Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
Forced degradation study of argatroban under conditions of hydrolysis(neutral, acidic and alkaline), oxidation,photolysis and thermal stress, as suggested in the ICH Q1 A(R2), was accomplished. The drug showed signifi...Forced degradation study of argatroban under conditions of hydrolysis(neutral, acidic and alkaline), oxidation,photolysis and thermal stress, as suggested in the ICH Q1 A(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,^(13)C NMR, 2 D NMR, Q-TOF-MSnand IR spectral analysis and the proposed degradation products structures were further confirmed by the individual synthesis.展开更多
BACKGROUND Argatroban is a novel direct thrombin inhibitor that has been used for treatment of acute ischemic stroke(AIS).To our knowledge,no systematic analysis has assessed the efficacy and safety of argatroban for ...BACKGROUND Argatroban is a novel direct thrombin inhibitor that has been used for treatment of acute ischemic stroke(AIS).To our knowledge,no systematic analysis has assessed the efficacy and safety of argatroban for treatment of AIS.AIM To evaluate the efficacy and safety of argatroban for treatment of AIS.METHODS Cochrane Library,Medline,PubMed,and Web of Science were searched to retrieve all studies associated with argatroban and AIS.Effective rate,adverse events rate,and 95%confidence intervals were calculated and pooled using metaanalysis methodology.RESULTS We only found four randomized controlled studies,comprising 354 cases with 213 in the argatroban group and 141 in the control group.Great heterogeneity was found in the four studies(c2=11.44,I2=74%,P=0.01).Subgroup analysis could not be performed because of the absence of detailed data.The two most recent studies showed acceptable heterogeneity(c2=1.56,I2=36%,P=0.21).Our analysis showed that argatroban was not more effective than the control therapy in the acute phase of ischemic stroke(Z=0.01,P=0.99).Argatroban did not increase the risk of bleeding compared with the control group(c2=0.37,I2=0%,P=0.54,Z=0.80,P=0.42).CONCLUSION Patients with AIS might not benefit from argatroban and combination therapy with argatroban does not increase bleeding tendency.展开更多
Objective: Analyze the effect of argatroban on neurological function in patients with acute cerebral infarction and explore its possible mechanisms. Methods: From August 2015 to August 2017, 140 patients with acute ce...Objective: Analyze the effect of argatroban on neurological function in patients with acute cerebral infarction and explore its possible mechanisms. Methods: From August 2015 to August 2017, 140 patients with acute cerebral infarction who were admitted to the Department of Neurology in our hospital were divided into a control group and an observation group according to the lottery method, with 70 cases in each group. Patients in the conventional group received routine treatment. Patients in the treatment group received routine treatment plus argatroban. The changes of neurological function, coagulation function and inflammatory factors were observed in the two groups. Result: Before treatment, there were no significant differences in neurological function parameters, coagulation function indexes and inflammatory factors between the two groups. After treatment, the neurological function indexes NT-proBNP, NPY and S-100β levels, coagulation function index FIB level, inflammatory factor indicators MMP-9, Lp-PLA2 and Hcy, vascular endothelial function index ET levels decreased, coagulation Functional indicators PT, TT and APTT are both elevated, and NO and CGRP levels are elevated. The levels of NT-proBNP, NPY and S-100β, FIB level, MMP-9, Lp-PLA2 and Hcy, ET levels in the treatment group were lower than those in the conventional group, while the levels of PT, TT and APTT levels, and NO and CGRP levels were higher than the conventional group. Conclusion: Argatroban treatment can significantly improve neurological function in patients with acute cerebral infarction. The possible mechanism is to improve coagulation function, vascular endothelial function and relieve inflammatory stress response.展开更多
Argatroban is an intravenous DTI （direct synthetic thrombin inhibitor） that is not routinely used for anticoagulation; thus, expertise surrounding its use is very limited. Therefore, this case reviews an unusually h...Argatroban is an intravenous DTI （direct synthetic thrombin inhibitor） that is not routinely used for anticoagulation; thus, expertise surrounding its use is very limited. Therefore, this case reviews an unusually high argatroban infusion rate, which was needed to prevent further emboli formation in a patient. In this case, a 61-year-old Caucasian male patient exhibited heparin resistance during an intraoperative vascular procedure as measured by activated clotting time and PTT （partial thromboplastin time）. The patient had multiple occlusions in his right lower extremities and underwent embolectomies of the right popliteal and posterior tibial arteries. The clinical pharmacist was consulted to manage the argatroban infusion once heparin was discontinued. The therapeutic window required a PTr of 1.5-3 times the patient baseline （35-75 s）. The patient was reported to be 89 kg with a baseline PTT of 24.7 s and INR （international normalized ratio） of 0.98. The starting dose ofargatroban was initiated by the pharmacist at 2 mcg/kg/min （10.7 mL/h） as the patient did not have hepatic failure or sepsis. The patient was maintained on argatroban in the therapeutic PTT window for more than 72 h; however, frequent and aggressive dose increases, to a final rate of 7.5 mcg/kg/min （40 mL/h）, were needed to maintain the therapeutic PTT level. From the case, the cause of heparin resistance still has not been determined despite a hematologic work-up; however, this patient required an unusually high infusion rate of argatroban to maintain a therapeutic PTT during the hospital course before being changed to an anticoagulation regimen for discharge.展开更多
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.
文摘Forced degradation study of argatroban under conditions of hydrolysis(neutral, acidic and alkaline), oxidation,photolysis and thermal stress, as suggested in the ICH Q1 A(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,^(13)C NMR, 2 D NMR, Q-TOF-MSnand IR spectral analysis and the proposed degradation products structures were further confirmed by the individual synthesis.
文摘BACKGROUND Argatroban is a novel direct thrombin inhibitor that has been used for treatment of acute ischemic stroke(AIS).To our knowledge,no systematic analysis has assessed the efficacy and safety of argatroban for treatment of AIS.AIM To evaluate the efficacy and safety of argatroban for treatment of AIS.METHODS Cochrane Library,Medline,PubMed,and Web of Science were searched to retrieve all studies associated with argatroban and AIS.Effective rate,adverse events rate,and 95%confidence intervals were calculated and pooled using metaanalysis methodology.RESULTS We only found four randomized controlled studies,comprising 354 cases with 213 in the argatroban group and 141 in the control group.Great heterogeneity was found in the four studies(c2=11.44,I2=74%,P=0.01).Subgroup analysis could not be performed because of the absence of detailed data.The two most recent studies showed acceptable heterogeneity(c2=1.56,I2=36%,P=0.21).Our analysis showed that argatroban was not more effective than the control therapy in the acute phase of ischemic stroke(Z=0.01,P=0.99).Argatroban did not increase the risk of bleeding compared with the control group(c2=0.37,I2=0%,P=0.54,Z=0.80,P=0.42).CONCLUSION Patients with AIS might not benefit from argatroban and combination therapy with argatroban does not increase bleeding tendency.
文摘Objective: Analyze the effect of argatroban on neurological function in patients with acute cerebral infarction and explore its possible mechanisms. Methods: From August 2015 to August 2017, 140 patients with acute cerebral infarction who were admitted to the Department of Neurology in our hospital were divided into a control group and an observation group according to the lottery method, with 70 cases in each group. Patients in the conventional group received routine treatment. Patients in the treatment group received routine treatment plus argatroban. The changes of neurological function, coagulation function and inflammatory factors were observed in the two groups. Result: Before treatment, there were no significant differences in neurological function parameters, coagulation function indexes and inflammatory factors between the two groups. After treatment, the neurological function indexes NT-proBNP, NPY and S-100β levels, coagulation function index FIB level, inflammatory factor indicators MMP-9, Lp-PLA2 and Hcy, vascular endothelial function index ET levels decreased, coagulation Functional indicators PT, TT and APTT are both elevated, and NO and CGRP levels are elevated. The levels of NT-proBNP, NPY and S-100β, FIB level, MMP-9, Lp-PLA2 and Hcy, ET levels in the treatment group were lower than those in the conventional group, while the levels of PT, TT and APTT levels, and NO and CGRP levels were higher than the conventional group. Conclusion: Argatroban treatment can significantly improve neurological function in patients with acute cerebral infarction. The possible mechanism is to improve coagulation function, vascular endothelial function and relieve inflammatory stress response.
文摘Argatroban is an intravenous DTI （direct synthetic thrombin inhibitor） that is not routinely used for anticoagulation; thus, expertise surrounding its use is very limited. Therefore, this case reviews an unusually high argatroban infusion rate, which was needed to prevent further emboli formation in a patient. In this case, a 61-year-old Caucasian male patient exhibited heparin resistance during an intraoperative vascular procedure as measured by activated clotting time and PTT （partial thromboplastin time）. The patient had multiple occlusions in his right lower extremities and underwent embolectomies of the right popliteal and posterior tibial arteries. The clinical pharmacist was consulted to manage the argatroban infusion once heparin was discontinued. The therapeutic window required a PTr of 1.5-3 times the patient baseline （35-75 s）. The patient was reported to be 89 kg with a baseline PTT of 24.7 s and INR （international normalized ratio） of 0.98. The starting dose ofargatroban was initiated by the pharmacist at 2 mcg/kg/min （10.7 mL/h） as the patient did not have hepatic failure or sepsis. The patient was maintained on argatroban in the therapeutic PTT window for more than 72 h; however, frequent and aggressive dose increases, to a final rate of 7.5 mcg/kg/min （40 mL/h）, were needed to maintain the therapeutic PTT level. From the case, the cause of heparin resistance still has not been determined despite a hematologic work-up; however, this patient required an unusually high infusion rate of argatroban to maintain a therapeutic PTT during the hospital course before being changed to an anticoagulation regimen for discharge.
