SULODEXIDE

Uses

Sulodexide is an orally active mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulfate (20%). Sulodexide exhibits antithrombotic activity through interaction with antithrombin III (AT III) and heparin cofactor II (HC II), and inhibition of thrombin formation. Sulodexide exhibits profibrinolytic activity through release of tissue plasminogen activator (tPA). Sulodexide exhibits endothelial protective and anti-inflammatory effect, ameliorates chronic venous disease[1].

Pharmacology

Sulodexide is a medium molecular weight glycosaminoglycan with effect on plasma viscosity by lowering plasma fibrinogen concentrations (Lunetta and Salanitri, 1992). Sulodexide disers from other glycosaminoglycans, like heparin, by having a longer half-life, reduced effect on systemic clotting and bleeding and increased lipolytic activity. Oral administration of sulodexide results in the release of tissue-type plasminogen activator (tPA) and an increase in fibrinolytic activities. Sulodexide has been used in chronic venous disease (Andreozzi, 2014), peripheral occlusive arterial disease with claudication (Shustov, 1997) and diabetic nephropathy (Vilayur and Harris, 2009). Parnetti et al. (1997) conducted a trial of sulodexide in patients fulfilling NINDSAIREN criteria for probable VaD; 46 patients were included in the active treatment group, compared with 40 in the pentoxifylline group. Larger reductions of plasma fibrinogen levels were seen with sulodexide, and both groups showed a slight reduction in activated factor VII levels. Dementia scores improved more in the sulodexide group.

Synthesis

A method for the production of sulodexide, using heparin by-product as raw material, oxidizing to obtain intermediate crude heparin solution; adding acetate to intermediate crude heparin solution, ultrafiltration separation, obtaining fast-moving heparin crude and dermatoxylin sulfate crude; and then refining fast-moving heparin crude and dermatoxylin sulfate crude, respectively; and finally, mixing and dissolving precipitate obtained from the refining, filtration, collection of filtrate, and lyophilization treatment, obtaining raw material of sulodexide. lyophilization treatment to obtain the raw material of sulodexide, specifically including the following steps:
(1) oxidation: dissolve the heparin by-products, then adjust the pH and temperature of the solution, then add hydrogen peroxide to the solution to oxidize it, after oxidation is completed, adjust the pH of the solution to 6.0-8.0, centrifugation to remove the precipitate, filtration of the supernatant, collection of the filtrate, and obtain the crude heparin solution of the intermediate;
(2) ultrafiltration: add sodium acetate to the intermediate crude heparin solution, recycle ultrafiltration, collect the retention solution to get the crude dermatoxylin sulfate, collect the permeate to get the crude fast-moving heparin, and store the crude fast-moving heparin at 38;
3) Refining: the fast-moving heparin crude and the dermatoxylin sulfate crude were refined separately;
4Mixing: the precipitates obtained from refining are mixed and dissolved, filtered, and the filtrate is collected and lyophilized to obtain the raw material of sulodexide.

in vivo

References

[1] Andreozzi GM. Sulodexide in the treatment of chronic venous disease. Am J Cardiovasc Drugs. 2012 Apr 1;12(2):73-81. DOI:10.2165/11599360-000000000-00000
[2] Yung S, et al. Sulodexide decreases albuminuria and regulates matrix protein accumulation in C57BL/6 mice with streptozotocin-induced type I diabetic nephropathy[J]. PloS one, 2013, 8(1): e54501. DOI:10.1371/journal.pone.0054501
[3] Jo H, et al. Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy[J]. BMB reports, 2014, 47(11): 637. DOI:10.5483/bmbrep.2014.47.11.009
[4] Huang R, et al. Sulodexide attenuates liver fibrosis in mice by restoration of differentiated liver sinusoidal endothelial cell[J]. Biomedicine & Pharmacotherapy, 2023, 160: 114396. DOI:10.1016/j.biopha.2023.114396
[5] Ying J, et al. Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis[J]. Frontiers in immunology, 2023, 14: 1172892. DOI:10.3389/fimmu.2023.1172892