Cyclodextrins make up a family of cyclic oligo- and polysaccharides containing 5 or more D-glucopyranoside units linked through a 1-4 glycosidic bonds. The most typical cyclodextrins contain 6 to 8 glucopyranoside units in a ring, creating a cone shape. Within this family, β-cyclodextrin have 7 glucopyranoside units in a ring. Classic sulfation procedures result in the sulfation of one, two or three hydroxyl groups of the glucopyranoside units.
Some medicinal uses of polysulphated cyclodextrins are already known in the art. For instance U.S. Pat. No. 6,930,098 teaches treating a human afflicted with arthrosis by administering a composition consisting essentially of a polysulphated cyclodextrin or an addition salt thereof, in combination with one or more non-toxic pharmaceutically acceptable excipients; preferably the dosage for such treatment ranges from 50 mg to 1,500 mg per day. According to Osteoarthritis and Cartilage (2008) 16:986-993, β-cyclodextrin polysulfate (CDPS), subcutaneously administered in a rabbit model of experimental osteoarthritis (OA) reduced the cartilage lesions and osteocyte formation in the affected joints. These data suggest that CDPS positively affects the tissue pathology underlying OA and this agent can therefore be classified as a structure or disease modifying OA drug.
Apart from the chondroprotective capacities, other characteristics of CDPS are described in the literature. Polysulfated cyclodextrins have been shown to possess important biological activities similar to those of heparin which can be explained by the similarities in their molecular structure. Apart from a strong binding affinity for a fibroblast growth factor, an anti-angiogeneic activity and a capacity of inhibiting cellular invasion by HIV retro virus, both polysaccharides possess anticoagulant properties and CDPS may elicit heparin-induced thrombocytopenia.
In vitro studies concerning CDPS and coagulation show prolongation of thrombin clotting times and a reduction in thrombus formation. Such biological activities were clearly shown to be related to the molecular structure of the polysaccharide and varied following distinct modifications. The introduction of distinct alkyl groups for example, did not prolong the activated partial thromboplastin time (aPTT) in vitro suggesting a reduced anti-coagulant activity compared to CDPS.
Next, the potency to induce heparin-induced thrombocytopenia (hereinafter referred as HIT) and thromboembolic accidents through cross reaction with heparin/platelet factor IV antibodies is a matter of concern. These antibodies can arise occasionally when activated thrombocytes release platelet factor IV (PF4) during heparin treatment. Heparin then forms a complex with PF4 that acts as an antigen which triggers the production of auto-antibodies. These anti-bodies bind to the complex via their F(ab)′ region and to the FcγRII (IgG CD32) of other platelets via the Fc portion thereby initiating platelet activation, aggregation and generation of platelet-derived microparticles. These pro-coagulant particles are likely to induce the thrombotic complications of HIT. It has been shown that some low molecular weight heparins as well as other sulphated polysaccharides, e. g. chondroitin polysulphates, can also bind to HIT antibodies in the presence of PF4 and that the reactivity is dependant on their molecular weight and the sulfation grade. Only a subset of patients will produce antibodies with platelet-activating properties after heparin therapy. Some of the later will develop thrombocytopenia and even less will develop thrombosis.
Thus, it is one problem to be addressed by the presently claimed invention to provide novel therapeutic agents with a preserved chondro-protective capacity, a reduced effect on coagulation and a reduced risk for heparin-induced thrombocytopenia.
It is another problem to be addressed by the presently claimed invention to provide novel therapeutic agents that are suitable for the prevention of platelet aggregation and vascular thrombosis in individuals afflicted with HIT syndrome.
It is another problem to be addressed by the present invention to provide novel therapeutic agents which can be used to treat HIT syndrome without inducing anti-coagulant activity.
Furthermore, it is another problem to be addressed by the presently claimed invention to provide novel therapeutic agents which can be used to treat HIT syndrome without inducing platelet activation or thrombosis in the presence of heparin- and platelet factor IV-complex reactive antibodies.
It is another problem to be addressed by the presently claimed invention to provide novel therapeutic agents which can be used for the treatment and/or prophylaxis of degenerative joint diseases such as osteoarthritis, articular rheumatism, arthrosis or degenerative arthritis, or for cartilage repair or connective tissue repair.