chondroitin and Thrombosis

Although the specific anticoagulant activity of dermatan sulphate is seventy times less than that of standard heparin, its venous antithrombotic activity, tested on a great number of experimental models, appears at gravimetric doses which are only seven fold higher. This antithrombotic activity is not correlated with the factor Xa inhibition, but is associated with thrombin generation inhibition and potentiation of heparin cofactor II. Meanwhile, others factors, still non entirely identified, i.e. like the release of endogenous tissue plasminogen activators, must probably be involved in the antithrombotic activity of dermatan sulphate. In contrast to heparin, dermatan sulphate possesses hemorrhagic properties only at doses which are forty times higher than the antithrombotic dose. These hemorrhagic properties seem associated with an inhibition of collagen induced platelet aggregation. Finally, the pharmacokinetic profile of dermatan sulphate after intravenous injection in the rabbit, is different from that of standard heparin, and close to that of low molecular weight heparins.

Topics: Animals; Antithrombin III; Antithrombins; Blood Coagulation; Blood Platelets; Chondroitin; Dermatan Sulfate; Glycoproteins; Heparin Cofactor II; Humans; Models, Biological; Rabbits; Rats; Thrombosis

Effects of isomers of chondroitin sulfate on atherosclerosis were clinically compared, based on sulfate linkage and the amount of sulfate, by using chondroitin 4-sulfate, chondroitin 6-sulfate and chondroitin polysulfate. Fourty eight age-matched atherosclerotic subjects were selected from a home for the elderly in order to the treatment with the agents. The isomers of chondroitin sulfate were given a daily dose of 4.5 g perorally. During the experimental period for 64 months, mortality, serum cholesterol, thrombus-formation time and thrombus weight were examined. The result obtained was as follows: mortality in the groups treated with the isomers of chondroitin sulfate was less than the age-matched untreated control group. Serum cholesterol value in the group treated by the isomers of chondroitin sulfate, chondroitin polysulfate group in particular, fell lower than the pre-treatment value. Thrombus formation time prolonged 150% in the group treated with chondroitin polysulfate over the untreated control group and the resultant thrombus weight was reduced in the treated group. Thus, these data indicated that the isomers of chondroitin sulfate are clinically effective on the treatment of atherosclerosis in the order of chondroitin polysulfate, chondroitin 4-sulfate and/or chondroitin 6-sulfate.

Topics: Aged; Arteriosclerosis; Blood Coagulation; Cholesterol; Chondroitin; Chondroitin Sulfates; Clinical Trials as Topic; Humans; Isomerism; Thrombosis

Topics: Animals; Blood Coagulation Tests; Chondroitin; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Male; Rabbits; Thrombosis

Standard heparin (SH) and dermatan sulfate (DS) two glycosaminoglycans with different pharmacological targets are effective antithrombotic agents in the rabbit. We have investigated the antithrombotic activity of the association DS plus SH. It was found that doses as low as 25 micrograms/kg for DS and 10 micrograms/kg for SH were ineffective when injected separately but generated a high and significant antithrombotic activity when injected together. These results were confirmed when higher doses of each compound were delivered in association. Further experiments were performed to determine if the enhancement of the antithrombotic activity of DS by HS resulted from its anti-factor IIa or anti-factor Xa activity or from its moiety without affinity to AT III. A low molecular weight heparin (CY 216) with an anti-factor Xa/anti-factor IIa ratio of 5, the synthetic pentasaccharide bearing the minimum binding sequence to antithrombin III, and a low affinity fraction of SH to AT III did not increase the antithrombotic activity of DS; in contrast a high affinity fraction of SH to AT III had the same effect than SH. We conclude that the enhancement of the antithrombotic activity of DS by SH mainly results from its anti-factor IIa activity.

Topics: Animals; Chondroitin; Dermatan Sulfate; Dose-Response Relationship, Drug; Drug Synergism; Factor Xa; Fibrinolytic Agents; Heparin; Heparin, Low-Molecular-Weight; Male; Prothrombin; Rabbits; Serine Proteinase Inhibitors; Thrombosis

The in vitro and in vivo pharmacological properties of two oversulfated dermatan sulfate (DS) derivatives, S-DS1 and S-DS2, containing 2 and 3.7 sulfate groups/disaccharide unit respectively were compared to those of the parent DS (1 sulfate group/disaccharide unit). In a purified system the ability of S-DS1 and of S-DS2 to catalyse thrombin inhibition by heparin cofactor II was increased by ten- and seventeen-fold respectively. These compounds also had more potent anticoagulant activities in the activated partial thromboplastin time and the thrombin clotting time assays. Plasma immunodepleted in antithrombin III, heparin cofactor II and both cofactors allowed it to be demonstrated that these enhanced anti-coagulant activities were partly (S-DS1) or totally (S-SD2) independent of any plasma cofactors. In spite of these enhanced anticoagulant activities in vitro the oversulfated derivatives did not exhibit an increased antithrombotic activity in a thromboplastin Wessler type model. Moreover, at the doses investigated, S-DS2 had no antithrombotic effect. The influence of oversulfation on the pharmacokinetic pattern of DS was also investigated. As reported for unfractionated heparin, the biological activities generated after IV injection of high doses of S-DS1 and S-DS2 disappeared according to a concave-convex pattern. This may result from the higher affinities of S-DS1 and of S-DS2 toward endothelial cells in comparison with that of DS.

Topics: Animals; Chondroitin; Dermatan Sulfate; Disease Models, Animal; Fibrinolytic Agents; Half-Life; Humans; Metabolic Clearance Rate; Partial Thromboplastin Time; Rabbits; Sulfuric Acids; Thrombosis

Heparin and dermatan sulphate are effective antithrombotic agents but the clinical use of heparin is complicated by haemorrhage. The haemorrhagic effect of dermatan sulphate is unknown. In this study we compared the antithrombotic, haemorrhagic and anticoagulant effects of heparin and dermatan sulphate in rabbits. The antithrombotic effect was measured as prevention of venous thrombus formation. The haemorrhagic effect was measured as 51Cr-blood loss from standardized cuts in rabbit ears. The anticoagulant effect was measured as changes in the APTT, TCT and circulating anti-factor Xa level, and the formation of 125I-thrombin/inhibitor complexes ex vivo. The effect of heparin and dermatan sulphate on collagen-induced platelet aggregation was measured ex vivo. Maximal antithrombotic effects of heparin and dermatan sulphate were achieved with 70 and 500 micrograms/kg respectively. A 20-fold increase in heparin dose caused an 8-fold increase in blood loss and higher doses (40- and 80-fold increases) caused further dose-related increases in blood loss (13- and 35-fold increases respectively). In contrast, a 20- to 40-fold increase in the antithrombotic dose of dermatan sulphate did not increase blood loss and an 80-fold dose increase caused only a 7-fold increase in blood loss. There was no relationship between the antithrombotic and haemorrhagic effects of either heparin or dermatan sulphate and their anticoagulant activities. In contrast, there was a relationship between the dose-related enhancement of blood loss by these glycosaminoglycans and the inhibition of collagen-induced platelet aggregation ex vivo. These results suggest that dermatan sulphate is less haemorrhagic than heparin at equivalent antithrombotic doses, and that the haemorrhagic effect is associated with a glycosaminoglycan-induced platelet defect.

Topics: Animals; Blood Coagulation; Chondroitin; Dermatan Sulfate; Dose-Response Relationship, Drug; Factor X; Factor Xa; Hemorrhage; Heparin; Platelet Aggregation; Rabbits; Thrombosis

Topics: Acids; Alkalies; Amino Alcohols; Animals; Appendix; Chondroitin; Electric Injuries; Ethylmaleimide; Female; Glucose; Heparin; Mesenteric Arteries; Mesenteric Veins; Podophyllin; Rats; Thrombosis

Topics: Animals; Chondroitin; Dogs; Heparin; Injections, Intravenous; Male; Sodium Chloride; Sulfates; Thrombosis; Time Factors

Topics: Aged; Chondroitin; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Sulfates; Thrombosis

Topics: Animals; Arteriosclerosis; Cholesterol; Chondroitin; Depression, Chemical; Hypolipidemic Agents; Phospholipids; Rabbits; Sulfates; Thrombosis; Time Factors; Triglycerides

Topics: Adult; Aged; Amino Sugars; Arteriosclerosis; Blood Coagulation Tests; Cholesterol; Chondroitin; Female; Galactose; Hexosamines; Humans; Injections, Intravenous; Lipids; Male; Middle Aged; Phospholipids; Sulfates; Thrombosis; Time Factors; Triglycerides