| This dissertation primarily focuses on the molecular weight and activity relationship of heparins and their depolymerized derivatives, in which a broad molecular weight range is covered. As a result, the agents included in this dissertation encompass polysaccharide and oligosaccharide chains ranging from 150 hexose units to trisaccharide. Not only the molecular weight but also the relative distribution of different molecular components greatly varies in these agents. One of the major objectives of this research was to investigate the pharmacological actions of an ultra low molecular weight heparin derived oligosaccharide mixture, namely subeparin (C3). The initial studies compared the starting material heparin with an irradiation degraded low molecular weight heparin, namely gammaparin and a highly depolymerized heparin derived oligosaccharide mixture, namely C3. A comprehensive molecular and structural analysis provided crucial data on the physiochemical behavior of these agents. A comprehensive biochemical analysis included extensive testing of the in vitro anticoagulant and antiprotease actions. The pharmacokinetic and pharmacodynamic profiles of these agents were investigated in specific animal models. In particular, the blood-brain barrier transport profiles of various agents were extensively investigated in a rat model. The pharmacokinetic profile of various agents was extensively investigated in a primate colony solely dedicated for the investigation of the pharmacokinetics of heparin. Since a homogeneous heparin-derived oligosaccharide of synthetic origin has been introduced for clinical use and several naturally obtained oligosaccharide mixtures such as RO-14 were being developed, these agents were also compared with C3. This dissertation provides a comprehensive biochemical and pharmacological investigation in which not only the molecular weight dependence, but also the differences between heparin-derived oligosaccharides were investigated. This research has also provided experimental evidence that heparin-derived oligosaccharides are different from heparin and low molecular weight heparins. Thus, this dissertation serves as a stepwise pre-clinical approach for an objective development of heparin-derived oligosaccharides. |
