Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1992-01-16
1994-06-14
Griffin, Ronald W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
514834, 536127, C08B 3100, A61K 31715
Patent
active
053211332
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel sulphated polysaccharides, obtained by controlled lysis of the fucans extracted from Phaeophyceae (brown algae), to the process for obtaining them, as well as to a novel anticoagulant and antithrombotic agent and a novel anticomplement agent.
The anticoagulant effect is defined as the inhibition of the formulation of active thrombin in the plasma, while the antithrombotic effect is defined as the inhibition of the formation of the thrombus and/or of its growth.
The anticoagulant drug most used at present is heparin, which is a sulphated polysaccharide consisting of 1.fwdarw.4-linked glucosamine and glucuronic acid units, in which the sulphate groups are present on the amine function of the glucosamine, and/or on alcohol functions of the glucoseamine and uronic acid. Heparin acts on the coagulation by boosting the anticoagulant action of two plasma inhibitors. The first, which is antithrombin III (AT III), acts both on thrombin (also known as factor IIa) and on activated factor X (or factor Xa); the second, called heparin cofactor two (HC II), acts on factor IIa, and not on factor Xa.
Moreover, as regards the prevention of thrombosis, heparins of low molecular weight obtained by depolymerization are being increasingly used- their action on the overall coagulation is weak; for example, they have no effect in vitro on the cephalin kaolin time (CKT), which examines in a global fashion the plasma coagulation by the endogenous pathway, that is to say all the plasma factors with the exception of factor VII and the platelet factors; in contrast, they permit in vivo the prevention of experimental thromboses. It has been shown that they boosted the inhibitory activity of AT III with respect to factor Xa, and that their activity with regard to factor IIa was low. However, it seems more and more probable that their action in the prevention of thromboses is exerted essentially by their low residual anti-IIa activity.
Heparin is also known for its anticomplement properties. The complement system is a set of plasma or membrane proteins which play an important role in the immune defence mechanism. It participates in the defence of the organism (destruction of infectious agents, clearance of immune complexes) and in pathological processes of an inflammatory type. In the blood it is additionally responsible for haemolysis or lysis of the red cells.
The complement proteins are in an inactivated forum in the serum. They are activated in a specific order in two sequences, the alternative pathway and the classical pathway. The activation of the alternative pathway is based on a non-specific mechanism of recognition of the target surface (bacteria, virus, parasite, tumour cell). The activation of the classical pathway is based on the specific recognition of the target by an antibody. In the alternative pathway, the initial phase is triggered by the fixation of a product of cleavage of C3 (C3b) and the release of C3a, anaphylatoxin responsible for inflammatory reactions. The C3b thus binds by covalent bonding to hydroxyl and amino groups on the surface. Once bound, it can bind factor B and, after activation of the latter by factor D, it forms the alternative C3 convertase. In the classical pathway, the initial phase is triggered by activation of C1, which is effected principally at the level of an antigen-antibody complex. After activation of C1, components C4 and C2 are in turn activated and form on the surface an enzymatic complex, classical C3 convertase. The activation of C4 is analogous to that of C3 with release of C4b and C4a. C4b fixes in a covalent manner to the same type of chemical groups as C3b.
Heparin acts as an inhibitor of the activation of the complement by its interaction with C3 convertase. It has been shown that this anticomplement activity of heparin is totally independent of its antithrombic (sic) activity and that it is associated with the presence on the amine function of a sulphate or acetyl group, in contrast to the anticoagulant activity which is not observed if th
REFERENCES:
patent: 4581233 (1986-04-01), Herve et al.
Patent Abstracts of Japan, vol. 10, No. 219 (C-363)(2275), Jul. 31, 1986, 61-57520 dated Mar. 24, 1986 to Kibun Food Chemiphar K.K.
B. Larsen, et al., "Sulphated Polysaccharides in Brown Algae", Acta Chemica Scandinavica, vol. 24, No. 9, 1970, pp. 3339-3352.
T. Nishino, et al., "Isolation, Purification, and Characterization of Fucose Containing Sulfated Polysaccharides from the Brown Seaweed Ecklonia kurome And Their Blood-Anticoagulant Activities", Carbohydrate Research, vol. 186, No. 1, Feb. 15, 1989, pp. 119-129.
F. C. Church, et al., "Antithrombin Activity of Fucoidan", The Journal of Biological Chemistry, vol. 264, No. 6, Feb. 25, 1989, pp. 3618-3623.
Bretaudiere Jacqueline
Colliec Sylvia
Durand Patrick
Fischer Anne-Marie
Jozefonvicz Jacqueline
Griffin Ronald W.
Institut Francais de Recherche pour l'Exploitation de la Mer-IFR
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