缺血性脑卒中神经保护剂临床转化研究进展
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摘要
脑卒中是中老年常见的急性脑血管病,是当今世界最主要的致死性疾病之一,其中缺血性脑卒中约占患者总数80%。我国脑卒中具有"高发病率、高死亡率、高致残率、高复发率、高经济负担"5大特点,是第一位死亡原因。除血管再通外,神经保护剂是目前最具潜力的一种脑卒中治疗策略。神经保护剂的研究已开展很长时间,目前已涉及49个种类,上百项临床试验,但多数药物在动物实验中证实有效,而在临床试验中无效或存在严重不良反应,其可能原因包括药物临床前实验及临床试验相关的多种复杂因素。本文重点阐述缺血性脑卒中神经保护剂临床转化过程中存在的问题及应对策略的相关研究进展。
Stroke is a common acute cerebrovascular disease in middle-aged and old people. It is the most dangerous diseases in the world today. Ischemic stroke accounts for about 80% of stroke patients. In our country,the stroke presents characteristics of "high morbidity,high mortality,high recurrence rate and high economic burden"and it is also the first cause of death. Besides vascular revascularization,neuroprotectant is the most promising strategy for treatment of ischemic stroke. The studies on neuroprotectants have been carried out for a long time. Currently,there are about 49 species of neuroprotectants involved in nearly hundreds of clinical trials.However,most of that proved effective in animal experiments failed clinical trials for poor efficacy or severe adverse events. The causes of the failure include a variety of complex factors related with the preclinical experiments and clinical trials. This paper reviews the existing problems in the clinical transformation of neuronprotectants for ischemic stroke and the research progress of the solutions.
Stroke is a common acute cerebrovascular disease in middle-aged and old people. It is the most dangerous diseases in the world today. Ischemic stroke accounts for about 80% of stroke patients. In our country,the stroke presents characteristics of "high morbidity,high mortality,high recurrence rate and high economic burden"and it is also the first cause of death. Besides vascular revascularization,neuroprotectant is the most promising strategy for treatment of ischemic stroke. The studies on neuroprotectants have been carried out for a long time. Currently,there are about 49 species of neuroprotectants involved in nearly hundreds of clinical trials.However,most of that proved effective in animal experiments failed clinical trials for poor efficacy or severe adverse events. The causes of the failure include a variety of complex factors related with the preclinical experiments and clinical trials. This paper reviews the existing problems in the clinical transformation of neuronprotectants for ischemic stroke and the research progress of the solutions.
引文
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[3]DEB P,SHARMA S,HASSAN KM.Pathophysiologic mechanisms of acute ischemic stroke:an overview with emphasis on therapeutic significance beyond thrombolysis[J].Pathophysiology,2010,17(3):197-218.
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[5]DOYLE KP,SIMON RP,STENZEL MP.Neuropharmacologyspecial issue on cerebral ischemia mechanisms of ischemic brain damage-review article[J].Neuropharmacol,2008,55(3):310-318.
[6]SUTHERLAND BA,MINNERUP J,BALAMI JS.Neuroprotection for ischaemic stroke:translation from the bench to the bedside[J].Int J Stroke,2012,7(5):407-418.
[7]TYMIANSKI M.Novel approaches to neuroprotection trials in acute ischemic stroke[J].Stroke,2013,44(10):2942-2950.
[8]SOMMER CJ.Ischemic stroke:experimental models and reality[J].Acta Neuropathol,2017,133(2):245-261.
[9]SAVITZ SI.A critical appraisal of the NXY-059 neuroprotection studies for acute stroke:a need for more rigorous testing of neuroprotective agents in animal models of stroke[J].Exp Neurol,2007,205(1):20-25.
[10]LEES KR,BORNSTEIN N,DIENER HC,et al.Results of membrane-activated chelator stroke intervention randomized trial of DP-b99 in acute ischemic stroke[J].Stroke,2013,44(3):580-584.
[11]Stroke therapy academic industry roundtable(STAIR).Recommendations for standards regarding preclinical neuroprotective and restorative drug development[J].Stroke,1999,30(12):2752-2758.
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[15]BOLTZE J,AYATA C,WAGNER DC,et al.Preclinical phase III trials in translational stroke research call for collective design of framework and guidelines[J].Stroke,2014,45(2):357.
[16]TYMIANSKI M.Neuroprotective therapies:preclinical reproducibility is only part of the problem[J].Sci Transl Med,2015,7(299fs32):1-3.
[17]TYMIANSKI M.Combining neuroprotection with endovascular treatment of acute stroke is there hope?[J].Stroke,2017,48(6):1700-1705.
[18]GOYAL M,MENON BK,VAN WH.Endovascular thrombectomy after large-vessel ischaemic stroke:a meta-analysis of individual patient data from five randomised trials[J].Lancet,2016,387(10029):1723-1731.
[19]COOK DJ,TEVES L,TYMIANSKI M.Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain[J].Nature,2012,483(7388):213-217.
[20]AMARO S,LAREDO C,RENU A,et al.Uric acid therapy prevents early ischemic stroke progression:a tertiary analysis of the URICO-ICTUS Trial(efficacy study of combined treatment with uric acid and r-tPA in acute ischemic stroke)[J].Stroke,2016,47(11):2874-2876.
[21]DEL GJ.The neurovascular unit in the setting of stroke[J].JIntern Med,2010,267(2):156-171.
[22]ZHANG JH,BADAUT J,TANG J.The vascular neural networka new paradigm in stroke pathophysiology[J].Nat Rev Neurol,2012,8(12):711-716.
[23]ZHANG L,ZHANG ZG,DING GL,et al.Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat[J].Circulation,2005,112(22):3486-3494.
[24]KANE RC,BROSS PF,FARRELL AT,et al.Velcade:U.S.FDA approval for the treatment of multiple myeloma progressing on prior therapy[J].Oncologist,2003,8(6):508-513.
[25]STANGL K,STANGL V.The ubiquitin-proteasome pathway and endothelial(dys)function[J].Cardiovasc Res,2010,85(2):281-290.
[26]LIU Z,CHOPP M.Astrocytes,therapeutic targets for neuroprotection and neurorestoration in ischemic stroke[J].Prog Neurobiol,2016,144:103-120.
[27]LANG W,STADLER CH,POLJAKOVIC Z.A prospective,randomized,placebo-controlled,double-blind trial about safety and efficacy of combined treatment with alteplase(rt-PA)and Cerebrolysin in acute ischaemic hemispheric stroke[J].Int J Stroke,2013,8(2):95-104.
[28]RAMANATHAN M,JUSTIN A,SUDHEER A,et al.Comparison of pre-and post-ischemic treatment of telmisartan and nimodipine combination in experimentally induced cerebral ischemia[J].Indian J Exp Biol,2016,54(9):560-568.
[29]管得宁,徐运,邵渊.依达拉奉联合前列腺素E治疗急性脑梗死疗效观察[J].中国新药杂志,2008,17(23):2059-2060.
[30]袁庆芳,李欣欣,张剑平,等.丁苯酞氯化钠注射液联合依达拉奉治疗新发脑梗死的疗效及神经功能和CRP水平分析[J].中国新药杂志,2017,26(23):2818-2821.
[31]YAMAGUCHI T,AWANO H,MATSUDA H,et al.Edaravone with and without.6 Mg/Kg Alteplase within 4.5 hours after ischemic stroke:a prospective cohort study(PROTECT4.5)[J].JStroke Cerebrovasc Dis,2016,26(4):756-765.
[32]GUO S,KIM WG,LOK J.Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons[J].Proc Natl Acad Sci USA,2008,27(105):7582-7587.
[2]MORETTI A,FERRARI F,VILLA RF.Neuroprotection for ischaemic stroke:current status and challenges[J].Pharm Ther,2015,146:23-34.
[3]DEB P,SHARMA S,HASSAN KM.Pathophysiologic mechanisms of acute ischemic stroke:an overview with emphasis on therapeutic significance beyond thrombolysis[J].Pathophysiology,2010,17(3):197-218.
[4]IADECOLA C,ANRATHER J.Stroke research at a crossroad:asking the brain for directions[J].Nat Neurosci,2011,14(11):1363-1368.
[5]DOYLE KP,SIMON RP,STENZEL MP.Neuropharmacologyspecial issue on cerebral ischemia mechanisms of ischemic brain damage-review article[J].Neuropharmacol,2008,55(3):310-318.
[6]SUTHERLAND BA,MINNERUP J,BALAMI JS.Neuroprotection for ischaemic stroke:translation from the bench to the bedside[J].Int J Stroke,2012,7(5):407-418.
[7]TYMIANSKI M.Novel approaches to neuroprotection trials in acute ischemic stroke[J].Stroke,2013,44(10):2942-2950.
[8]SOMMER CJ.Ischemic stroke:experimental models and reality[J].Acta Neuropathol,2017,133(2):245-261.
[9]SAVITZ SI.A critical appraisal of the NXY-059 neuroprotection studies for acute stroke:a need for more rigorous testing of neuroprotective agents in animal models of stroke[J].Exp Neurol,2007,205(1):20-25.
[10]LEES KR,BORNSTEIN N,DIENER HC,et al.Results of membrane-activated chelator stroke intervention randomized trial of DP-b99 in acute ischemic stroke[J].Stroke,2013,44(3):580-584.
[11]Stroke therapy academic industry roundtable(STAIR).Recommendations for standards regarding preclinical neuroprotective and restorative drug development[J].Stroke,1999,30(12):2752-2758.
[12]Stroke therapy academic industry roundtable II(STAIR II).Recommendations for clinical trial evaluation of acute stroke therapies[J].Stroke,2001,32(7):1598-1606.
[13]Stroke therapy academic industry roundtable(STAIR).Recommendations for advancing development of acute stroke therapies:stroke therapy academic industry roundtable 3[J].Stroke,2003,34(6):1539-1546.
[14]FISHER M.New approaches to neuroprotective drug development[J].Stroke,2011,42(Suppl 1):S24-S27.
[15]BOLTZE J,AYATA C,WAGNER DC,et al.Preclinical phase III trials in translational stroke research call for collective design of framework and guidelines[J].Stroke,2014,45(2):357.
[16]TYMIANSKI M.Neuroprotective therapies:preclinical reproducibility is only part of the problem[J].Sci Transl Med,2015,7(299fs32):1-3.
[17]TYMIANSKI M.Combining neuroprotection with endovascular treatment of acute stroke is there hope?[J].Stroke,2017,48(6):1700-1705.
[18]GOYAL M,MENON BK,VAN WH.Endovascular thrombectomy after large-vessel ischaemic stroke:a meta-analysis of individual patient data from five randomised trials[J].Lancet,2016,387(10029):1723-1731.
[19]COOK DJ,TEVES L,TYMIANSKI M.Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain[J].Nature,2012,483(7388):213-217.
[20]AMARO S,LAREDO C,RENU A,et al.Uric acid therapy prevents early ischemic stroke progression:a tertiary analysis of the URICO-ICTUS Trial(efficacy study of combined treatment with uric acid and r-tPA in acute ischemic stroke)[J].Stroke,2016,47(11):2874-2876.
[21]DEL GJ.The neurovascular unit in the setting of stroke[J].JIntern Med,2010,267(2):156-171.
[22]ZHANG JH,BADAUT J,TANG J.The vascular neural networka new paradigm in stroke pathophysiology[J].Nat Rev Neurol,2012,8(12):711-716.
[23]ZHANG L,ZHANG ZG,DING GL,et al.Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat[J].Circulation,2005,112(22):3486-3494.
[24]KANE RC,BROSS PF,FARRELL AT,et al.Velcade:U.S.FDA approval for the treatment of multiple myeloma progressing on prior therapy[J].Oncologist,2003,8(6):508-513.
[25]STANGL K,STANGL V.The ubiquitin-proteasome pathway and endothelial(dys)function[J].Cardiovasc Res,2010,85(2):281-290.
[26]LIU Z,CHOPP M.Astrocytes,therapeutic targets for neuroprotection and neurorestoration in ischemic stroke[J].Prog Neurobiol,2016,144:103-120.
[27]LANG W,STADLER CH,POLJAKOVIC Z.A prospective,randomized,placebo-controlled,double-blind trial about safety and efficacy of combined treatment with alteplase(rt-PA)and Cerebrolysin in acute ischaemic hemispheric stroke[J].Int J Stroke,2013,8(2):95-104.
[28]RAMANATHAN M,JUSTIN A,SUDHEER A,et al.Comparison of pre-and post-ischemic treatment of telmisartan and nimodipine combination in experimentally induced cerebral ischemia[J].Indian J Exp Biol,2016,54(9):560-568.
[29]管得宁,徐运,邵渊.依达拉奉联合前列腺素E治疗急性脑梗死疗效观察[J].中国新药杂志,2008,17(23):2059-2060.
[30]袁庆芳,李欣欣,张剑平,等.丁苯酞氯化钠注射液联合依达拉奉治疗新发脑梗死的疗效及神经功能和CRP水平分析[J].中国新药杂志,2017,26(23):2818-2821.
[31]YAMAGUCHI T,AWANO H,MATSUDA H,et al.Edaravone with and without.6 Mg/Kg Alteplase within 4.5 hours after ischemic stroke:a prospective cohort study(PROTECT4.5)[J].JStroke Cerebrovasc Dis,2016,26(4):756-765.
[32]GUO S,KIM WG,LOK J.Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons[J].Proc Natl Acad Sci USA,2008,27(105):7582-7587.