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In vitro and in vivo characterization of a reversible synthetic heparin analog.

ABSTRACT: The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogs. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine.We sought to further characterize this new compound in vitro using biochemical and global coagulation assays and in vivo using thrombosis and hemostasis assays.The anticoagulant activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and plasma-based thrombin generation assays were roughly equivalent with a 50% reduction in peak thrombin generation occurring at approximately 325nM. When protamine was titrated against a fixed concentration of S12-mer in plasma or blood, the S12-mer displayed a significant restitution of thrombin generation and clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent as Enoxaparin, with similar bleeding profiles.These data show that the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa inhibition, while displaying significant reversibility with protamine. Taken together with the ability to ensure purity and homogeneity from batch to batch, the S12-mer is a promising new synthetic heparin analog with a potentially enhanced safety profile.

SUBMITTER: Whelihan MF

PROVIDER: S-EPMC4751072 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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In vitro and in vivo characterization of a reversible synthetic heparin analog.

Whelihan Matthew F MF Cooley Brian B Xu Yongmei Y Pawlinski Rafal R Liu Jian J Key Nigel S NS

Thrombosis research 20151210

<h4>Background</h4>The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically sy ...[more]

PMID: 26709038

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Project description:BackgroundSchistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries. Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority. Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites.Methodology/principal findingsWe found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms. Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis-like processes in cells in the close vicinity to the tegument. Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis.Conclusions/significanceOur data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro. Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death. Oral administration of edelfosine diminished worm and egg burdens in S. mansoni-infected CD1 mice. Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo.

Project description:Essentials Platelet transfusion suffers from availability, portability, contamination, and short shelf-life. SynthoPlate™ (synthetic platelet technology) can resolve platelet transfusion limitations. SynthoPlate™ does not activate resting platelets or stimulate coagulation systemically. SynthoPlate™ significantly improves hemostasis in thrombocytopenic mice dose-dependently. SUMMARY:Background Platelet transfusion applications face severe challenges, owing to the limited availability and portability, high risk of contamination and short shelf-life of platelets. Therefore, there is significant interest in synthetic platelet substitutes that can provide hemostasis while avoiding these issues. Platelets promote hemostasis by injury site-selective adhesion and aggregation, and propagation of coagulation reactions on their membranes. On the basis of these mechanisms, we have developed a synthetic platelet technology (SynthoPlate™) that integrates platelet-mimetic site-selective 'adhesion' and 'aggregation' functionalities via heteromultivalent surface decoration of lipid vesicles with von Willebrand factor-binding, collagen-binding and active platelet integrin glycoprotein (GP) IIb-IIIa-binding peptides. Objective To evaluate SynthoPlate for its effects on platelets and plasma in vitro, and for systemic safety and hemostatic efficacy in severely thrombocytopenic mice in vivo. Methods In vitro, SynthoPlate was evaluated with aggregometry, fluorescence microscopy, microfluidics, and thrombin and fibrin generation assays. In vivo, SynthoPlate was evaluated for systemic safety with prothrombin and fibrin assays on plasma, and for hemostatic effects on tail-transection bleeding time in severely thrombocytopenic (TCP) mice. Results SynthoPlate did not aggregate resting platelets or spontaneously promote coagulation in plasma, but could amplify the recruitment and aggregation of active platelets at the bleeding site, and thereby site-selectively enhance fibrin generation. SynthoPlate dose-dependently reduced bleeding time in TCP mice, to levels comparable to those in normal mice. SynthoPlate has a reasonable circulation residence time, and is cleared mostly by the liver and spleen. Conclusion The results demonstrate the promise of SynthoPlate as a synthetic platelet substitute in transfusion treatment of platelet-related bleeding complications.

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In vitro and in vivo characterization of a reversible synthetic heparin analog.

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In vitro and in vivo characterization of a reversible synthetic heparin analog.

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