Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a gua...Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a guanine nucleotide exchange factor that is related to microglial activation.However,how Vav1 participates in the inflammato ry response after cerebral ischemia/reperfusion inj ury remains unclea r.In this study,we subjected rats to occlusion and repe rfusion of the middle cerebral artery and subjected the BV-2 mic roglia cell line to oxygen-glucose deprivatio n/reoxygenation to mimic cerebral ischemia/repe rfusion in vivo and in vitro,respectively.We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral arte ry and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation.Silencing Vav1 reduced the cerebral infarct volume and brain water content,inhibited neuronal loss and apoptosis in the ischemic penumbra,and im p roved neurological function in rats subjected to occlusion and repe rfusion of the middle cerebral artery.Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3(NLRP3) inflammasome in the ischemic penumbra,as well as the expression of inflammato ry facto rs.In addition,Vov1 knoc kdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxyge nation.Taken together,these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/repe rfusion through inhibiting the activation of mic roglia and NLRP3 inflammasome.展开更多
Background Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and(+)-borneol,a food additive with an anti-inflammatory effect in animal ischaemic stroke models.This study aims to assess the...Background Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and(+)-borneol,a food additive with an anti-inflammatory effect in animal ischaemic stroke models.This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke(AIS).Methods In this multicentre,randomised,double-blind,multiple-dose,active-controlled,phaseⅡclinical trial,patients with AIS within 48 hours after stroke onset were randomly assigned(1:1:1:1)to low-dose(12.5 mg),medium-dose(37.5 mg)or high-dose(62.5 mg)Edaravone Dexborneol groups,and an active control group with edaravone(30 mg)by 30 min intravenous infusion every 12 hours,for 14 consecutive days.The primary efficacy outcome was the proportion of modified Rankin Scale(mRS)score≤1 at 90 days and National Institutes of Health Stroke Scale(NIHSS)score change from baseline to 14 days after randomisation.The safety outcome included any adverse event during 90 days after treatment.Results Of 385 patients included in the efficacy analysis,94 were randomised to low-dose group,97 to medium-dose group,98 to high-dose group and 96 to the control group.No significant difference was observed among the four groups on mRS score(mRS≤1,p=0.4054)at 90 days or NIHSS score change at 14 days(p=0.6799).However,a numerically higher percentage of patients with mRSscore≤1 at 90 days in the medium-dose(69.39%)and high-dose(65.63%)groups was observed than in the control group(60.64%).No significant difference in severe adverse events was found among the four groups(p=0.3815).Conclusions Compared with edaravone alone,Edaravone Dexborneol was safe and well tolerated at all doses,although no significant improvement in functional outcomes was observed at 90days.展开更多
Background Tenecteplase(TNK)possesses several pharmacological characteristics superior to conventional alteplase(rt-PA),with well-established safety and efficacy profile in Caucasians.There exists controversy over the...Background Tenecteplase(TNK)possesses several pharmacological characteristics superior to conventional alteplase(rt-PA),with well-established safety and efficacy profile in Caucasians.There exists controversy over the optimal dose of intravenous rt-PA for East Asians with acute ischaemic stroke(AIS).Current study aimed to determine the safety dose range of recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)for patients with AIS in China.Methods This multicentre,prospective,randomised,open-label,blinded end-point,phase II study compared three tiers of 0.1,0.25,0.32 mg/kg rhTNK-tPA(to a maximum of 40 mg)with standard 0.9 mg/kg rt-PA(to a maximum of 90 mg)in patients who were eligible for intravenous thrombolysis.The safety outcome were symptomatic intracranial haemorrhage(sICH)within 36 hours.Results Between May 2018 and February 2020,240 patients were randomly assigned to four group,4 of whom did not receive study treatment.The intention-to-treat analysis included 236 patients.There was no difference in the improvement on National Institutes of Health Stroke Scale at day 14 in the 3 tiers and control group(63.3%,77.2%,66.7%vs 62.7%).The number of sICH was 3 of 60(5.0%)in the 0.1 mg/kg group,none in the 0.25 mg/kg group,2 of 60(3.3%)in the 0.32 mg/kg group and 1(1.7%)of 59 in the rt-PA group.There were no significant between-group differences in severe adverse events.Conclusions Similar to the Caucasians,rhTNK-tPA was well tolerated in Chinese patients with AIS at all doses administered within 3 hours of symptom onset.The dose-efficacy profile of rhTNK-tPA needs to be established with future investigations.展开更多
background and purpose Data on the efficacy and safety of alteplase for acute ischaemic stroke(AIS)administered 3-4.5 hours after the onset of stroke symptoms in Chinese patients is limited.We sought to determine whet...background and purpose Data on the efficacy and safety of alteplase for acute ischaemic stroke(AIS)administered 3-4.5 hours after the onset of stroke symptoms in Chinese patients is limited.We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective,multicentre,single-arm trial in China.Materials and methods Eligible AIS patients were given 0.9 mg/kg alteplase intravenously.The primary efficacy endpoint was a favourable outcome at 3 months,defined as a score of 0 or 1 on the modified Rankin Scale.Thresholds for the primary efficacy endpoint were determined to be 40%based on the literature review.The primary safety endpoint was symptomatic intracranial haemorrhage(sICH)according to the European Cooperative Acute Stroke Study III(ECASS III)trial definition.Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching(PSM)method.results A total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study.The median time from onset of symptoms to needle was 3 hours 54 min.The percentage of patients with a favourable outcome was 63.3%(95%CI 54.4 to 71.4),significantly higher than the predefined threshold(p<0.0001).Three patients(2.5%,95%CI 0.5 to 7.1)had sICH,including two fatal sICH.Six patients died within 3 months after treatment.The post hoc PSM analysis showed a numerically higher rate of the primary efficacy endpoint in this study(63.3%)than the matched placebo arm(56.7%)in the ECASS III trial.Conclusions Intravenous alteplase with a standard dose administered between 3 and 4.5 hours after onset of symptoms is effective and safe for Chinese AIS patients.展开更多
Background A recent study shows that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy for minor stroke,which is defined as a National Institutes of Health Stroke Scale(NIHSS)s...Background A recent study shows that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy for minor stroke,which is defined as a National Institutes of Health Stroke Scale(NIHSS)score of≤3.However,acute mild-moderate ischaemic stroke(4≤NIHSS≤10)still needs aggressive antiplatelet intervention to prevent deterioration and recurrence of stroke.The efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy in the population are not clear.A multicentre clinical trial is designed to evaluate the efficacy and safety of clopidogrel plus aspirin therapy versus aspirin monotherapy within 48 hours of symptom onset of mild-moderate ischaemic stroke.Methods/Design The study is a randomised,open-label,multicentre,prospective trial with a target enrolment of 2700 patients from 60 centres in Northeast China.A treatment allocation identification number to each enrolled patient will be provided by a random number generator.The follow-up time for the clopidogrel plus aspirin and aspirin monotherapy groups is 90 days.The primary efficacy endpoint is a stroke progression event,which is defined as≥4 point increase in the NIHSS score in 48 hours.The second efficacy endpoints include new ischaemic stroke within 90 days,change in the NIHSS score within 14 days,modified Rankin Scale score on day 90 and other vascular or death events within 90 days.The safety endpoints include mucocutaneous haemorrhage,organ haemorrhage and intracranial haemorrhage,adverse events and severe adverse events.χ^(2)test,t-test(or Mann-Whitney test),survival analysis and Cox proportional hazards models will be conducted.The findings of the study may provide an important evidence for clinical practice for these patients.Discussion The trial will be conducted under a rational design and will provide valuable evidence on the appropriate treatment for this population.Ethics and dissemination The study was reviewed and approved by the Ethics Committee of the General Hospital of Shen-Yang Military Region(no K(2016)6).Trial registration number NCT02869009;Pre-results.展开更多
Background Intravenous recombinant tissue plasminogen activator(r-tPA)and urokinase(UK)are both recommended for the treatment of acute ischaemic stroke(AIS)in China,but with few comparative outcome data being availabl...Background Intravenous recombinant tissue plasminogen activator(r-tPA)and urokinase(UK)are both recommended for the treatment of acute ischaemic stroke(AIS)in China,but with few comparative outcome data being available.We aimed to compare the outcomes of these two thrombolytic agents for the treatment of patients within 4.5 hours of onset of AIS in routine clinical practice in China.Methods A pre-planned,prospective,nationwide,multicentre,real-world registry of consecutive patients with AIS(age≥18 years)who received r-tPA or UK within 4.5 hours of symptom onset according to local decision-making and guideline recommendations during 2017-2019.The primary effectiveness outcome was the proportion of patients with an excellent functional outcome(defined by modified Rankin scale scores 0 to 1)at 90 days.The key safety endpoint was symptomatic intracranial haemorrhage according to standard definitions.Multivariable logistic regression was used for comparative analysis,with adjustment according to propensity scores to ensure balance in baseline characteristics.Results Overall,4130 patients with AIS were registered but 320 had incomplete or missing data,leaving 3810 with available data for analysis of whom 2666 received r-tPA(median dose 0.88(IQR 0.78-0.90)mg/kg)and 1144 received UK(1.71(1.43-2.00)×104 international unit per kilogram).There were several significant intergroup differences in patient characteristics:r-tPA patients were more educated,had less history of stroke,lower systolic blood pressure,greater neurological impairment and shorter treatment times from symptom onset than UK patients.However,in adjusted analysis,the frequency of excellent outcome(OR 1.18,95%CI 1.00 to 1.40,p=0.052)and symptomatic intracranial haemorrhage(OR 0.70,95%CI 0.33 to 1.47,p=0.344)were similar between groups.Conclusions UK may be as effective and carry a similar safety profile as r-tPA in treating mild to moderate AIS within guidelines in China.Registration http://www.clinicaltrials.gov.unique identifier:NCT02854592.展开更多
基金Natural Science Foundation of Liaoning Province (General Program),No.2017010825 (to JQ)。
文摘Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a guanine nucleotide exchange factor that is related to microglial activation.However,how Vav1 participates in the inflammato ry response after cerebral ischemia/reperfusion inj ury remains unclea r.In this study,we subjected rats to occlusion and repe rfusion of the middle cerebral artery and subjected the BV-2 mic roglia cell line to oxygen-glucose deprivatio n/reoxygenation to mimic cerebral ischemia/repe rfusion in vivo and in vitro,respectively.We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral arte ry and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation.Silencing Vav1 reduced the cerebral infarct volume and brain water content,inhibited neuronal loss and apoptosis in the ischemic penumbra,and im p roved neurological function in rats subjected to occlusion and repe rfusion of the middle cerebral artery.Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3(NLRP3) inflammasome in the ischemic penumbra,as well as the expression of inflammato ry facto rs.In addition,Vov1 knoc kdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxyge nation.Taken together,these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/repe rfusion through inhibiting the activation of mic roglia and NLRP3 inflammasome.
基金Simcere Pharmaceutical Group supported the present study
文摘Background Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and(+)-borneol,a food additive with an anti-inflammatory effect in animal ischaemic stroke models.This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke(AIS).Methods In this multicentre,randomised,double-blind,multiple-dose,active-controlled,phaseⅡclinical trial,patients with AIS within 48 hours after stroke onset were randomly assigned(1:1:1:1)to low-dose(12.5 mg),medium-dose(37.5 mg)or high-dose(62.5 mg)Edaravone Dexborneol groups,and an active control group with edaravone(30 mg)by 30 min intravenous infusion every 12 hours,for 14 consecutive days.The primary efficacy outcome was the proportion of modified Rankin Scale(mRS)score≤1 at 90 days and National Institutes of Health Stroke Scale(NIHSS)score change from baseline to 14 days after randomisation.The safety outcome included any adverse event during 90 days after treatment.Results Of 385 patients included in the efficacy analysis,94 were randomised to low-dose group,97 to medium-dose group,98 to high-dose group and 96 to the control group.No significant difference was observed among the four groups on mRS score(mRS≤1,p=0.4054)at 90 days or NIHSS score change at 14 days(p=0.6799).However,a numerically higher percentage of patients with mRSscore≤1 at 90 days in the medium-dose(69.39%)and high-dose(65.63%)groups was observed than in the control group(60.64%).No significant difference in severe adverse events was found among the four groups(p=0.3815).Conclusions Compared with edaravone alone,Edaravone Dexborneol was safe and well tolerated at all doses,although no significant improvement in functional outcomes was observed at 90days.
基金supported by the National Natural Science Foundation of China(81870905)the National Key R&D Program of China(2017YFC1308204)+2 种基金the National Science and Technology Major Project(2017ZX09304018)the Beijing Municipal Administration of Hospitals Incubating Program(PX2018022)sponsored and funded by Guangzhou Recomgen Biotech Co.,Ltd.
文摘Background Tenecteplase(TNK)possesses several pharmacological characteristics superior to conventional alteplase(rt-PA),with well-established safety and efficacy profile in Caucasians.There exists controversy over the optimal dose of intravenous rt-PA for East Asians with acute ischaemic stroke(AIS).Current study aimed to determine the safety dose range of recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)for patients with AIS in China.Methods This multicentre,prospective,randomised,open-label,blinded end-point,phase II study compared three tiers of 0.1,0.25,0.32 mg/kg rhTNK-tPA(to a maximum of 40 mg)with standard 0.9 mg/kg rt-PA(to a maximum of 90 mg)in patients who were eligible for intravenous thrombolysis.The safety outcome were symptomatic intracranial haemorrhage(sICH)within 36 hours.Results Between May 2018 and February 2020,240 patients were randomly assigned to four group,4 of whom did not receive study treatment.The intention-to-treat analysis included 236 patients.There was no difference in the improvement on National Institutes of Health Stroke Scale at day 14 in the 3 tiers and control group(63.3%,77.2%,66.7%vs 62.7%).The number of sICH was 3 of 60(5.0%)in the 0.1 mg/kg group,none in the 0.25 mg/kg group,2 of 60(3.3%)in the 0.32 mg/kg group and 1(1.7%)of 59 in the rt-PA group.There were no significant between-group differences in severe adverse events.Conclusions Similar to the Caucasians,rhTNK-tPA was well tolerated in Chinese patients with AIS at all doses administered within 3 hours of symptom onset.The dose-efficacy profile of rhTNK-tPA needs to be established with future investigations.
基金The study was funded by Boehringer Ingelheim(China)Investment.The study was also funded by Clinical Research with Features for Application in the Capital(no.Z161100000516079)and the National Key Research and Development Plan(no.2017YFC1308204)。
文摘background and purpose Data on the efficacy and safety of alteplase for acute ischaemic stroke(AIS)administered 3-4.5 hours after the onset of stroke symptoms in Chinese patients is limited.We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective,multicentre,single-arm trial in China.Materials and methods Eligible AIS patients were given 0.9 mg/kg alteplase intravenously.The primary efficacy endpoint was a favourable outcome at 3 months,defined as a score of 0 or 1 on the modified Rankin Scale.Thresholds for the primary efficacy endpoint were determined to be 40%based on the literature review.The primary safety endpoint was symptomatic intracranial haemorrhage(sICH)according to the European Cooperative Acute Stroke Study III(ECASS III)trial definition.Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching(PSM)method.results A total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study.The median time from onset of symptoms to needle was 3 hours 54 min.The percentage of patients with a favourable outcome was 63.3%(95%CI 54.4 to 71.4),significantly higher than the predefined threshold(p<0.0001).Three patients(2.5%,95%CI 0.5 to 7.1)had sICH,including two fatal sICH.Six patients died within 3 months after treatment.The post hoc PSM analysis showed a numerically higher rate of the primary efficacy endpoint in this study(63.3%)than the matched placebo arm(56.7%)in the ECASS III trial.Conclusions Intravenous alteplase with a standard dose administered between 3 and 4.5 hours after onset of symptoms is effective and safe for Chinese AIS patients.
基金The work was supported by grants from the Science and Technology Project Plan of Liaoning Province(2014225008).
文摘Background A recent study shows that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy for minor stroke,which is defined as a National Institutes of Health Stroke Scale(NIHSS)score of≤3.However,acute mild-moderate ischaemic stroke(4≤NIHSS≤10)still needs aggressive antiplatelet intervention to prevent deterioration and recurrence of stroke.The efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy in the population are not clear.A multicentre clinical trial is designed to evaluate the efficacy and safety of clopidogrel plus aspirin therapy versus aspirin monotherapy within 48 hours of symptom onset of mild-moderate ischaemic stroke.Methods/Design The study is a randomised,open-label,multicentre,prospective trial with a target enrolment of 2700 patients from 60 centres in Northeast China.A treatment allocation identification number to each enrolled patient will be provided by a random number generator.The follow-up time for the clopidogrel plus aspirin and aspirin monotherapy groups is 90 days.The primary efficacy endpoint is a stroke progression event,which is defined as≥4 point increase in the NIHSS score in 48 hours.The second efficacy endpoints include new ischaemic stroke within 90 days,change in the NIHSS score within 14 days,modified Rankin Scale score on day 90 and other vascular or death events within 90 days.The safety endpoints include mucocutaneous haemorrhage,organ haemorrhage and intracranial haemorrhage,adverse events and severe adverse events.χ^(2)test,t-test(or Mann-Whitney test),survival analysis and Cox proportional hazards models will be conducted.The findings of the study may provide an important evidence for clinical practice for these patients.Discussion The trial will be conducted under a rational design and will provide valuable evidence on the appropriate treatment for this population.Ethics and dissemination The study was reviewed and approved by the Ethics Committee of the General Hospital of Shen-Yang Military Region(no K(2016)6).Trial registration number NCT02869009;Pre-results.
基金This study was funded by National Key R&D Program of China(2017YFC1308200)Stroke Prevention and Treatment Project of the National Health Commission-Research and Popularization of Appropriate Intervention Technology for the Stroke High Risk Group in China(GN-2016R0008).
文摘Background Intravenous recombinant tissue plasminogen activator(r-tPA)and urokinase(UK)are both recommended for the treatment of acute ischaemic stroke(AIS)in China,but with few comparative outcome data being available.We aimed to compare the outcomes of these two thrombolytic agents for the treatment of patients within 4.5 hours of onset of AIS in routine clinical practice in China.Methods A pre-planned,prospective,nationwide,multicentre,real-world registry of consecutive patients with AIS(age≥18 years)who received r-tPA or UK within 4.5 hours of symptom onset according to local decision-making and guideline recommendations during 2017-2019.The primary effectiveness outcome was the proportion of patients with an excellent functional outcome(defined by modified Rankin scale scores 0 to 1)at 90 days.The key safety endpoint was symptomatic intracranial haemorrhage according to standard definitions.Multivariable logistic regression was used for comparative analysis,with adjustment according to propensity scores to ensure balance in baseline characteristics.Results Overall,4130 patients with AIS were registered but 320 had incomplete or missing data,leaving 3810 with available data for analysis of whom 2666 received r-tPA(median dose 0.88(IQR 0.78-0.90)mg/kg)and 1144 received UK(1.71(1.43-2.00)×104 international unit per kilogram).There were several significant intergroup differences in patient characteristics:r-tPA patients were more educated,had less history of stroke,lower systolic blood pressure,greater neurological impairment and shorter treatment times from symptom onset than UK patients.However,in adjusted analysis,the frequency of excellent outcome(OR 1.18,95%CI 1.00 to 1.40,p=0.052)and symptomatic intracranial haemorrhage(OR 0.70,95%CI 0.33 to 1.47,p=0.344)were similar between groups.Conclusions UK may be as effective and carry a similar safety profile as r-tPA in treating mild to moderate AIS within guidelines in China.Registration http://www.clinicaltrials.gov.unique identifier:NCT02854592.
