Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Patent
1989-01-27
1991-08-13
Rollins, John W.
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
424639, 424641, 424682, 514 56, 536 21, A61K 3334, A61K 3332
Patent
active
050395297
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel complexes of metal ions as defined below, in particular copper ions, with such fractions of heparin, heparan sulfate, low molecular weight heparin, low molecular weight heparan sulfate, heparin fragments, heparan sulfate fragments, and oligosaccharides derived from heparin or heparan sulfate that specifically bind to such metal ions, or a salt of such fractions, to a process for obtaining such metal-binding fractions and metal complexes thereof, and to the use of such complexes in therapy. It was unexpectedly found that the inhibitory properties on angiogenesis of these novel complexes of the invention in vivo in presence of a suitable angiostatic agent, especially a steroid were markedly enhanced with respect to such fractions that were not bound to metal ions and also with respect to the unfractionated products.
BACKGROUND OF THE INVENTION
It has been shown that a combination of heparin or a hexasaccharide fragment together with a suitable steroid cause inhibition of angiogenesis in mammals and that tumor masses in mammals are caused to regress and metastasis is prevented (Folkman et al.; Science 1983, 221, 719-725). It was also shown that this combination was effectively inhibiting other angiogenesis depending processes such as fertilization of the rat (Folkman et al., European Patent Application No. EP-0114589). It is also effective in reducing osteoporosis and in treating deseases involving neovascularization, such as neovascular diseases of the eye. Also because of the occurrence of angiogenesis in psoriasis and arthritis, it is expected that this combination will be useful in treating those diseases.
Whereas further research and development with respect to the steroid part of this combination that inhibits angiogenesis has yielded more potent and specific steroids (Crum et al., Science 1985, 230, 1375-1378), no such progress has been made with regards to the heparin component of the heparin steroid composition. A synthetic highly sulfated non-anticoagulant pentasaccharide was recently shown to possess inhibiting effect on angiogenesis in the presence of a steroid to the same extent as its highly anticoagulant active analogue (the 3-O-sulfated analogue) (Choay et al., European Patent Application No. EP-0140781). This finding further supports the finding that the anticoagoulant (anti-Xa) properties of heparin and heparin fragments are not required for the heparin and heparin fragments to be inhibitory on angiogenesis in the presence of steroids (Folkman et al., Science 1983, 221, 719-725; Crum et al., Science 1985, 230, 1375-1378).
Heparin is a glycosidically linked highly sulfated copolymer of uronic acids and D-glucosamine. The uronic acids being L-iduronic acid or D-glucuronic acid of which the former usually is sulfated and the latter usually nonsulfated. The glucosamine is either N-sulfated or N-acetylated and also frequently 6-O-sulfated. Small amounts of other structural variants also occur. The exact structure of heparin and the precise nature of its antithrombotic mechanism of action has not been elucidated although it has been in widespread use for almost 50 years. Heparin is polydisperse with a molecular weight range from 3,000-30,000 with many structural variations within a given chain. The exact composition of heparin varies depending on its source, which usually is porcine intestinal mucosa, bovine lung, bovine intestinal mucosa, or ovine intestinal mucosa and also depending on the method for its preparation and purification. Low molecular weight heparin (molecular weight range 2,000-10,000) has been isolated in small amounts by fractionation of standard heparin. Heparin fragments of molecular weight range 500-10,000 has been prepared by partial depolymerization of heparin by chemical or enzymatic methods. Chemical depolymerization has been carried out in many different ways, frequently by nitrites at low pH, by alkaline .beta.-elimination usually after esterification of uronic acids or by oxidative methods usually using p
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Bergendal Karin H. L.
Johansson Rolf A.
Svahn Carl M. E.
Kabivitrum AB
Rollins John W.
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