药学学报, 2016, 51(8): 1185-1195
引用本文:
彭英, 李萍萍, 李琳, 张喻, 侯伟贞, 崔丹丹, 李江, 王玲, 王庆利, 王晓良. 抗阿尔茨海默病药物临床研究进展[J]. 药学学报, 2016, 51(8): 1185-1195.
PENG Ying, LI Ping-ping, LI Lin, ZHANG Yu, HOU Wei-zhen, CUI Dan-dan, LI Jiang, WANG Ling, WANG Qing-li, WANG Xiao-liang. Progress of clinical trials in Alzheimer's disease drugs[J]. Acta Pharmaceutica Sinica, 2016, 51(8): 1185-1195.

抗阿尔茨海默病药物临床研究进展
彭英1, 李萍萍2, 李琳1, 张喻1, 侯伟贞1, 崔丹丹1, 李江1, 王玲1, 王庆利3, 王晓良1
1. 中国医学科学院、北京协和医学院药物研究所, 新药作用机制研究与药效评价北京市重点实验室(BZ0150), 北京 100050;
2. 中国生物技术发展中心, 北京 100039;
3. 国家食品药品监督管理局药品审评中心, 北京 100038
摘要:
阿尔茨海默病(AD)是老年人中引起痴呆最常见的一种慢性神经退行性疾病。目前AD发病机制不明确,没有有效的治疗手段,现有的治疗仅局限在缓解症状。因此研发有效的AD治疗药物迫在眉睫。本文根据公开发表的文献,对目前全球已经完成和正在进行Ⅰ、Ⅱ、Ⅲ期临床试验的AD治疗药物进行了总结,众多临床试验失败的教训提示单一靶点的治疗对于AD这种复杂疾病很难奏效。而多靶点药物和鸡尾酒组方药物可能是未来AD药物研发的一个重要方向。此外通过小分子化合物促进神经再生也可能是一种新的研发策略。中国在天然产物研究方面具有得天独厚的优势,很多天然产物都具有多靶点的药理学活性,并且对神经再生有促进作用,都值得进一步深入开发。
关键词:    阿尔茨海默病      β淀粉样蛋白      Tau蛋白      神经递质      神经炎症      多靶点      神经再生      天然产物     
Progress of clinical trials in Alzheimer's disease drugs
PENG Ying1, LI Ping-ping2, LI Lin1, ZHANG Yu1, HOU Wei-zhen1, CUI Dan-dan1, LI Jiang1, WANG Ling1, WANG Qing-li3, WANG Xiao-liang1
1. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150), Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. China National Center for Biotechnology Development, Beijing 100039, China;
3. Center for Drug Evaluation, China Food and Drug Administration, Beijing 100038, China
Abstract:
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease. The pathogenesis of AD is unclear, and it is presently incurable. Medicines currently available for AD treatment are only for improving the cognitive symptoms, but not able to stop or delay disease progression. Here, we summarized the interventions in early phases of AD in clinical trial. As a complex disease, AD is difficult to be restored through a treatment on a single target. Multi-target and cocktail drugs might be a strategy for development of AD therapies. In addition, AD is characterized by progressive neuronal loss in the cortex and hippocampus. The induction of neurogenesis by small molecule compounds has drawn attention in the AD field. The study of natural products in China is leading the way in the AD world. Numerous natural products have been identified for pharmacological effects on multi-targets in the regulation of neurogenic activity, which may open up a new avenue for AD treatments.
Key words:    Alzheimer's disease    β-amyloid    Tau    neurotransmitter    neuroinflammation    multi-target    neurogenesis    natural product   
收稿日期: 2015-12-03
DOI: 10.16438/j.0513-4870.2015-1100
基金项目: 国家自然科学基金资助项目(81473200);国家“重大新药创制”科技重大专项资助项目(2012ZX09301002-004,2014ZX09507003-001).
通讯作者: 王庆利,Tel:86-10-68585566,Fax:86-10-68584189,E-mail:wangql@cde.org.cn;Tel/Fax:86-10-63165330,E-mail:wangxl@imm.ac.cn
Email: wangql@cde.org.cn;wangxl@imm.ac.cn
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参考文献:
[1] Selkoe DJ.Normal and abnormal biology of the betaamyloid precursor protein[J].Annu Rev Neurosci,1994,17:489-517.
[2] Prince M,Prina M,Guerchet M,et al.World Alzheimer Report 2013,Journey of Caring:An Analysis of Long-Term Care for Dementia[M].London:Alzheimers Disease International,2013.
[3] Berk C,Paul G,Sabbagh M.Investigational drugs in Alzheimer's disease:current progress[J].Expert Opin Investig Drugs,2014,23:837-846.
[4] Selkoe DJ.Alzheimer's disease:genes,proteins,and therapy[J].Physiol Rev,2001,81:741-766.
[5] Hardy J,Selkoe DJ.The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J].Science,2002,297:353-356.
[6] Miller BW,Willett KC,Desilets AR.Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease[J].Ann Pharmacother,2011,45:1416-1424.synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice[J].J Neurosci Res,2012,90:508-517.
[51] Peng Y,Sun J,Hon S,et al.L-3-n-Butylphthalide improves cognitive impairment and reduces amyloid-β in a transgenic model of Alzheimer's disease[J].J Neurosci,2010,30:8180-8189.
[52] Liu X,Hao W,Qin Y,et al.Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease[J].Brain Behav Immun,2015,46:121-131.
[53] Shi YQ,Huang TW,Chen LM,et al.Ginsenoside Rg1 attenuates amyloid-β content,regulates PKA/CREB activity,and improves cognitive performance in SAMP8 mice[J].J Alzheimers Dis,2010,19:977-989.
[54] Zhang L,Fang Y,Xu Y,et al.Curcumin improves amyloid β-peptide (1-42) induced spatial memory deficits through BDNF-ERK signaling pathway[J].PLoS One,2015,10:e0131525.
[55] Zhang Y,Zhao YM,Wang XL,et al.Advance and challenges in stem cell therapy for Alzheimer's disease[J].Chin Pharmacol Bull (中国药理学通报),2015,31:889-894.
[7] Menting KW,Claassen JA.β-Secretase inhibitor;a promising novel therapeutic drug in Alzheimer's disease[J].Front Aging Neurosci,2014,6:165.
[8] Coric V,van Dyck CH,Salloway S,et al.Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease[J].Arch Neurol,2012,69:1430-1440.
[9] Xie YL.Progress of Alzheimer's disease drugs[J].Pharm Clin Res (药学与临床研究),2011,19:1-7.
[10] Schneider LS,Mangialasche F,Andreasen N,et al.Clinical trials and late-stage drug development for Alzheimer's disease:an appraisal from 1984 to 2014[J].J Intern Med,2014,275:251-283.
[11] Vellas B,Sol O,Snyder PJ,et al.EHT0202 in Alzheimer's disease:a 3-month,randomized,placebo-controlled,doubleblind study[J].Curr Alzheimer Res,2011,8:203-212.
[12] Schrott LM,Jackson K,Yi P,et al.Acute oral bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease[J].Curr Alzheimer Res,2015,12:22-31.
[13] Menard C,Bastianetto S,Quirion R.Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma[J].Front Cell Neurosci,2013,7:281.
[14] Faux NG,Ritchie CW,Gunn A,et al.PBT2 rapidly improves cognition in Alzheimer's disease:additional phase Ⅱ analyses[J].J Alzheimers Dis,2010,20:509-516.
[15] Salloway S,Sperling R,Keren R,et al.A phase 2 randomized trial of ELND005,scyllo-inositol,in mild to moderate Alzheimer disease[J].Neurology,2011,77:1253-1262.
[16] Schenk D,Barbour R,Dunn W,et al.Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse[J].Nature,1999,400:173-177.
[17] Ryan JM,Grundman M.Anti-amyloid-β immunotherapy in Alzheimer's disease:ACC-001 clinical trials are ongoing[J].J Alzheimers Dis,2009,17:243.
[18] Winblad B,Andreasen N,Minthon L,et al.Safety,tolerability,and antibody response of active A β immunotherapy with CAD106 in patients with Alzheimer's disease:randomised,double-blind,placebo-controlled,first-in-human study[J].Lancet Neurol,2012,11:597-604.
[19] Mandler M,Santic R,Gruber P,et al.Tailoring the antibody response to aggregated Aβ using novel Alzheimer-vaccines[J].PLoS One,2015,10:e0115237.
[20] Wisniewski T,Goñi F.Immunotherapeutic approaches for Alzheimer's disease[J].Neuron,2015,85:1162-1176.
[21] Salloway S,Sperling R,Fox NC,et al.Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease[J].N Engl J Med,2014,370:322-333.
[22] Siemers ER,Sundell KL,Carlson C,et al.Phase 3 solanezumab trials:secondary outcomes in mild Alzheimer's disease patients[J].Alzheimers Dement,2015.DOI:10.1016/j.jalz.2015.06.1893.
[23] Tucker S,Möller C,Tegerstedt K,et al.The murine version of BAN2401(mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice[J].J Alzheimers Dis,2015,43:575-588.
[24] Bouter Y,Lopez Noguerola JS,Tucholla P,et al.Abeta targets of the biosimilar antibodies of bapineuzumab,crenezumab,solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models[J].Acta Neuropathol,2015,130:713-729.
[25] Miyoshi I,Fujimoto Y,Yamada M,et al.Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease:a multicenter,randomized,double-blind,placebo-controlled,dose-escalation study[J].Int J Clin Pharmacol Ther,2013,51:911-923.
[26] Panza F,Solfrizzi V,Imbimbo BP,et al.Efficacy and safety studies of gantenerumab in patients with Alzheimer's disease[J].Expert Rev Neurother,2014,14:973-986.
[27] Kwon H,Crisostomo AC,Smalls HM,et al.Anti-aβ oligomer IgG and surface sialic acid in intravenous immunoglobulin:measurement and correlation with clinical outcomes in Alzheimer's disease treatment[J].PLoS One,2015,10:e0120420.
[28] Lawlor B,Kennelly S,O'Dwyer S,et al.NILVAD protocol:a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease[J].BMJ Open,2014,4:e006364.
[29] Wang JZ,Wang DL.Alzheimer's Disease and Relasted Disorders (老年性痴呆及相关疾病)[M].Beijing:Scientific and Technical Documents Publishing House,2006:267-282.
[30] Tariot PN,Aisen PS.Can lithium or valproate untie tangles in Alzheimer's disease[J].J Clin Psychiatry,2009,70:919-921.
[31] Lovestone S,Boada M,Dubois B,et al.A phase Ⅱ trial of tideglusib in Alzheimer's disease[J].J Alzheimers Dis,2015,45:75-88.
[32] Peng Y,Hu Y,Xu S,et al.L-3-n-Butylphthalide reduces tau phosphorylation and improves cognitive deficits in A β PP/PS1-Alzheimer's transgenic mice[J].J Alzheimers Dis,2012,29:379-391.
[33] Peng Y,Xing C,Lemere CA,et al.L-3-n-Butylphthalide ameliorates beta-amyloid-induced neuronal toxicity in cultured neuronal cells[J].Neurosci Lett,2008,434:224-229.
[34] Anand K,Sabbagh M.Early investigational drugs targeting tau protein for the treatment of Alzheimer's disease[J].Expert Opin Investig Drugs,2015,24:1355-1360.
[35] Grüninger F.Invited review:drug development for tauopathies[J].Neuropathol Appl Neurobiol,2015,41:81-96.
[36] Morimoto BH,Schmechel D,Hirman J,et al.A double-blind,placebo-controlled,ascending-dose,randomized study to evaluate the safety,tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment[J].Dement Geriatr Cogn Disord,2013,35:325-336.
[37] Lou K,Yao Y,Hoye AT,et al.Brain-penetrant,orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies[J].J Med Chem,2014,57:6116-6127.
[38] Calcul L,Zhang B,Jinwal UK,et al.Natural products as a rich source of tau-targeting drugs for Alzheimer's disease[J].Future Med Chem,2012,4:1751-1761.
[39] Kontsekova E,Zilka N,Kovacech B,et al.First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model[J].Alzheimers Res Ther,2014,6:44.
[40] Collin L,Bohrmann B,Göpfert U,et al.Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease[J].Brain,2014,137:2834-2846.
[41] Fukushima T,Nakamura A,Iwakami N,et al.T-817MA,a neuroprotective agent,attenuates the motor and cognitive impairments associated with neuronal degeneration in P301L tau transgenic mice[J].Biochem Biophys Res Commun,2011,407:730-734.
[42] America's Biopharmaceutical Research Company.Medicine in Development Alzheimer's Disease.2013 Report[R].Washington:Pharmaceutical Research and Manufacturers of America,2013.
[43] Yin M.Full-scale setback and thinking in R&D of Alzheimer's diseasedrug[J].Acta Pharm Sin (药学学报),2014,49:757-763.
[44] Lei H,Wang XL,Peng Y.Mitochondrial dysfuncion and Alzheimer's disease[J].Chin Pharmacol Bull (中国药理学通报),2013,29:1337-1341.
[45] Galasko DR,Peskind E,Clark CM,et al.Antioxidants for Alzheimer disease:a randomized clinical trial with cerebrospinal fluid biomarker measures[J].Arch Neurol,2012,69:836-841.
[46] Leoutsakos JM,Muthen BO,Breitner JC,et al.Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease:findings from the randomized controlled Alzheimer's disease anti-inflammatory prevention trial[J].Int J Geriatr Psychiatry,2012,27:364-374.
[47] Shah RC,Matthews DC,Andrews RD,et al.An evaluation of MSDC-0160,a prototype mTOT modulating insulin sensitizer,in patients with mild Alzheimer's disease[J].Curr Alzheimer Res,2014,11:564-573.
[48] Burstein AH,Grimes I,Galasko DR,et al.Effect of TTP488 in patients with mild to moderate Alzheimer's disease[J].BMC Neurol,2014,14:12.
[49] Feldman HH,Doody RS,Kivipelto M,et al.Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease:LEADe[J].Neurology,2010,74:956-964.
[50] Wang Y,Tang XC,Zhang HY.Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice[J].J Neurosci Res,2012,90:508-517.
[51] Peng Y,Sun J,Hon S,et al.L-3-n-Butylphthalide improves cognitive impairment and reduces amyloid-β in a transgenic model of Alzheimer's disease[J].J Neurosci,2010,30:8180-8189.
[52] Liu X,Hao W,Qin Y,et al.Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease[J].Brain Behav Immun,2015,46:121-131.
[53] Shi YQ,Huang TW,Chen LM,et al.Ginsenoside Rg1 attenuates amyloid-β content,regulates PKA/CREB activity,and improves cognitive performance in SAMP8 mice[J].J Alzheimers Dis,2010,19:977-989.
[54] Zhang L,Fang Y,Xu Y,et al.Curcumin improves amyloid β-peptide (1-42) induced spatial memory deficits through BDNF-ERK signaling pathway[J].PLoS One,2015,10:e0131525.
[55] Zhang Y,Zhao YM,Wang XL,et al.Advance and challenges in stem cell therapy for Alzheimer's disease[J].Chin Pharmacol Bull (中国药理学通报),2015,31:889-894.
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