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Protamine, the only registered antidote of unfractionated heparin (UFH), may produce a number of adverse effects, such as anaphylactic shock or serious hypotension. We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce. As a starting material, we have chosen generally non-toxic, biocompatible, widely available, inexpensive, and easy to functionalize polysaccharides. Our approach was to synthesize, purify and characterize cationic derivatives of dextran, hydroxypropylcellulose, pullulan and γ-cyclodextrin, then to screen them for potential heparin-reversal activity using an in vitro assay and finally examine efficacy and safety of the most active polymers in Wistar rat and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation, activated partial thromboplastin time, bleeding time, and anti-factor Xa activity; safety studies included the measurement of hemodynamic, hematologic and immunologic parameters. Linear, high molecular weight dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3) is the most potent and the safest UFH inhibitor showing activity comparable to that of protamine while possessing lower immunogenicity. Cationic polysaccharides of various structures neutralize UFH. Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine.

Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD. [ABSTRACT FROM AUTHOR]

Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents. [ABSTRACT FROM AUTHOR]

[Display omitted] • The need for safe and controllable anticoagulant drugs is still widely recognized. • Polyionic block copolymers hold great potential for controlling blood clotting. • Attaching neutral blocks to charged copolymers decreases their toxicity. • Safety studies are needed to select promising anticoagulants from block copolymers. Thrombosis is a leading cause of death worldwide, necessitating the search for more effective and safer treatments. Current parenteral anticoagulant medications indicated for the prevention and treatment of thrombosis include polyanionic heparins. Despite their well-established status, these medications have drawbacks and fail to meet the criteria for an ideal anticoagulant. The predictability and control of heparin's biological activity pose challenges due to the chaotic structure of this polymer, characterized by a mixture of larger and smaller molecules with a loosely defined linear architecture. Consequently, cases of heparin overdose are common. Protamine sulphate can halt bleeding caused by unfractionated heparin but concurrently elicits significant adverse effects. Although novel antidotes for anticoagulants have been developed, bleeding during anticoagulation therapy remains a concern. Over the past two decades, research into heparin mimetics has witnessed a significant surge. This intensification is underscored by statistical evidence indicating an increase in thrombotic episodes, highlighting the necessity for new anticoagulant alternatives. This review outlines the efforts to replace heparins and their antidotes with block copolymers. We have concentrated on studies involving well-defined synthetic anionic and cationic block copolymers, which are obtained by free radical polymerization techniques. Block copolymers comprised of anionic poly(sodium 4-styrenesulphonate) or poly(2-acryloylamido-2-methylpropanesulphonic acid) blocks and a neutral poly(ethylene glycol) block seem to be the most promising candidates for future anticoagulants. Complementary polycationic antidotes to regulate anticoagulant activity have also been proposed; however, further research focusing on structure–activity relationships and safety is necessary to confirm their utility. [ABSTRACT FROM AUTHOR]