected Monocytes: Implications for HIV-associated Neurological Disease" J. Exp. Med. 181:735-745 (1995).
Cattell et al., "Localization of Inducible Nitric Oxide Synthase in Acute Renal Allograft Rejection in the Rat.sup.1 " Transplatation 58:1399-1402 (1994).
Claria et al., "Pathogenisis of Arterial Hypotension in Cirrhotic Rats with Ascites: Role of Endogenous Nitric Oxide" Hepatology 15:343-349 (1992).
Corbett et al., "Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans" Proc. Natl. Acad. Sci. 90:1731-1735 (1993).
Devlin et al., "Nitric Oxide Generation" Transplantation 58:592-595 (1994).
Dorheim et al., "Nitric Oxide Synthase Acitivity is Elevated in Brain Microvessels in Alzheimer's Disease" Biochem. & Biophys. Res. Commun. 205:659-665 (1994).
Eizirik et al., "Cytokines Suppress Human Islet Function Irrespective of Their Effects on Nitric Oxide Generation" J. Clin. Invest. 93:1968-1974 (1994).
Eizirik et al., "Major species differences between humans and rodents in the susceptibility to pancreatic .beta.-cell injury" Proc. Natl. Acad. Sci. U.S.A. 9253-9256 (1994).
Evans et al., "Evidence of Increase Nitric Oxide Production in Patients With the Sepsis Syndrome" Circulatory Shock 41:77-81 (1993).
Evans et al., "Inhibition of Nitric Oxide Synthase in Experimental Gram-Negative Sepsis" J. Infectious Diseases 169:343-349 (1994).
Farrel et al., "Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic disease" Annals of Rhumatic Diseases 51:1219-1222 (1992).
Froncisz and Hyde, "The Loop-Gap Resonator: A New Microwave Lumped Circut ESR Sample Structure" J. Magn. Reson. 47:515-521 (1982).
Gomez-Jimenez et al., "L-agrinine: Nitric oxide pathway in endotoxemia and human septic shock" Critical Care Medicine 23:253-258 (1995). Biological Fluids" Anal. Biochem. 126:131-138 (1982).
Guarner et al., "Increased Serum Nitrite and Nitrate Levels in Patients with Cirrhosis: Relationship to Endotoxemia" Heptology 18:1139-1143 (1993).
Hamid et al., "Induction of nitric oxide synthase in asthma " Lancet 342:1510-1513 (1993).
Harbrecht et al., "Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury" J. Leuk. Biol. 52:390-394 (1992).
Henderson et al., "The Effects of Nitric Oxide Inhibition on Regional Hemodynamics During Hyperdynamic Endotoxemia" Arch. Surg. 129:1271-1275 (1994).
Hibbs et al., "Evidence for Cytokine-inducible Nitric Oxide Synthesis from L-Arginine in Patients Receiving Interleukin-2 Therapy" J. Clin. Invest. 89:867-877 (1992).
Hotchkiss et al., "Inhibition of NO synthesis in septic shock" Lancet 339:434-435 (1992).
Ignarro, L.J., "Biosynthesis and Metabolism of Endothelium-Derived Nitric Oxide" Ann. Rev. Toxicol. 30:535-560 (1990).
Johnson et al., "Evidence for increased nitric oxide production in multiple sclerosis" J. Neurology, Neurosurgery and Phyciatry 58:107-115 (1995).
Kaur and Halliwell, "Evidence for nitric oxide mediated oxidative damage in chronic inflammation" FEBS Letters 350:9-12 (1994).
Kelm and Schrader, "Control of Coronary Vascular Tone by Nitric Oxide" Circ. Res. 66:1561-1575 (1990).
Kharitonov et al., "Increased of nitric oxide in exhaled air of asthmatic patients" Lancet 343:133-135 (1994).
Kilbourn et al., "N.sup.G -Methyl-L-arginine inhibits tumor necrosis factor-induced hypotension Implications for the involvement of nitric oxide" Proc. Natl. Adac. Sci. U.S.A. 87:3629-3632 (1990).
Kilbourn et al., "Reversal of Endotoxin-Mediated Shock by N.sup.G -Methyl-L-Arginine, an Inhibitor of Nitric Oxide Synthesis" Biochem. & Biophys. Res. Commun. 172:1132-1138 (1990).
Kilbourn and Griffith, "Overproduction of nitric oxide in cytokine-mediated and septic shock" J. Natl. Cancer Instit. 84:827-831 (1992).
Kilbourn et al., "Cell-Free Hemoglobin Reverses the Endotoxin-Mediated Hyporesponsivity of Rat Aoritic Rings to .beta.-Adrenergic Agents" Biochem, & Biophys. Res. Commun. 199:155-162 (1994).
Kilbourn et al., "N.sup.G -methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs" J. Appl. Physiol. 76:1130-1137 (1994).
Komarov et al., "In Vivo Spin Trapping of Nitric Oxide in Mice" Biochem. Biophys. Res. Commun. 195:1191-1198 (1993).
Komarov and Lai, "Detection of nitric oxide production in mice by spin-trapping electron paramagnetic resonance spectroscopy" Biochimica et Biophysica Acta 1272:29-36 (1995).
Konturek et al., "Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers" European J. Pharmacol. 239:215-217 (1993).
Kovacs et al., "Increases in CD4 T Lymphoc
MCW Research Foundation
Reiter Stephen E.
Rotman Alan L.
Smith Lyman H.
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