- Evaluation of anticoagulant agents for the treatment of human metapneumovirus infection in mice. [Journal Article]
- JGJ Gen Virol 2018 Aug 10
- Thrombin has been demonstrated to be involved in several viral diseases including human metapneumovirus (hMPV) infections. We previously showed that immediate administration of thrombin inhibitor arg...
Thrombin has been demonstrated to be involved in several viral diseases including human metapneumovirus (hMPV) infections. We previously showed that immediate administration of thrombin inhibitor argatroban post-infection protected mice against hMPV disease. This current work aims at determining whether warfarin and heparin, two other anticoagulants inhibiting thrombin formation and activities, may also be used for treatment against hMPV in vivo. We found that immediate injections of argatroban, warfarin or heparin after virus challenge protected mice against hMPV infection, as evidenced by decreased or no mortality, less weight loss, reduced viral load and attenuated inflammation. However, delayed treatments starting 1 day post-infection with argatroban or warfarin almost did not impact the survival whereas delayed treatment with heparin induced an increased mortality during infection. Moreover, these treatments also did not reduce weight loss, viral replication and inflammation. In agreement with these results, thrombin generation was decreased upon immediate anticoagulant treatments but was unaltered upon delayed treatments. Thus, thrombin generation occurs at the onset of hMPV infection and thrombin inhibition may be only useful for the treatment of this disease when initiated in the early stage. In this case, heparin is not recommended because of its reduced efficacy on mortality in infected mice whereas argatroban and warfarin appear as safe and effective drugs for the treatment of hMPV disease. The antiviral and anti-inflammatory effects of argatroban occur via thrombin-dependent pathways whereas the mechanisms by which warfarin exerts its beneficial effects against hMPV infection were not elucidated and need to be further studied.
- Small-Volume Flow Cytometry-Based Multiplex Analysis of the Activity of Small GTPases. [Journal Article]
- MMMethods Mol Biol 2018; 1821:177-195
- Small, monomeric guanine triphosphate hydrolases (GTPases) are ubiquitous cellular integrators of signaling. A signal activates the GTPase, which then binds to an effector molecule to relay a signal ...
Small, monomeric guanine triphosphate hydrolases (GTPases) are ubiquitous cellular integrators of signaling. A signal activates the GTPase, which then binds to an effector molecule to relay a signal inside the cell. The GTPase effector trap flow cytometry assay (G-Trap) utilizes bead-based protein immobilization and dual-color flow cytometry to rapidly and quantitatively measure GTPase activity status in cell or tissue lysates. Beginning with commercial cytoplex bead sets that are color-coded with graded fluorescence intensities of a red (700 nm) wavelength, the bead sets are derivatized to display glutathione on the surface through a detailed protocol described here. A different glutathione-S-transferase-effector protein (GST-effector protein) can then be attached to the surface of each set. For the assay, users can incubate bead sets individually or in a multiplex format with lysates for rapid, selective capture of active, GTP-bound GTPases from a single sample. After that, flow cytometry is used to identify the bead-borne GTPase based on red bead intensity, and the amount of active GTPase per bead is detected using monoclonal antibodies conjugated to a green fluorophore or via labeled secondary antibodies. Three examples are provided to illustrate the efficacy of the effector-functionalized beads for measuring the activation of at least five GTPases in a single lysate from fewer than 50,000 cells.
- Argatroban plus aspirin versus aspirin in acute ischemic stroke. [Journal Article]
- NRNeurol Res 2018 Jul 27; :1-6
- CONCLUSIONS: Argatroban is effective and safe for the treatment of moderate AIS with similar efficacy to high-dose aspirin in the acute phase of AIS, although no additional benefit on short-term outcome was observed. For patients with mild AIS, argatroban may be inferior to high-dose aspirin.
- Treatment of refractory delayed onset heparin-induced thrombocytopenia after thoracic endovascular aortic repair with intravenous immunoglobulin (IVIG). [Journal Article]
- RPRes Pract Thromb Haemost 2017; 1(1):134-137
- Argatroban administration as therapy for thrombosis in patients with continuous-flow ventricular assist devices. [Journal Article]
- JTJ Thorac Dis 2018; 10(Suppl 15):S1720-S1727
- CONCLUSIONS: Argatroban appears to be an alternative to other pharmacological treatment options in VAD thrombosis. Efficacy and safety characteristics are acceptable, but further investigation on larger populations is necessary.
- An infrequent complication of a not so infrequent disease. Hit by HIT. [Journal Article]
- ACAsian Cardiovasc Thorac Ann 2018 Jan 01; :218492318791076
- Heparin-induced thrombocytopenia is not uncommon in cardiac surgery. Thrombosis is the most frequent complication. A 77-year-old man suffered cardiac arrest due to right coronary emboli. Transesophag...
Heparin-induced thrombocytopenia is not uncommon in cardiac surgery. Thrombosis is the most frequent complication. A 77-year-old man suffered cardiac arrest due to right coronary emboli. Transesophageal echocardiography revealed tissue valve thrombosis. He required support with an extracorporeal membrane oxygenator that also thrombosed. Heparin-induced thrombocytopenia was diagnosed, and anticoagulation was switched to argatroban. Heparin- induced thrombocytopenia normally presents as vascular thrombosis. In this case, the first symptom was tissue valve thrombosis causing an acute coronary syndrome. It is not an uncommon complication and should be considered if unexpected thrombosis and a sudden drop in platelet count develops after heparin exposure.
- Comparison of argatroban and fondaparinux for the management of patients with isolated heparin-induced thrombocytopenia. [Journal Article]
- AHAnn Hematol 2018 Jul 12
- Heparin-induced thrombocytopenia (HIT) is a serious complication of the administration of heparin and its derivatives. Non-heparin anticoagulants such as argatroban and fondaparinux are widely used i...
Heparin-induced thrombocytopenia (HIT) is a serious complication of the administration of heparin and its derivatives. Non-heparin anticoagulants such as argatroban and fondaparinux are widely used in the management of HIT to compare the effectiveness of argatroban and fondaparinux in the resolution of thrombocytopenia and to compare clinical outcomes in patients with isolated HIT. A retrospective cohort analysis was performed at King Abdulaziz Medical City (KAMC) on patients diagnosed with isolated HIT between 31 Jan, 2014 and 30 June, 2017. Demographics data, non-heparin anticoagulants, related laboratory results, and clinical outcomes were retrieved and analysed. The cohort comprised a total of 95 adult patients who received either argatroban (56 patients) or fondaparinux (39 patients) for isolated HIT. The median age and sex distribution were similar in both argatroban and fondaparinux groups. The mean (+ SD) time (in days) for the resolution of thrombocytopenia was 3.5 (± 1.8) for patients who received argatroban and 3.7 (± 1.7) for patients administered fondaparinux (p = 0.843). Thromboembolic events occurred in five patients (8.9%) administered argatroban and in three patients (7.7%) administered fondaparinux (p = 0.382). There was no significant difference in the rates of bleeding or death (p = 0.829); however, the small number of cases limits our ability to draw conclusions about these outcomes. In this retrospective study, fondaparinux and argatroban were similarly effective in resolving thrombocytopenia, preventing further thromboembolic events, and maintaining safety in patients with confirmed HIT. To confirm this observation, larger prospective studies are needed.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- If argatroban is required by the mother, it is not a reason to discontinue breastfeeding, but because no information is available on the use of argatroban during breastfeeding, an alternate drug is p...
If argatroban is required by the mother, it is not a reason to discontinue breastfeeding, but because no information is available on the use of argatroban during breastfeeding, an alternate drug is preferred.
- Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study. [Journal Article]
- MCMol Cell Biochem 2018 Jul 03
- Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favour...
Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.
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- Self-assembled, bivalent aptamers on graphene oxide as an efficient anticoagulant. [Journal Article]
- BSBiomater Sci 2018 May 29
- Graphene oxide (GO) has unique structural properties, can effectively adsorb single-strand DNA through π-π stacking, hydrogen bonding and hydrophobic interactions, and is useful in many biotechnology...
Graphene oxide (GO) has unique structural properties, can effectively adsorb single-strand DNA through π-π stacking, hydrogen bonding and hydrophobic interactions, and is useful in many biotechnology applications. In this study, we developed a thrombin-binding-aptamers (15- and 29-mer) conjugated graphene oxide (TBA15/TBA29-GO) composite for the efficient inhibition of thrombin activity towards the formation of fibrin from fibrinogen. The TBA15/TBA29-GO composite was simply obtained by the self-assembly of TBA15/TBA29 hybrids on GO. The high density and appropriate orientation of TBA15/TBA29 on the GO surface enabled TBA15/TBA29-GO to acquire an ultrastrong binding affinity for thrombin (dissociation constant = 2.9 × 10-12 M). Compared to bivalent TBA15h20A20/TBA29h20A20 hybrids, the TBA15/TBA29-GO composite exhibited a superior anticoagulant potency (ca. 10-fold) against thrombin-mediated coagulation as a result of steric blocking effects and a higher binding affinity for thrombin. In addition, the prolonged thrombin clotting time, prothrombin time (PT), and activated partial thromboplastin time (aPTT) of TBA15/TBA29-GO were at least 2 times longer than those of commercially available drugs (heparin, argatroban, hirudin, and warfarin). The in vitro cytotoxicity and hemolysis analyses revealed the high biocompatibility of TBA15/TBA29-GO. The rat-tail bleeding assay of the hemostasis time and ex vivo PT and aPTT further revealed that TBA15/TBA29-GO is superior (>2-fold) to heparin, which is commonly used in the treatment and prevention of thrombotic diseases. Our multivalent, oligonucleotide-modified GO nanocomposites are easy to prepare, cost-effective, and highly biocompatible and they show great potential as effective anticoagulants for the treatment of thrombotic disorders.