Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated tha...Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage （ICH）. The results showed that fingolimod decreased the numbers of circulating CD4~ T, CD8~ T, CD19~ B, NK, and NKT cells and they recovered quickly after the drug＇ was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.展开更多
BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analy...BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analysis of animal experiments has concluded that fingolimod could treat stroke in animal models by effectively reducing lymphocyte infiltration.However,no evidence-based efficacy and safety evaluation of fingolimod in stroke patients is currently available.AIM To determine whether fingolimod could promote reduction of infarction lesion or hematoma and improve neurological prognosis in stroke patients.METHODS Data extracted for treatment effect included count of T-lymphocytes with cluster of differentiation 8 expression(CD8^(+)T cells,×106/mL),lesion volume(infarction or hematoma,mL),and modified Barthel indexes.Data extracted for safety was risk ratio(RR).Overall standard mean difference(SMD)with its 95%confidence interval(95%CI)and pooled effect with its 95%CI were calculated with a fixedeffects model.I-square(I^(2))was used to test the heterogeneity.Funnel plot symmetry and Egger's regression were used to evaluate publication bias.RESULTS Four high-quality randomized controlled trials were included.There was a significant difference in CD8^(+)T cell count(I^(2)=0,overall SMD=-3.59,95%CI:-4.37-2.80,P=0.737)and modified Barthel index(I^(2)=0,overall SMD=2.42,95%CI:1.63-3.21,P=0.290)between the fingolimod and control groups.However,there was no significant difference in lesion volume(I^(2)=10.6%,overall SMD=-0.17,95%CI:-0.75-0.42,P=0.917),fever(pooled RR=0.93,95%CI:0.97-2.32,P=0.864),suspected lung infection(pooled RR=0.90,95%CI:0.33-2.43,P=0.876),or any adverse events occurring at least once(pooled RR=0.82,95%CI:0.36-1.87,P=0.995)between the fingolimod and control groups.There was no publication bias.All of the results were stable as revealed by sensitivity analysis.CONCLUSION Fingolimod improves neurological function in stroke patients without promotion of lesion absorption.Taking fingolimod orally(0.5 mg/d,3 consecutive days)is safe except for patients with rare severe adverse events.展开更多
Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pa...Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.展开更多
基金supported by the National Basic Research Development Program of China (2013CB966900)the National Natural Science Foundation of China (81241144, 81371372)the National Key Clinical Specialty Construction Program of China
文摘Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage （ICH）. The results showed that fingolimod decreased the numbers of circulating CD4~ T, CD8~ T, CD19~ B, NK, and NKT cells and they recovered quickly after the drug＇ was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.
文摘BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analysis of animal experiments has concluded that fingolimod could treat stroke in animal models by effectively reducing lymphocyte infiltration.However,no evidence-based efficacy and safety evaluation of fingolimod in stroke patients is currently available.AIM To determine whether fingolimod could promote reduction of infarction lesion or hematoma and improve neurological prognosis in stroke patients.METHODS Data extracted for treatment effect included count of T-lymphocytes with cluster of differentiation 8 expression(CD8^(+)T cells,×106/mL),lesion volume(infarction or hematoma,mL),and modified Barthel indexes.Data extracted for safety was risk ratio(RR).Overall standard mean difference(SMD)with its 95%confidence interval(95%CI)and pooled effect with its 95%CI were calculated with a fixedeffects model.I-square(I^(2))was used to test the heterogeneity.Funnel plot symmetry and Egger's regression were used to evaluate publication bias.RESULTS Four high-quality randomized controlled trials were included.There was a significant difference in CD8^(+)T cell count(I^(2)=0,overall SMD=-3.59,95%CI:-4.37-2.80,P=0.737)and modified Barthel index(I^(2)=0,overall SMD=2.42,95%CI:1.63-3.21,P=0.290)between the fingolimod and control groups.However,there was no significant difference in lesion volume(I^(2)=10.6%,overall SMD=-0.17,95%CI:-0.75-0.42,P=0.917),fever(pooled RR=0.93,95%CI:0.97-2.32,P=0.864),suspected lung infection(pooled RR=0.90,95%CI:0.33-2.43,P=0.876),or any adverse events occurring at least once(pooled RR=0.82,95%CI:0.36-1.87,P=0.995)between the fingolimod and control groups.There was no publication bias.All of the results were stable as revealed by sensitivity analysis.CONCLUSION Fingolimod improves neurological function in stroke patients without promotion of lesion absorption.Taking fingolimod orally(0.5 mg/d,3 consecutive days)is safe except for patients with rare severe adverse events.
基金Private DonationLa Trobe Research Focus AreasMultiple Sclerosis Australia,Grant/Award Number:20-032。
文摘Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.
文摘目的探讨芬戈莫德(fingolimod,FTY720)对试验性自身免疫性脑脊髓炎(EAE)小鼠脑组织中一氧化氮(NO)含量和诱导型一氧化氮合酶(i NOS)表达的影响。方法 48只雌性C57BL/6小鼠随机平均分为3组,EAE组运用MOG35-55构建EAE小鼠模型;CFA组由生理盐水代替MOG35-55构建模型;FTY720干预组在EAE基础上给予FTY720腹腔注射,CFA组、EAE组给予生理盐水腹腔注射。HE染色和LBF染色观察炎症情况和脱髓鞘情况,ELLISA检测小鼠脑组织中的NO含量,RT-PCR检测的诱导型一氧化氮合酶(i NOS)mRNA表达。结果 FTY720组EAE小鼠较EAE组临床症状减轻,炎症程度和脱髓鞘程度减轻(P<0.05)。FTY720组小鼠脑组织NO含量较EAE组降低(P<0.05),i NOS mRNA表达量降低(P<0.05)。结论 FTY720能抑制EAE小鼠脑组织中i NOS mRNA表达,从而减少NO含量。
