Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Multienzyme complexes or mixtures of enzymes
Patent
1996-09-30
1999-04-27
Naff, David M.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Multienzyme complexes or mixtures of enzymes
424 941, 424 9464, 424 9463, 514 76, 514834, 514925, A61K 3843, A61K 3854, A61K 3848, A61K 31685
Patent
active
058978607
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field Of The Invention
The present invention is related to a novel hemostatic composition. More specifically, the present invention is related to a hemostatic composition comprising thrombin, casein kinase II, and sphingosine or a sphingosine derivative and providing rapid clotting and hemostasis.
2. Description Of The Prior Arts
Hemostasis involves three complex mechanisms: clot formation, rapid constriction of the injured blood vessel and the aggregation of platelets to form a plug on the injured surface of the blood vessel. A clot is formed by a series of transformations involving more than ten different proteins, calcium ion (Ca2+) and thromboplastin. When bleeding occurs, fibrinogen, which is highly soluble, is converted into insoluble fibrin monomer by the proteolytic action of thrombin. The fibrin monomers spontaneously associate to form a clot, on which factor XIIIa acts to aggregate platelets to form a plug on the injured surface of the blood vessel.
It has been reported that phosphate groups attached to fibrinogen affect the gelation of thrombin (Forsberg, P. O., Thromb. Res., 53, 1-9, 1989). And, various protein kineses such as protein kinase A (Engstrim, L., Edlund B., Rangnarsson, U., Dahlqvist-Edberg, U., and Humble, E., Biochem. Biophys. Res. Commun., 96, 1507, 1980), protein kinase C, casein kinase I (Itarte, E., Plana, M., Guasch, M. D., and Martos, C., Biochem. Biophys, Res. Commun., 117, 631-636, 1983), and casein kinase II (Humble, E., Heldin, P., Forsberg, P. O. and Engstrom, L., Arch, Biochem. Biophys., 241, 225-231, 1985) have been reported to be involved in the phosphorylation of fibrinogen. The effect of the phosphorylation of fibrinogen on the thrombin-induced gelation of fibrinogen varies depending on thekinase used to phosphorylate fibrinogen. The phosphorylated fibrinogen is ineffeciently cleaved by plasmin regardless of the kind of the kinase involved in the phosphorylation thereof (Martin, S. C., et al., Thromb. Res. 61, 243252, 1991).
Sphingosine, which is one kind of sphingolipid, has important roles in the growth and differentiation of cells. Further, sphingosine also is reported to have an ability to increase the activity of casein kinase II (McDonald, O.Bradley; Hannun, Yusuf A.; Reynolds, E. Hugh and Sahyoun, Naji, Journal of Biological Chem., Vol. 266, No. 32, pp 21773-21776, 1991).
A property required to serve as an efficient hemostatic agent is fast control of bleeding in order to prevent entry of pathogens at the bleeding site or massive hemorrhage during operations. Thrombin preparations have been most widely employed as commercially available hemostatic compositions.
The inventors conducted extensive studies to develop a more efficient hemostatic composition, which allows a faster hemostasis than conventional hemostatic compositions. As a result thereof, they surprisingly found that, if the thrombin-containing hemostatic compositions contains casein kinase II, a protein phosphorylation enzyme, together with sphingosine or a sphingosine derivative, it can exhibit its hemostatic activity in a shorter period of time.
SUMMARY OF THE INVENTION
Thus, an object of the present invention is to provide a hemostatic composition comprising particular additives which can promote formation of fibrin clots.
This object of the present invention can be accomplished by a hemostatic composition comprising thrombin, casein kinase II, and sphingosine or a sphingosine derivative.
BRIEF DESCRIPTION OF DRAWINGS
This invention will be described in more detail with reference to the accompanying drawings in which:
FIG. 1 is a graph showing hemostatic activities of hemostatic compositions containing various materials, in which the line -.smallcircle.- indicates a fibrinogen solution; the line -.circle-solid.- indicates a fibrinogen solution containing thrombin; the line -.gradient.- indicates a fibrinogen solution containing casein kinase II plus thrombin; and the line -.tangle-soliddn.- indicates a fibrinogen solution containing sphingosine, casein kina
REFERENCES:
patent: 4952683 (1990-08-01), Tschannen et al.
patent: 5151360 (1992-09-01), Handa et al.
Eriksson et al., Endothelial cells release casein kinase II-like activity capable of phosphorylating fibrinogen in response to thrombin, Thromb. Res. 72:315-320, 1993.
Guyton, Human Physiology and Mechanisms of Disease, 4th ed., W.B. Saunders and Company, Philadelphia, PA, Chapter 21, p. 220, 1987.
Thrombosis Research 61, pp. 243-252, (1991) Article "The Effects of in Vitro Phosphorylation and Dephosphorylation on the Thrombin-Induced Gelation and Plasmin Degradation of Fibrinogen" / Martin, et al.
Archives of Biochemistry and Biophysics, vol. 241, No. 1, Aug. 15, 1985, pp. 225-231, Article: "Phosphorylation in Vitro of Fibrinogen from Three Mammalian Species with Four Different Protein Kinases" / Humble, et al.
Biochemistry and Biophysical Research Communications, vol. 117, No. 2, Dec. 16, 1983, pp. 631-636, Article: "Phosphorylation of Fibrinogen by Casein Kinase" / Itarte, et al.
Biochemistry and Biophysical Research Communications, vol. 96, No. 4, Oct. 31, 1980, pp. 1503-1507, Article: "Phosphorylation of Human Fibrinogen in Vitro with Cyclic 3', 5'-AMP-Stimulated Protein Kinase and (.sup.32 p) APT"/ Engstrom, et al.
The Journal of Biophysical Chemistry, vol. 266, No. 32, Nov. 13, 1991, pp. 21773-21776, Article: "Activation of Casein Kinase II by Sphingosine" / McDonald, et al.
Thrombosis Research 53, pp. 1-9, (1989) Article "Dephosphorylation of Human Fibrinogen Previously Phosphorylated in Vitro by Protein Kinase C, by Whole Blood or Intestinal Alkaline Phosphatase Effects on Thrombin-Induces Gelation of in Vitro Dephosphorylated Human Fibrinogen" / Forsberg.
Febs Letters, vol. 143, No. 4, (Jul. 1992) pp. 199-204, Article "Phosphorylation of Human Fibrinogen in Vitro with Calcium-Activated,
Han Moon Hi
Kim Seung-Ho
Lee Jin Young
Kerr Janet M.
Korea Institute of Science & Technology
Naff David M.
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