Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-07-12
2004-12-07
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S056000, C514S059000
Reexamination Certificate
active
06828307
ABSTRACT:
The present invention relates to the use of a sulfated polysaccharide with a molar mass of less than or equal to 10,000 g/mol, which can be obtained by radical depolymerization of a crude fucan derived from Phaeophyceae, for producing a medicinal product with activity against arterial thrombosis and against arterial restenosis.
Thrombosis consists of the formation of a clot (thrombus) in the circulatory system, this clot obstructing the lumen of the vessel in which it forms. It is the consequence of the pathological activation of the physiological phenomena of haemostasis, i.e. of the phenomena which contribute to the prevention and arrest of bleeding.
Thrombosis brings into a play a complex process involving the activation, in cascade, of various factors, resulting in the formation of thrombin, which is a key clotting enzyme, and then in fibrin formation. The formation of the thrombus begins with adhesion of the platelets to the subendothelial connected tissue, exposed by a lesion of the vascular endothelium. The platelets aggregate with one another and the aggregate becomes surrounded by a fibrin network which also traps white blood cells and red blood cells, forming the thrombus.
Arterial thrombosis differs from venous thrombosis in that, most commonly, it occurs on an artery in which there is a lesion due to the presence of an atheroma plaque; this lesion is also characterized by the proliferation and the migration toward the intima of the smooth muscle cells of the media. Arterial thrombosis often occurs when the atheroma plaque ruptures, with loss of continuity of the vascular endothelium. The adhesion and aggregation of platelets plays a primordial role in the phenomenon of arterial thrombosis.
The entire process of response to the lesion of an artery involves many cellular biological phenomena which involve modifications of the phenotype of smooth muscle cells (SMCs), and also the expression of growth factors which promote the proliferation of endothelial cells.
In the treatment of venous thrombosis, anticoagulants, in particular heparin, are conventionally used, which have the property of inhibiting thrombin and its formation.
Heparin is a sulfated polysaccharide consisting of units of glucosamine and of uronic acids which are 1,4-linked, in which the sulfate groups are present on the amine function of the glucosamine and/or on alcohol functions of the glucosamine and of the uronic acid. This polysaccharide, the anticoagulant properties of which are well known, is currently widely used in the treatment of thrombotic accidents. However, heparin has very significant side effects (bleeding, risk of immunoallergic thrombopenia) and it is relatively ineffective in arterial thrombosis. In addition, the animal origin of this product may cause a potential risk of contamination with unconventional infectious agents.
Techniques of chemical or enzymatic depolymerization have made it possible to produce, from NFH (nonfractionated heparin, the molecular weight of which is approximately 15,000 g/mol), polysaccharide chains of low molecular weight, i.e. of molecular weight of between 2000 and 10,000 g/mol, named LMWHs (low molecular weight heparins). Many LMWHs have been synthesized and are in particular marketed under the names Enoxaparin®, Reviparin®, Dalteparin®, Fraxiparin®, Tinzaparin®, Certoparin®, Opocrin®, Parnaparin® etc.
Clinical studies have shown that the effectiveness of the LMWHs in the prophylaxis of venous thromboembolic accidents is identical to, if not greater than, that of NFH. However, the LMWHs do not abolish the hemorrhagic risk and can cause, just as NFH, although less frequently, immunoallergic thrombopenia.
Furthermore, it has been shown, in particular by M. Lerch et al. (European Heart Journal, August 1998, 19, 495) and H. Rickli et al. (European Heart Journal, August 1998, 19, 470), that LMWHs (Reviparin® and Fraxiparin® respectively’) are ineffective in combating restenosis after angioplasty, i.e. the phenomenon of reappearance of a stricture of the lumen of an artery linked to the involvement of a balloon catheter in vascular surgery.
Sulfated polysaccharides other than heparins exist, for example fucans. These sulfated polysaccharides, of high molecular weight (100 to 800 kDa), are present in the cell walls of the thalli of brown algae. They are polymers of sulfated L-fucose and may also contain D-xylose, D-galactose, D-mannose and uronic acids, the latter not being sulfated, contrary to those of heparin. Fucans also differ from heparin in that they do not comprise any amino sugars.
Fucans have various properties which make their use in many therapeutic domains particularly advantageous.
It has in particular been shown that fractions of low molar mass fucan, obtained by acid hydrolysis as described in European patent 0 403 377, have an anticoagulant (S. Colliec et al., Thromb. Res., 1991, 64, 143-154) and antithrombotic activity, when given intravenously (S. Mauray et al., Thrombosis and Haemostasis, 1995, 74(5), (280-1285) or subcutaneously (J. Millet et al., Thrombosis and Haemostasis, 1999, 81, 391-395) comparable to that of the low molecular weight heparins.
It has also been shown that these same fucan fractions are capable of inhibiting, like heparin, the growth of vascular smooth muscle cells in culture (D. Logeart et al., Eur. J. Cell. Biol., 1997, 74, 376-384 and 385-390). The effects observed are reversible, are not related to a cytotoxic action and depend on the concentration of the compound in the culture medium. This antiproliferative effect on the growth of smooth muscle cells appears to be specific since, at these concentrations, no inhibition is observed on the growth of fibroblast lines, and these compounds are observed to be capable of potentiating endothelial cell growth in culture (J. L. Giraux et al., Eur. J. Cell. Biol. 1998, 77, 352-359).
Giraux et al. have shown, in Thromb. Haemost., 1998, 80, 692-695, that the same fucan fractions, obtained by acid hydrolysis according to the protocol described in European patent 0 403 377, induce, in vitro, the release of TFPI (Tissue Factor Pathway Inhibitor) by human umbilical cord vein endothelial cells, this being an effect which may contribute to the antithrombotic action of these fucan fractions.
In addition, it has been shown, in Patent application EP 0 846 129, that fucan fractions, obtained by radical depolymerization of a fucan from Phaeophyceae in the presence of a metal catalyst and of hydrogen peroxide, and having a molar mass of less than or equal to 10,000 g/mol, conserve, in vitro, the anticoagulant properties of crude fucan. Such fucan fragments, obtained by radical depolymerization of a high molecular weight fucan, are different, with respect to their chemical structure, from fucan fragments obtained by acid hydrolysis of a crude fucan, as demonstrated in Patent application EP 0 846 129.
Besides NFH, LMWHs and fucans, other anticoagulants have been described for their antithrombotic action (inhibition of the formation of the thrombus and/or of its growth): these are in particular heparinoids (mixture of low molecular weight glycosaminoglycans, for example Orgarane marked by Organon Inc.), antivitamins K and hirudins. Hirudins, for example Lepirudin (Refludan®) marketed by Behrinwerke AG—Hoechst Marion Roussel or Desirudin (Revasc®) marketed by Novartis—Rhône Poulenc Rorer, can cause, in the same way as nonfractionated heparin, a considerable hemorrhagic risk.
Two classes of compounds can be used or are being studied in arterial thrombosis (Samama M. M. and Desnoyer P. C., “
Les bases pharmacologiques des traitements antithrombotiques—Agents antithrombotiques actuels et futurs” [The pharmacological bases of antithrombotic treatments—Current and future antithrombotic agents],
1995, publisher Masson): there are anti-platelet aggregation agents, for example acetylsalicylic acid, dipyridamole, ticlopidine, clopidogrel and anti-GPIIb/IIIa antibody, and fibrinolytics (streptokinase, urokinase, etc.), which dissolve the clot by activation of the fibrinolytic system and rele
Colliec-Jouault Sylvia
Durand Patrick
Fischer Anne-Marie
Jozefonvicz Jacqueline
Letourneur Didier
Alston & Bird LLP
Barts Samuel
Institut Francais de Recherche Pour L'Exploitation de la Me
Maier Leigh C.
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