heparitin-sulfate and glucuronyl-glucosamine-glycan-sulfate

Heparin is the first glycosaminoglycan ever identified. All the heparin-like glycosaminoglycans that are also isolated from animal tissues or any polysaccharides that mimic the biological activities of heparin are called heparinoids. Heparin is the mostly sulfated glycosaminoglycan made by mast cells and an essential anticoagulant drug in modern medicine. Heparin inhibits both thrombin generation and thrombin activity, releases tissue factor pathway inhibitor, and possesses anti-inflammatory, anti-viral, anti-angiogenesis, anti-neoplastic, and anti-metastatic properties though high affinity interactions with a variety of proteins in the blood circulation. The multi-pharmacological effects of heparin are both sequence- and sulfation degree dependent. Less sulfated heparinoids have been indicated to have more physiological functions than heparin. Since the anticoagulant heparin is associated with severe side effects, such as bleeding and heparin-induced thrombocytopenia and thrombosis, it is expected that the less sulfated heparinoids might serve as alternative drugs for patients who cannot use heparin. The crude heparin isolated from animal tissues contains ~50% heparin and ~50% less sulfated heparinoids. Indeed, the less sulfated waste heparinoids 1 during heparin production is chemically degraded and developed into the clinical drug Danaparoid and the more sulfated waste heparinoids 2 during heparin production is chemically degraded and developed into the clinical drug Sulodexide. Moreover, clinical studies indicate that Danaparoid and Sulodexide have the expected pharmacological activities. We will provide an update on the chemical characteristics and clinical use of the heparinoids Danaparoid and Sulodexide. In addition, the potential clinical applications of Danaparoid and Sulodexide in other therapeutic area will also be discussed.

Topics: Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Glycosaminoglycans; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans

The endothelial glycocalyx has a profound influence at the vascular wall on the transmission of shear stress, on the maintenance of a selective permeability barrier and a low hydraulic conductivity, and on attenuating firm adhesion of blood leukocytes and platelets. Major constituents of the glycocalyx, including syndecans, heparan sulphates and hyaluronan, are shed from the endothelial surface under various acute and chronic clinical conditions, the best characterized being ischaemia and hypoxia, sepsis and inflammation, atherosclerosis, diabetes, renal disease and haemorrhagic viral infections. Damage has also been detected by in vivo microscopic techniques. Matrix metalloproteases may shed syndecans and heparanase, released from activated mast cells, cleaves heparan sulphates from core proteins. According to new data, not only hyaluronidase but also the serine proteases thrombin, elastase, proteinase 3 and plasminogen, as well as cathepsin B lead to loss of hyaluronan from the endothelial surface layer, suggesting a wide array of potentially destructive conditions. Appropriately, pharmacological agents such as inhibitors of inflammation, antithrombin and inhibitors of metalloproteases display potential to attenuate shedding of the glycocalyx in various experimental models. Also, plasma components, especially albumin, stabilize the glycocalyx and contribute to the endothelial surface layer. Though symptoms of the above listed diseases and conditions correlate with sequelae expected from disturbance of the endothelial glycocalyx (oedema, inflammation, leukocyte and platelet adhesion, low reflow), therapeutic studies to prove a causal connection have yet to be designed. With respect to studies on humans, some clinical evidence exists for benefits from application of sulodexide, a preparation delivering precursors of the glycocalyx constituent heparan sulphate. At present, the simplest option for protecting the glycocalyx seems to be to ensure an adequate level of albumin. However, also in this case, definite proof of causality needs to be delivered.

Topics: Animals; Anti-Inflammatory Agents; Endothelium, Vascular; Enzyme Inhibitors; Glycocalyx; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Peptide Hydrolases; Renal Insufficiency; Reperfusion Injury; Sepsis; Serum Albumin; Syndecans

One of the most interesting glycosaminoglycans (GAGs) is heparansulphate, known as the physiological activator of antithrombin III and involved in the maintenance of the antithrombotic potential of uninjured endothelium. The aim of our study was to evaluate the tolerability and effectiveness of heparansulphate with respect to sulodexide, another GAG suitable for the treatment of venous diseases. The study was performed in a open-label, controlled, with parallel and randomized groups, design. Thirty patients (aged 32-72 years) suffering from superficial thrombophlebitis were treated for two weeks with heparansulphate 100 mg t.i.d. or sulodexide 250 LSU b.i.d., both given orally. Some coagulative and fibrinolytic parameters (PT; aPTT; fibrinogen; euglobulin lysis time; t-PA; PAI-1; ATIII; alpha 2-antiplasmin; D-Dimer and platelets count) were assayed at the beginning and at the end of the study. Moreover signs and symptoms of disease (skin trophism; local pain; itch and oedema) were assessed. Heparansulphate and sulodexide were able to reduce signs and symptoms with similar degree and to significantly modify t-PA, alpha 2-antiplasmin and ATIII levels without any difference between treatments. Our issues show that heparansulphate can be useful in superficial thrombophlebitis management.

Topics: Adult; Aged; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hypolipidemic Agents; Male; Middle Aged; Thrombophlebitis

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation Tests; Disease Models, Animal; Fibrinolytic Agents; Glycosaminoglycans; Heparitin Sulfate; Humans; Injections, Intravenous; Macaca mulatta; Male; Rabbits