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William de Wildt, Huub Kooijman, Carel Funke, Bülent Üstün, Afranina Leika, Maarten Lunenburg, Frans Kaspersen, Edwin Kellenbach
Fondaparinux sodium is a synthetic pentasaccharide representing the high affinity antithrombin III binding site in heparin. It is the active pharmaceutical ingredient of the anticoagulant drug Arixtra(®). The single crystal X-ray structure of Fondaparinux sodium is reported, unequivocally confirming both structure and absolute configuration. The iduronic acid adopts a somewhat distorted chair conformation. Due to the presence of many sulfur atoms in the highly sulfated pentasaccharide, anomalous dispersion could be applied to determine the absolute configuration...
August 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Franklin E Leach, Nicholas M Riley, Michael S Westphall, Joshua J Coon, I Jonathan Amster
The structural characterization of sulfated glycosaminoglycan (GAG) carbohydrates remains an important target for analytical chemists attributable to challenges introduced by the natural complexity of these mixtures and the defined need for molecular-level details to elucidate biological structure-function relationships. Tandem mass spectrometry has proven to be the most powerful technique for this purpose. Previously, electron detachment dissociation (EDD), in comparison to other methods of ion activation, has been shown to provide the largest number of useful cleavages for de novo sequencing of GAG oligosaccharides, but such experiments are restricted to Fourier transform ion cyclotron resonance mass spectrometers (FTICR-MS)...
September 2017: Journal of the American Society for Mass Spectrometry
Ragnar Flengsrud, Simen Gjelseth Antonsen
Pentapeptides have been shown to bind the synthetic heparin fondaparinux (Arixtra) as well the biological heparins dalteparin (Fragmin) and salmon heparin. In contrast to heparin binding consensus sequences, the pentapeptides are acidic or neutral, with no arginine or histidine residue. The peptides showed an effect on in vitro heparin anti-factor X activity with a reduction of fondaparinux activity by 65-95%. Heparin binding was further studied by using peptide solid phase chromatography and NMR analysis.
November 1, 2015: Bioorganic & Medicinal Chemistry Letters
I Mahé, J-P Daurès, D Pouchain, I Quéré, C Aubin, J Doussaint, S Schück, C Leroyer
OBJECTIVE: To evaluate the mean duration of treatment course with fondaparinux 2.5 mg (ARIXTRA(®)) in the setting of ambulatory general medicine, with respect to its indication in thromboprophylaxis for medically ill patients and to describe the population treated. METHODS: Observational, prospective, national, multicenter, pharmaco-epidemiological study, performed in France, at the request of the Transparency Commission (a division of the French Health Regulatory Authority)...
December 2015: Journal des Maladies Vasculaires
Yuejie Zhao, Arunima Singh, Lingyun Li, Robert J Linhardt, Yongmei Xu, Jian Liu, Robert J Woods, I Jonathan Amster
We validate the utility of ion mobility to measure protein conformational changes induced by the binding of glycosaminoglycan ligands, using the well characterized system of Antithrombin III (ATIII) and Arixtra, a pharmaceutical agent with heparin (Hp) activity. Heparin has been used as a therapeutic anticoagulant drug for several decades through its interaction with ATIII, a serine protease inhibitor that plays a central role in the blood coagulation cascade. This interaction induces conformational changes within ATIII that dramatically enhance the ATIII-mediated inhibition rate...
October 21, 2015: Analyst
Andrew B Dykstra, Matt D Sweeney, Julie A Leary
Understanding chemokine interactions with glycosaminoglycans (GAG) is critical as these interactions have been linked to a number of inflammatory medical conditions, such as arthritis and asthma. To better characterize in vivo protein function, comprehensive knowledge of multimeric species, formed by chemokines under native conditions, is necessary. Herein is the first report of a tetrameric assembly of the human chemokine CCL11, which was shown bound to the GAG Arixtra™. Isothermal titration calorimetry data indicated that CCL11 interacts with Arixtra, and ion mobility mass spectrometry (IM-MS) was used to identify ions corresponding to the CCL11 tetrameric species bound to Arixtra...
2013: Biomolecules
Meredith M Dinges, Kemal Solakyildirim, Cynthia K Larive
The anticoagulant properties of heparin stem in part from high-affinity binding to antithrombin-III (AT-III) inducing a 300-fold increase in its inhibitory activity against the coagulation protease factor Xa. The minimal structural requirements for AT-III binding are contained in the rare heparin pentasaccharide sequence containing a 3,6-O-sulfated N-sulfoglucosamine residue. ACE is used in this work to measure the relative AT-III binding affinities of the low molecular weight heparins (LWMHs) dalteparin, enoxaparin, and tinzaparin and the synthetic pentasaccharide drug fondaparinux (Arixtra)...
May 2014: Electrophoresis
Nadia I Awad, Craig Cocchio
OBJECTIVE: Prothrombin complex concentrate (PCC) products are emerging as alternative strategies for reversing anticoagulant pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activated PCC (aPCC). Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding with surgical interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have suggested that the product may be used off-label as an anticoagulant-reversal agent...
November 2013: P & T: a Peer-reviewed Journal for Formulary Management
Owen M McDougal, Nic Cornia, S V Sambasivarao, Andrew Remm, Chris Mallory, Julia Thom Oxford, C Mark Maupin, Tim Andersen
DockoMatic 2.0 is a powerful open source software program (downloadable from that allows users to utilize a readily accessible computational tool to explore biomolecules and their interactions. This manuscript describes a practical tutorial for use in the undergraduate curriculum that introduces students to macromolecular structure creation, ligand binding calculations, and visualization of docking results. A student procedure is provided that illustrates the use of DockoMatic to create a homology model for the amino propeptide region (223 amino acids with two disulfide bonds) of collagen α1 (XI), followed by molecular docking of the commercial drug Arixtra(®) to the homology model of α1 (XI), and finally, analysis of the results of the docking experiment...
March 2014: Biochemistry and Molecular Biology Education
Consuelo N Beecher, Robert P Young, Derek J Langeslay, Leonard J Mueller, Cynthia K Larive
Heparin is best known for its anticoagulant activity, which is mediated by the binding of a specific pentasaccharide sequence to the protease inhibitor antithrombin-III (AT-III). Although heparin oligosaccharides are thought to be flexible in aqueous solution, the recent discovery of a hydrogen bond between the sulfamate (NHSO3(-)) proton and the adjacent 3-O-sulfo group of the 3,6-O-sulfated N-sulfoglucosamine residue of the Arixtra (fondaparinux sodium) pentasaccharide demonstrates that definable elements of local structure are accessed...
January 16, 2014: Journal of Physical Chemistry. B
Károly Mazák, Consuelo N Beecher, Márta Kraszni, Cynthia K Larive
The main sites of calcium binding were determined for the low molecular weight heparin drug enoxaparin and the synthetic pentasaccharide Arixtra (fondaparinux). [(1)H,(13)C] HSQC pH titrations were carried out to characterize the acid-base properties of these samples both in the presence and absence of calcium. The differences in the titration curves were used to determine the structural components of enoxaparin and fondaparinux responsible for Ca(2+) binding. In enoxaparin both unsubstituted and 2-O-sulfated iduronic acid residues are important in calcium binding and the presence of the 2-O-sulfo group does not seem to influence the Ca(2+) binding capability of the iduronate ring...
January 30, 2014: Carbohydrate Research
Rongrong Huang, Jian Liu, Joshua S Sharp
As members of the glycosaminoglycan (GAG) family, heparin and heparan sulfate (HS) are responsible for mediation of a wide range of essential biological actions, most of which are mediated by specific patterns of modifications of regions of these polysaccharides. To fully understand the regulation of HS modification and the biological function of HS through its interactions with protein ligands, it is essential to know the specific HS sequences present. However, the sequencing of mixtures of HS oligosaccharides presents major challenges due to the lability of the sulfate modifications, as well as difficulties in separating isomeric HS chains...
June 18, 2013: Analytical Chemistry
K Hartung, F Meyer, F Bock, B Isermann
BACKGROUND: Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e...
February 2014: Zentralblatt Für Chirurgie
L Carlucci, M De Pomerol, D Laguerre, E Gimbert, M Dautheribes, F San-Galli, D Liguoro, M Le-Gall, J-R Vignes
BACKGROUND AND PURPOSE: Antithrombotic (anticoagulants and antiplatelets) are responsible for iatrogenic accidents, with a specific impact in neurosurgery. Bleeding complications are the most common and best-known. But the link to antiplatelet or to dual association of antithrombotic treatment with intracranial haemorrhage is not complete yet. We studied the proportion of patients under antithrombotic treatment, when an intracranial hemorrhage occurred, as well as the morbi-mortality of each group of patients (with or without antithrombotic treatment)...
February 2013: Neuro-Chirurgie
Xianxuan Zhou, Lingyun Li, Robert J Linhardt, Jian Liu
Heparin has been the most commonly used anticoagulant drug for nearly a century. The drug heparin is generally categorized into three forms according to its molecular weight: unfractionated (UF, average molecular weight 13 000), low molecular weight (average molecular weight 5000) and ultra-low-molecular-weight heparin (ULMWH, average molecular weight 2000). An overdose of heparin may lead to very dangerous bleeding in patients. Protamine sulfate may be administered as an antidote to reverse heparin's anticoagulant effect...
May 2013: FEBS Journal
Derek J Langeslay, Robert P Young, Szabolcs Beni, Consuelo N Beecher, Leonard J Mueller, Cynthia K Larive
Sulfamate groups (NHSO(3)(-)) are important structural elements in the glycosaminoglycans (GAGs) heparin and heparan sulfate (HS). In this work, proton nuclear magnetic resonance (NMR) line-shape analysis is used to explore the solvent exchange properties of the sulfamate NH groups within heparin-related mono-, di-, tetra- and pentasaccharides as a function of pH and temperature. The results of these experiments identified a persistent hydrogen bond within the Arixtra (fondaparinux sodium) pentasaccharide between the internal glucosamine sulfamate NH and the adjacent 3-O-sulfo group...
September 2012: Glycobiology
Iwao Suzuki, Yasushi Ozeki
No abstract text is available yet for this article.
March 2012: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
Derek J Langeslay, Szabolcs Beni, Cynthia K Larive
Recently, experimental conditions were presented for the detection of the N-sulfoglucosamine (GlcNS) NHSO(3)(-) or sulfamate (1)H and (15)N NMR resonances of the pharmaceutically and biologically important glycosaminoglycan (GAG) heparin in aqueous solution. In the present work, we explore further the applicability of nitrogen-bound proton detection to provide structural information for GAGs. Compared to the detection of (15)N chemical shifts of aminosugars through long-range couplings using the IMPACT-HNMBC pulse sequence, the more sensitive two-dimensional (1)H-(15)N HSQC-TOCSY experiments provided additional structural data...
March 2012: Journal of Magnetic Resonance
A V Potekhina, T I Arefieva, T L Krasnikova, S I Provatorov, V P Masenko, M K Osyaeva, E A Noeva
The time course of inflammatory reaction markers in the blood of patients with unstable angina was studied during therapy including arixtra. Plasma concentration of monocytic chemotaxic protein-1 (MCP-1) decreased on days 2 and 3 in patients receiving arixtra and a trend to an increase in MCP-1 concentration was observed on day 7 after the drug was discontinued. After 1 month, MCP-1 level decreased in all patients. The concentration of highly sensitive C-reactive protein also decreased 1 month after the disease onset; no changes in the concentrations of IL-8 and IL-2 receptor α-subunit were detected during these periods...
March 2011: Bulletin of Experimental Biology and Medicine
Chirag Modi, Dhaval Satani, Kelly L Cervellione, Jose Cervantes, Jonas Gintautas
Heparin is the most commonly used anticoagulant drug for prevention and treatment of thromboembolic diseases. Heparin-induced thrombocytopenia (HIT) is a well-known and potentially fatal side-effect of heparin therapy. HIT type 1 (HIT-1) is transient and relatively common; it usually develops within 1-7 days of initial heparin exposure. Type 2 HIT (HIT-2) is more severe and is associated with thrombocytopenia and thrombosis. HIT-2 usually develops 5 or more days after initial heparin exposure. It is an immune-mediated disorder that is presumably caused by development of platelet activating antibody against platelet factor 4 (PF4)/heparin complex...
2009: Proceedings of the Western Pharmacology Society
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