- [Safety of Dual Antiplatelet Therapy with Argatroban in Patients with Acute Ischemic Stroke]. [Journal Article]
- BNBrain Nerve 2018; 70(5):557-562
- To prevent early neurological worsening or recurrence in stroke patients with intracranial arterial stenosis or branch atheromatous disease, aggressive antithrombotic therapy, such as dual antiplatel...
To prevent early neurological worsening or recurrence in stroke patients with intracranial arterial stenosis or branch atheromatous disease, aggressive antithrombotic therapy, such as dual antiplatelet therapy (DAPT) with or without anticoagulant therapy, is warranted. Such an aggressive antithrombotic therapy, however, may increase the bleeding risk. We studied the risks of DAPT with the anticoagulant argatroban in patients with acute ischemic stroke or transient ischemic attack (TIA). Between October 2011 and September 2015, 341 patients with stroke or TIA, who received DAPT with argatroban within 48 hours after onset, were retrospectively studied. The endpoint was any bleeding event during hospitalization or 30 days after admission. Median duration of DAPT was 12 days, and 66% of the patients received intravenous heparin (median duration, 5 days) following argatroban. No symptomatic intracerebral hemorrhages were observed, while severe, moderate, and mild extracranial hemorrhages occured in one (0.3%), three (0.9%), and four (1.2%) patients, respectively. In conclusion, DAPT with argatroban can be safely administered to patients with acute ischemic stroke or TIA. (Received July 24, 2017; Accepted January 15, 2018; Published May 1, 2018).
- Evaluation of thrombin inhibitory activity of catechins by online capillary electrophoresis-based immobilized enzyme microreactor and molecular docking. [Journal Article]
- TTalanta 2018 Aug 01; 185:16-22
- An online capillary electrophoresis (CE)-based thrombin (THR) immobilized enzyme microreactor (IMER) method was established to screen THR inhibitors in this study. S-2366 was used as chromogenic subs...
An online capillary electrophoresis (CE)-based thrombin (THR) immobilized enzyme microreactor (IMER) method was established to screen THR inhibitors in this study. S-2366 was used as chromogenic substrate for determination of THR activity and other kinetic constants. After continuously run for 50 times, the prepared IMER could still remain 89% of the initial immobilized enzyme activity. The Michaelis-Menten constant (Km) of immobilized THR was measured as 0.514 mmol/L and the half-maximal inhibitory concentration (IC50) and inhibition constant (Ki) of argatroban on THR were determined as 78.07 and 26.53 nmol/L, respectively, which indicated that CE-based THR IMER was successfully established and could be applied to screen THR inhibitors. Then the prepared IMER was used to investigate the inhibitory potency on THR of four main catechins in green tea including epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG). The results showed that ECG and EGCG had good THR inhibition activity and their inhibition rates at concentration of 200 μmol/L were 53.2 ± 3.8% and 55.8 ± 2.6%, respectively, which was in consistent with the results of microplate reader assay. Additionally, molecular docking results showed that the benzopyran groups of ECG and EGCG were inserted into the THR active pocket and interacted with residues LYS60F, TRP60D, TRY60A, IEU99, GLY216, HIS57 and SER195, but EC and EGC did not. Therefore, the developed CE-based THR IMER is reliable method for measuring THR inhibitory activity of natural inhibitors.
- Synthesis and biocompatibility of an argatroban-modified polysulfone membrane that directly inhibits thrombosis. [Journal Article]
- JMJ Mater Sci Mater Med 2018 May 09; 29(5):66
- Anticoagulation therapy plays a vital role in the prevention of blood clot formation during hemodialysis and hemofiltration, especially for critical care patients. Here, we synthesized a novel argatr...
Anticoagulation therapy plays a vital role in the prevention of blood clot formation during hemodialysis and hemofiltration, especially for critical care patients. Here, we synthesized a novel argatroban (Arg)-modified polysulfone (PSf) membrane for anticoagulation. Arg was grafted onto the PSF membrane via chemical modification to increase membrane hydrophilicity. Protein adsorption, coagulation, as well as activation of platelets and complement systems were greatly reduced on the Arg-modified PSf membrane. Thus, the recalcification time and the activated partial thrombin time (APTT) were increased after the modification. In comparison with the pristine PSf membrane, the Arg-modified PSf membrane showed better hemocompatibility and anticoagulation properties, indicating its potential for applications in hemodialysis and hemofiltration. Modification of the PSf membrane has been investigated in attempts to further enhance the anticoagulation properties of the hemodialysis membranes, including a heparin-modified PSf membrane. However, heparin can inhibit plasma-free thrombin, and cause the occurrence of heparin-induced thrombocytopenia (HIT), which increases the risk of bleeding during dialysis in critical care patients. To address this problem, we modified PSf membrane with as a novel direct thrombin inhibitors, argatroban (Arg). It can reversibly bind to thrombin, inhibiting not only the plasma-free thrombin in the blood, but also clot-bound thrombin.
- Investigation of Interactions between Thrombin and Ten Phenolic Compounds by Affinity Capillary Electrophoresis and Molecular Docking. [Journal Article]
- JAJ Anal Methods Chem 2018; 2018:4707609
- Thrombin plays a vital role in blood coagulation, which is a key process involved in thrombosis by promoting platelet aggregation and converting fibrinogen to form the fibrin clot. In the receptor co...
Thrombin plays a vital role in blood coagulation, which is a key process involved in thrombosis by promoting platelet aggregation and converting fibrinogen to form the fibrin clot. In the receptor concept, drugs produce their therapeutic effects via interactions with the targets. Therefore, investigation of interaction between thrombin and small molecules is important to find out the potential thrombin inhibitor. In this study, affinity capillary electrophoresis (ACE) and in silico molecular docking methods were developed to study the interaction between thrombin and ten phenolic compounds (p-hydroxybenzoic acid, protocatechuic acid, vanillic acid, gallic acid, catechin, epicatechin, dihydroquercetin, naringenin, apigenin, and baicalein). The ACE results showed that gallic acids and six flavonoid compounds had relative strong interactions with thrombin. In addition, the docking results indicated that all of optimal conformations of the six flavonoid compounds were positioned into the thrombin activity centre and had interaction with the HIS57 or SER195 which was the key residue to bind thrombin inhibitors such as argatroban. Herein, these six flavonoid compounds might have the potential of thrombin inhibition activity. In addition, the developed method in this study can be further applied to study the interactions of other molecules with thrombin.
- Novel degradation products of argatroban: Isolation, synthesis and extensive characterization using NMR and LC-PDA-MS/Q-TOF. [Journal Article]
- JPJ Pharm Anal 2018; 8(2):86-95
- Forced degradation study of argatroban under conditions of hydrolysis (neutral, acidic and alkaline), oxidation, photolysis and thermal stress, as suggested in the ICH Q1A (R2), was accomplished. The...
Forced degradation study of argatroban under conditions of hydrolysis (neutral, acidic and alkaline), oxidation, photolysis and thermal stress, as suggested in the ICH Q1A (R2), was accomplished. The drug showed significant degradation under hydrolysis (acidic, alkaline) and oxidation (peroxide stress) conditions. The drug remained stable under thermal and photolytic stress conditions. In total, seven novel degradation products (DP-1 to DP-7) were found under diverse conditions, which were not reported earlier. The chemical structures of these degradation products were characterized by 1H NMR, 13C NMR, 2D NMR, Q-TOF-MSn and IR spectral analysis and the proposed degradation products structures were further confirmed by the individual synthesis.
- Argatroban is stable in citrated whole blood for 24 hours. [Journal Article]
- IJInt J Lab Hematol 2018 Apr 29
- CONCLUSIONS: This study proposes that patients receiving treatment in hospitals who cannot provide a dedicated argatroban plasma concentration method could have their samples sent on whole blood within 24 hours of venepuncture to a laboratory who could provide the test.
- Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke. [Journal Article]
- JSJ Stroke Cerebrovasc Dis 2018 Apr 26
- CONCLUSIONS: Argatroban therapy was not superior to control with ozagrel therapy in acute noncardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.
- Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition. [Journal Article]
- THThromb Haemost 2018 Apr 03
- CONCLUSIONS: Targeting staphylothrombin with DTIs is feasible in a subset of S. aureus bacteraemic patients, with comparable safety to standard thromboprophylaxis. In future studies of staphylothrombin inhibition, feasibility can be further improved by rapid diagnostics and by strategies without concomitant anticoagulant effect.
- Heparin-Induced Thrombocytopenia in Infants after Heart Surgery. [Journal Article]
- TCThorac Cardiovasc Surg 2018 Apr 01
- CONCLUSIONS: Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study.
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- Anticoagulation Management during First Five Days of Infant-Pediatric Extracorporeal Life Support. [Journal Article]
- JEJ Extra Corpor Technol 2018; 50(1):30-37
- Anticoagulation during infant-pediatric extracorporeal life support (ECLS) has been a topic of study for many years, but management of anticoagulation is still only partially understood. Adequate ant...
Anticoagulation during infant-pediatric extracorporeal life support (ECLS) has been a topic of study for many years, but management of anticoagulation is still only partially understood. Adequate anticoagulation during ECLS is imperative for successful outcomes and understanding the individual variables that play part is crucial for properly implementing anticoagulation management strategies. The purpose of our study was to compare the relationships between the variables of activated partial thromboplastin time (aPTT), activated clotting time, international normalized ratio, bleeding, thrombus formation, kaolin + heparinase thromboelastograph alpha angle, kaolin thromboelastograph reaction time (KTEG R-time), heparin dose rates (HDR), antithrombin (AT), anti-Xa, bivalirudin dose rate, argatroban dose rate, interventions, and transfusions. We hypothesized that the relationship between measures of anticoagulation would be influenced by the AT levels, and a therapeutic aPTT (60-80 seconds) could be achieved by increasing, or maintaining, the overall AT above a specific threshold for infant-pediatric patients on ECLS. Thirty-five infant-pediatric patients underwent ECLS between January 2013 and January 2016. The median age was 39 days with an average weight of 3.9 ± 4.3 kg. ECLS parameters collected at least every 24 hours for the first five ECLS days. Parameters recorded by retrospective chart review were analyzed using linear regression and receiver operator characteristic (ROC) analysis. We were unable to report a significant correlation between optimal aPTT and HDR at various AT levels. However, ROC analysis suggested that to maintain an aPTT above 60 seconds, an AT threshold of 42% or higher was observed when the HDR was >12 U/kg/h ROC analysis also determined that no thrombus was associated with an aPTT >64 seconds and decreased bleeding was associated with a KTEG R-time below 30 minutes. Based on these findings, we report multiple correlations that may help develop future standardized infant-pediatric ECLS anticoagulation protocols.