Drug – bio-affecting and body treating compositions – Designated inorganic nonactive ingredient or elemental...
Patent
1998-07-30
2000-08-15
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated inorganic nonactive ingredient or elemental...
514824, 514929, 514970, 428718, 604 24, 604507, 604508, 604509, A61K 3300
Patent
active
061037699
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention concerns a pharmaceutical composition of a sterile, injectable physiologically acceptable solution containing nitric oxide (NO), a method for its preparation and a detection method for physiologically present NO.
Physiologically present nitric oxide (NO), through a variety of biological functions, can influence essential key processes in the development of arteriosclerosis, such as relaxation of smooth vascular muscles, inhibition of adhesion of thrombocytes, granulocytes and monocytes to the vascular wall, inhibition of proliferation of secretory smooth muscle cells and direct effects on endothelial metabolism.
Thus, in recent years it has been shown that endothelial nitric oxide (NO) influences the metabolism as well as the function of the vascular wall by a great many mechanisms: of smooth vascular muscles, and and arterial blood pressure, vascular muscle cells, granulocytes to the vascular wall, and altered expression of adhesive molecules on the superficial membrane. Overviews of this are found in: N.Engl.J.Med. 329: 2002-2012, 1993. nitric oxide. Thromb. Haemost. 70:36-41, 1993 266 (5):68-77, 1992. remodeling. N.Engl.J.Med. 330:1431-1438, 1994.
All of the processes mentioned represent key events in the development of pathologic vascular wall changes in arteriosclerosis. Recognized risk factors of arteriosclerosis, which also affect endothelial function, are arterial hypertension, hyperlipoproteinemia, diabetes mellitus, nicotine consumption and possibly age and sex (see Moncada, S. and Higgs, A. The L-arginine-nitric oxide pathway. N. Engl. J. Med. 329:2002-2012, 1993, Ross, R. The pathogenesis of atherosclerosis--an update. N. Engl. J. Med. 324 (No. 8):488-500, 1986; Safar, M. E. and Frohlich, E. D. The arterial system in hypertension. A prospective view. Hypertension 26:10-14, 1995).
However, the pathophysiologically significant demonstration of altered activity of endothelial NO synthesis has hitherto been successful only in experimental preparations with cultured cells or isolated organ circulatory systems in which a quantification of NO or its catabolic products was possible. Regarding this, however, in man so far only phenomenological findings with regard to an altered acetylcholine-induced flow response in various vascular regions have been described as indirect markers of endothelium-dependent vasodilatation. Exact quantification of the activity of endothelial constitutive NO synthesis in man as an indicator of endothelial dysfunction has previously not been possible.
Lastly, in past decades a variety of classes of NO donors for the treatment of arteriosclerotic vascular wall alterations such as, for example, coronary heart disease, have been successfully developed and employed (overviews on this are found in Feelisch, M. The biochemical pathways of nitric oxide formation from nitrovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J. Cardiovasc. Pharmacol. 17 (suppl. 3): S25-S33, 1991; Feelisch, M. and Noack, E. The vitro metabolism of nitrovasodilators and their conversion into vasoactive species. In: Heart Failure Mechanism- and Management, edited by Lewis, B. S. and Kimchi, A., Springer: Berlin, Heidelberg, 1991, p. 241-255; Harrison, D. G. and Bates, J. N. The nitrovasodilators. Circulation 87:1461-1467, 1993; De Caterina, R. Nitrate als Thrombozytenfunctionshemmer [Nitrates as thrombocyte function inhibitors]. Z. Kardiol. 83:463-473, 1994).
NO donors act in the arterial as well as in the venous portion of the circulatory system and also influence NO-dependently the interaction of the vascular wall with the corpuscular components of the blood (thrombocytes, neutrophil granulocytes and monocytes). To date, however, there has as yet been no therapeutic development that permits NO to be used directly in the form of authentic NO solutions in the human circulatory system. This may have its roots in the extremely rapid metabolism and inactivation of NO in the human circulatory system which,
REFERENCES:
patent: 5536241 (1996-07-01), Zapol
European Journal of Gastroenterology & Hepatology, 1995, vol. 7 No. 3, David C. Rees, et al., Are serum concentrations of nitric oxide metabolites useful for predicting the clinical outcome of severe ulcerative colitis?, p. 227-230.
Spectrophotometric Detection of Nitrogen Oxides Using Azo Dyes, W. Ross Tracey, vol. 1, No. 2, Oct., pp. 125-131, 1992.
Research Advances Series, David G. Harrison, MD et al, The Nitrovasodilators New Ideas About Old Drugs, pp. 1461-1467 vol. 87, No. 5, May 1993.
Journal of Chromatography, Steven A. Everett, et al, Nitric oxide in biological fluids: analysis of nitrite by high-performance ion chromatography, pp. 437-442, 1993.
Journal of Cardiovascular Pharmacology 17 (Suppl.3) S25-S33--M. Feelisch, The Biochemical Pathways of Nitric Oxide Formation from Nitrovasodialtors: Appropriate Choice of Exogenous NO Donors and Aspects of Preparation and Handling of Aqueous NO Solutions, 1993.
Role of Nitric Oxide in the Regulation of Coronary Vascular Tone in Hearts from Hypertensive Rats, Malte Kelm et al--vol. 25, No. 2 Feb. 1995.
Abstract of Japanese Patent No. JP7165610 Jun. 27, 1995.
Krass Frederick
Schwarz Pharma AG
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