Use of chemically modified heparin derivates in sickle cell disease
The present invention relates to chemically modified heparin for use in the treatment of sickle cell disease, with an antifactor II activity of less than 10 IU/mg, an antifactor Xa activity of less than 10 IU/mg and an average molecular weight (Mw) between about 6.5 and 9.5 kDa.
1. A method of treating sickle cell disease, comprising:
administering to a patient having sickle cell disease a therapeutically effective amount of a chemically modified heparin having an antifactor IIa activity and an antifactor Xa activity, wherein the antifactor IIa activity is less than 10 IU/mg and the antifactor Xa activity is up to 10 IU/mg, the chemically modified heparin having a weight average molecular weight from about 6.5 to about 9.5 kDa, wherein the chemically modified heparin comprises polysaccharide chains having:
(i) at least 90% of the sulfate groups of the corresponding native heparin;
(ii) a reduction in chemically intact saccharide sequences providing an antithrombin-mediated anticoagulant effect, when compared to the polysaccharide chains of native heparin, and a reduction in unsulfated iduronic and/or glucuronic acid units when compared to native heparin; and
(iii) a predominant disaccharide having the chemical structure:
wherein R′ is a threonate residue and n is an integer of from 2 to 25, such that it comprises from 2 to 25 disaccharide units corresponding to molecular weights from 1.2 to 15 kDa.
2. The method according to claim 1 , wherein at least 30% of the polysaccharide chains have a molecular weight of at least 8 kDa.
3. The method according to claim 1 , wherein the polysaccharide chains have glycol-split residues of the chemical structure:
4. The method according to claim 1 , wherein 3-15% of the polysaccharide chains have a molecular mass of at least 15 kDa.
5. The method according to claim 1 , wherein from 25-47% of the polysaccharide chains have a molecular mass of at least 9 kDa.
6. The method according to claim 1 , wherein from 40-60% of the polysaccharide chains have a molecular mass of at least 7 kDa.
7. The method according to claim 1 , wherein from 60-80% of the polysaccharide chains have a molecular mass of at least 5 kDa.
8. The method according to claim 1 , wherein at least 85% of the polysaccharide chains have a molecular mass of at least 3 kDa.
9. The method according to claim 1 , wherein at least 95% of the polysaccharide chains have a molecular mass of at least 2 kDa.
10. The method according to having claim 1 , wherein the chemically modified heparin has, in a 1 H-NMR spectrum, no unidentified signals in the ranges 0.10-2.00 ppm, 2.10-3.10 ppm and 5.70-8.00 ppm larger than 4 percent when compared to the height of the signal present in native heparin at 5.42 ppm.
11. The method according to claim 1 , wherein the predominantly occurring polysaccharide chains have from 6 to 16 disaccharide units with molecular weights from about 3.6 to about 9.6 kDa.
12. The method according to claim 1 , the treatment is of vaso-occlusive crisis in sickle cell disease.