idraparinux sodium (SANORG 34006) / Sanofi - LARVOL DELTA

Effects on mortality of extended versus short-term anticoagulation in venous thromboembolism: a systematic review and meta-analysis of randomized trials. (PubMed, Res Pract Thromb Haemost) - "One study used idraparinux and the others used vitamin K antagonists...Extended anticoagulation has no benefit on overall mortality compared with short-term treatment. However, subgroup analysis shows a benefit of DOACs that reduces overall mortality, contrary to vitamin K antagonists.."

Journal • Retrospective data • Cardiovascular • Hematological Disorders • Respiratory Diseases • Venous Thromboembolism

Interactions of heparin derivatives with recombinant human keratinocyte growth factor: structural stability and bioactivity effect study. (PubMed, Proteins) - "Because FGF7 (KGF) has an important role in tissue repair and maintaining the integrity of the mucosal barrier, recombinant human keratinocyte growth factor (rhKGF, palifermin) has been approved for the treatment of wound healing and oral cavity...The result showed that rhKGF-Idraparinux (-6.9 kcal/mol) and rhKGF-Heparin (-6.0 kcal/mol) complexes had significant binding affinity as well as they had a more stable binding to rhKGF than to other LMWH during 100 ns simulation...The result showed that rhKGF-Idraparinux (-6.9 kcal/mol) and rhKGF-Heparin (-6.0 kcal/mol) complexes had significant binding affinity as well as they had a more stable binding to rhKGF than to other LMWH during 100 ns simulation. However, in order to confirm the curative effect of these drugs, clinical trials must be done."

Journal • FGF7

Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity. (PubMed, J Org Chem) - "In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity...The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of l-iduronic acid."

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Anticoagulants as Potential SARS-CoV-2 M Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies. (PubMed, Int J Mol Sci) - "Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 M. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds...Interestingly, promising SARS-CoV-2 M inhibitory potential was attained for fondaparinux sodium with an IC value of 2.36 µM, surpassing the reference tipranavir (IC = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 M inhibitory potential was attained for dabigatran with an IC value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Conformational Analysis of Heparin-Analogue Pentasaccharides by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulations. (PubMed, J Chem Inf Model) - "In this study, we performed conformational analysis using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations on the heparin pentasaccharide analogue idraparinux, its disulfonatomethyl analogue, which features a slightly improved blood coagulation property, and a trisulfonatomethyl analogue, in which the activity has been totally abolished...Both G and E ring flips are also accompanied by changes along the interglycosidic linkages, which take place highly synchronously with the ring flips. These findings indicate that conformational plasticity of the G ring and the dominance of the S skewed boat populations do not necessarily warrant the biological activity of the derivatives and hence the impact of other factors also needs to be considered."

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Comparison of carbohydrate force fields using Gaussian Accelerated Molecular Dynamics simulations and development of force field parameters for heparin-analogue pentasaccharides. (PubMed, J Chem Inf Model) - "Furthermore, we propose a torsion angle parameter for the sulfonato-methyl group, which was developed for the chosen CHARMM force field using quantum chemical calculations and validated by comparison with NMR data. The work lays down the foundation of using MD simulations to gain insight into the conformational properties of sulfonato-methyl group modified idraparinux derivatives and to understand their structure-activity relationship thus enabling rational design of further modifications."

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An Efficient Modular One-Pot Synthesis of Heparin-Based Anticoagulant Idraparinux. (PubMed, J Am Chem Soc) - "The uronic acid was incorporated in a disaccharide module used in the one-pot synthesis to avoid the complicated late-stage installation of these acidic sugars. The one-pot synthesis of Idraparinux demonstrated here is an effective strategy and should be applicable to the modular assembly of other heparan sulfates with regiodefined sulfation pattern for functional study."

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Immobilisation of an anti-platelet adhesion and anti-thrombotic drug (EP224283) on polydopamine coated vascular stent promoting anti-thrombogenic properties. (PubMed, Mater Sci Eng C Mater Biol Appl) - "In this paper, we aimed to develop a polydopamine (PDA) coated chromium‑cobalt (CoCr) stent functionalised with EP224283 (Endotis Pharma SA), which combines both a GPIIbIIIa antagonist (tirofiban moiety) and a factor Xa inhibitor (idraparinux moiety) to reduce acute stent thrombosis. Interestingly, after seven days of degradation, the anticoagulant activity was persistent in both strategies and looked more important with the strategy 2 than in strategy 1. Throughout this work, we developed an innovative vascular stent through the immobilisation of EP224283 onto CoCr-PDA-PEI-(avidin) system, which provides a promising solution to reduce ISR and thrombosis after stent implantation."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

Predictive abilities of the HAS-BLED and ORBIT bleeding risk scores in non-warfarin anticoagulated atrial fibrillation patients: An ancillary analysis from the AMADEUS trial. (PubMed, Int J Cardiol) - "In this comparison of the HAS-BLED and ORBIT scores in a cohort of non-warfarin anticoagulated patients with AF, we show that the HAS-BLED score more accurately predicted any clinically relevant bleeding amongst patients with AF who were anticoagulated with a non-warfarin anticoagulant, when compared with the ORBIT score."

Journal • Biosimilar

Residual Risk of Stroke and Death in Anticoagulated Patients According to the Type of Atrial Fibrillation: AMADEUS Trial. (PubMed) - "The risk of cardiovascular death, stroke, or systemic embolism is higher in anticoagulated patients with permanent AF than in those with nonpermanent AF, regardless of pre-existing heart failure."

Journal • Acute Coronary Syndrome • Biosimilar • Diabetes • Diabetic Nephropathy • Heart Failure

The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian Accelerated Molecular Dynamics simulations. (PubMed, J Biomol Struct Dyn) - "We were able to observe the binding of the pentasaccharide idraparinux to a "non-activated" AT conformation in two separate trajectories with low root mean square deviation (RMSD) values compared to X-ray structures of the bound state..."Generalized correlation" matrices revealed possible paths of allosteric signal propagation to the binding sites for the target proteases, factor Xa and IXa. Enhanced MD simulations of ligand binding to AT may assist the design of new anticoagulant drugs."

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Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose - Synthesis and conformational analysis. (PubMed, Sci Rep) - "The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable C chair conformation of their 6-deoxy-L-talopyranoside residues."

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A Propensity Score Matched Comparison of Clinical Outcomes in Atrial Fibrillation Patients Taking Vitamin K Antagonists: Comparing the "Real-World" vs Clinical Trials. (PubMed, Mayo Clin Proc) - "This study comparing the Murcia AF Project and the AMADEUS trial demonstrates that there is a great heterogeneity in both populations, which is translated into a higher risk of several adverse outcomes in the real-world cohort, including major bleeding, ischemic stroke, and mortality."

Clinical • Journal • Real-World Evidence