Following a screening program for orally active antithrombotic drugs, it was found that a series of thioxyloside compounds presented with good venous antithrombotic properties. Of more than 500 compounds, LF 09-0055, LF 04-0212, and LF 05-0030 were the most active at inhibiting venous thrombus formation in the rat and rabbit Wessler model after intravenous and oral dosing. LF 05-0030 showed the greatest activity with an ED80 value of 6 mg/kg on oral administration in rats. This activity was maintained in several different models of venous thrombosis and shown to be devoid of anticoagulant effects or hemorrhage. Kinetic studies have demonstrated that maximal levels of activity, following either intravenous or oral dosing, occurred between 2 and 4 hours after administration. This may reflect the type of mechanism involved, since it has been well documented in the literature that xylosides are capable of initiating glycosaminoglycan (GAG) synthesis. Moreover, in vitro galactosyltransferase 1 (the second enzyme involved in GAG polymerization) enzymic assays showed that these thioxyloside derivatives were good acceptors for galactose transfer and therefore at initiating GAG formation. Further in vivo experimentation demonstrated that after treatment by these molecules an important elevation in circulating GAG occurred, with LF 05-0030 presenting the greatest activity, being five times higher than control levels. In addition it was found that dermatan sulfate levels, expressed as antithrombin activity by heparin cofactor II, were significantly increased over control values. As such, this dermatan sulfate moiety is believed to support the antithrombotic activity observed. Studies are underway to investigate the activity of these interesting molecules in atherosclerosis and other vessel wall diseases.
The Derivatograph has been found to be suitable for the investigation of biopolymers consisting of polysaccharides and proteins. It could be demonstrated that interactions between the macromolecules of the collagen-proteoglycan-glycoprotein complexes significantly influence the thermal stability of the individual components.Studies concerning physiological and pathological changes in the composition and structure of connective tissues are at tl-~e focus of interest of biological and medical research.The literature contains a great amount of information on the chemical composition of connective tissues, obtained by the analysis of fractions from various extraction-fractionation procedures. However, the extractability of the different tissue components is a function not only of the chemical composition of the tissue, but also of the original macromolecular structure (degree of intra-and intermolecular crosslinks) of the biological material. Thus, the yields and compositions of the fractions obtained by a given extraction method from different tissue samples may be characteristically different, depending on the source of the tissue (species and organ differences), the stage of development (age-related changes) and the condition of health of the individual (pathological alterations). However, these differences are often not reflected in the results of chemical analysis (hexose, hexosamine, hexuronic acid, hydroxyproline, etc. determinations). In our experiments a complex thermoanalytical method [1] was applied to study various collagen-proteoglycan-glycoprotein complexes prepared from different connective tissues by the method of Robert et al. [2]. Thermal analysis was successfully used in our previous investigations for the quantitative determination of polysaccharides [3], for the characterization of protein structure [4], and for the estimation of age-related [5,6] and pathological [7][8][9][10][11][12][13] changes in proteoglycan-and collagen-containing biological tissues. Materials and MethodsFibrinogen (for the preparation of glycopeptides and S-sulfo-fibrinogen) and ovalbumin were purchased from Sigma (St. Louis). Purified bovine fibrinogen, fibrin and orosomucoid (Cohn fraction VI) for thermoanalytical studies were .1. Thermal Anal. 7, 1975
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