Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-04-19
1998-06-16
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
A61K 3170
Patent
active
057671036
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/US94/05650 filed May 17, 1994.
FIELD OF THE INVENTION
The present invention provides a method of sequestering nitric oxide from the bloodstream, endothelium or tissues of mammals by administering a cobalamin to such mammals. The present invention further provides a method of treating diseases in a mammal characterized by elevated nitric oxide levels in the bloodstream, endothelium or tissues of such mammals by administering a therapeutic dose of a cobalamin. In particular, the present invention describes a method of treating mammals with sepsis by administering a therapeutic dose of hydroxocobalamin. A method of reducing pathologic nitric oxide levels in mammals by administering a therapeutic dose of a cobalamin to sequester the excess nitric oxide is also described by the present invention. A method of alleviating systemic hypotension in a septic patient is further provided by the invention. A pharmaceutical composition comprising a cobalamin in a concentration ranging from 0.5 to 50 mg composition/kg body weight for mammals is also provided.
BACKGROUND OF THE INVENTION
Furchgott and Zowadzki discovered that vascular endothelium played a critical role in the regulation of vascular tone through the release of endothelium-derived relaxing factor (EDRF). Furchgott et al. (1980) Nature 280:373-376. In 1988, Palmer et al. concluded that EDRF was actually nitric oxide when they observed that the release of nitric oxide from the endothelial cells occurred in amounts sufficient to account for the biological activity attributed to EDRF. Palmer et al. (1987) Nature 327:524-526. It is now known that nitric oxide regulates a continuous vasodilator tone and thereby maintains normal homeostatic blood pressure.
A number of pathological conditions are characterized by excess nitric oxide production. Such diseases include the systemic inflammatory response syndrome (SIRS) including sepsis and septic shock; endotoxemia; GI inflammatory diseases such as ileitis, colitis and Crohn's Disease; chronic inflammatory disease; autoimmune disorders; and rheumatoid arthritis. Moncada et al. (1993) N. Engl. J. Med., 329: 2002-2012. Most recently, pertussis (whooping cough) was found to be characterized by an excess production of nitric oxide. Leff (1994) Bioworld Today, 5:1. Various treatments, such as treating cancer with cytokines, can also lead to elevated nitric oxide levels.
The importance of understanding the role of nitric oxide in these pathological conditions is evident from the incidence and mortality rates associated with these diseases. For example, the Centers for Disease Control estimates that sepsis occurs in approximately 500,000 patients in the United States and 400,000 patients in the European community annually and is associated with a 35% mortality rate. It is the most common cause of death in noncoronary, intensive care units. With regard to GI inflammatory conditions, the Crohn's and Colitis Foundation of America estimates that 1 million people suffer from ulcerative colitis in the United States with 15,000 new cases reported annually. Further, approximately 2 million people are reported to have rheumatoid arthritis.
Nitric oxide is synthesized in mammalian cells from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, via the L-arginine-nitric oxide pathway. Moncada et al. (1993) N. Engl. J. Med., 329:2002-2012. The production of nitric oxide via the nitric oxide-arginine pathway begins when a guanidine nitrogen of L-arginine undergoes a five-electron oxidation to yield the gaseous radical nitric oxide via an N.sup.w -hydroxyl-L-arginine intermediate. NADPH (nicotine adenine diphosphonucleotide, reduced) donates two electrons for the formation of this intermediate and one electron for its further oxidation. Both steps are catalyzed by nitric oxide synthase. In addition to the gaseous radical nitric oxide, L-citrulline is also produced. Molecular oxygen is incorporated into both the L-citrulline and the nitric oxide formed. Tetrahydrobiopterin is required for
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Greenberg Stanley S.
Miller Mark J. S.
Xie Jianming
Zatarian-Kuebel Judith
Henley III Raymond
Research Corporation Tech. Inc.
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