盘点 :国内外阿尔茨海默病在研新药一览

2017-07-18 华义文 医药魔方数据

国内外阿尔茨海默病在研新药一览

老吾老,以及人之老;幼吾幼,以及人之幼。之前聊了聊儿童用药,这篇谈一谈老年人特有疾病,即老年痴呆领域的国内外新药研发,尤其以阿尔茨海默病为主。


随着社会老龄化愈发明显,老年人相关疾病也呈现高发态势,其中就包括阿尔茨海默病,由于多发于老年人,且症状表现为认知功能退化,人们通常称为老年痴呆,或者“老糊涂”。痴呆症是一种神经退行性疾病,现在业内也呼吁将这种病症称为“认知症”以消除人们对这类疾病的误解,并且给予患者和家属以尊重。认知症可以分成很多类型,其中阿尔茨海默病是其中最为常见的一种。临床表现为认知和记忆功能不断退化,日常生活能力进行性减退,伴有各种神经精神症状和行为障碍。通常病情呈现进行性加重,并逐渐丧失独立生活能力,发病后10~20年因并发症而死亡。

由于阿尔茨海默病的发病机理尚无定论,也缺乏有效治疗手段,患者人群巨大,给家庭和社会带来的沉重压力,已经成为社会负担最重的疾病之一。在我国未富先老的社会中,尤其需要引起重视。

什么是阿尔茨海默病?

阿尔茨海默病是与年龄相关的进行性记忆丧失和认知功能减退的神经系统退行性疾病,其病理变化主要表现为:细胞外聚集的β淀粉样蛋白沉积、细胞内高度磷酸化Tau蛋白所致神经元纤维缠结,以及前脑基底神经细胞凋亡。

阿尔茨海默病发病机制是什么?

目前阿尔茨海默病发病机制主要集中在以下几种假说:1)神经递质相关神经元损伤。目前已经上市的药物就是基于这一假说:乙酰胆碱是记忆相关的一种重要神经递质,胆碱酯酶会破坏大脑中的乙酰胆碱,胆碱酯酶抑制剂可以通过抑制胆碱酯酶水解从而提高乙酰胆碱浓度,增强胆碱能,改善神经元。这类药物有多奈哌齐。此外,神经递质谷氨酸过高会产生黏连,使过量钙进入脑细胞,引起损伤,谷氨酸受体拮抗剂可以阻断谷氨酸浓度病理性升高导致的神经元损伤。这类药物有美金刚;2)β淀粉样蛋白(β-amyloid,Aβ)沉积。目前的研发热点多基于这一假说设计和开发新的药物,但遇到很多挫折;3)Tau蛋白高度磷酸化所致神经元纤维缠结。科研人员开始加大力度在这一领域研发新药;4)免疫异常以及神经免疫细胞释放促炎症细胞因子导致神经炎症。

阿尔茨海默病发病假说众多,批准上市的药物十分稀少,且都是延缓疾病进展和改善症状,并没有能够治愈疾病的药物。研发人员在开发新药的路上已经付出了很多,也遭遇了很多挫折。虽然自从2003年批准新化合物美金刚治疗中重度阿尔茨海默病以来就再也没有新药问世,但是业内对这一疾病的攻克热情并未消减,依然有很多新药处于各个研发阶段。以下简单介绍一下国外处于研发后期的新药,帮助大家对这一领域有一点了解。

国外研发后期新药

01 甲基蓝

该化合物注射剂已经被美国FDA批准用于获得性高铁血红蛋白症。本品口服制剂在进行多项III期临床研究。2016年公布的数据表明本品单独给药,高低剂量组都优于本品联合其他阿尔茨海默病药物;此外,低剂量组比高剂量组表现出患者疾病进展更缓慢,且有更好的耐受性和安全性。因此,下一步将比较单独给药低剂量和安慰剂之间的差别。

02 azeliragon

在血脑屏障、神经元细胞和小胶质细胞内淀粉样蛋白与晚期糖化终产物受体(Receptor for Advanced GlycationEndproducts,RAGE)长期相互作用,对淀粉样蛋白斑块形成、神经炎症和慢性神经元功能障碍都起着十分重要的作用。临床前证据表明,抑制RAGE介导的转导对改善认知有效。

本品为RAGE抑制剂,已经获得FDA快速审评资格,目前在III期临床研究阶段。研究分成两部分,其中A部分于2016年9月完成受试者招募,预计在2018年初获得数据,而B部分预计在2018年末获得数据。

03 色甘酸钠和布洛芬

色甘酸钠吸入剂已经批准用于哮喘,布洛芬是十分常见的消炎药。III期临床研究将两种药品联合使用,用于治疗早期阿尔茨海默病,计划在2018年3月结束。

04 左乙拉西坦

该化合物在包括我国在内的多个国家批准用于治疗癫痫。本品调整为更低剂量的缓释剂型,开发用于治疗遗忘型轻微认知障碍。这一病症通常是阿尔茨海默病的前兆。临床II期研究表明可以有效保护脑功能和记忆能力。计划在2017年开展III期临床研究。

05 lanabecestat

本品最初由阿斯利康研发,在2014年9月礼来也加入其中并负责临床研究,而阿斯利康负责生产。

β-淀粉样蛋白(Aβ)是老年斑的主要组成部分,具有神经毒性可导致神经细胞死亡。β-淀粉样蛋白转换酶(BACE1)可以催化Aβ的产生,因此发展β-淀粉样蛋白转换酶(BACE1)抑制剂成为一个重要研究方向。目前在进行中的有两项III期临床研究,分别于2014年9月和2016年7月开始,计划分别于2019年8月和2021年4月结束。

06 aducanumab

本品是一种高亲和力全人IgG1单克隆抗体,靶向于致病性Aβ构象表位。由于半衰期长,可在脑中累积。2015年8月,两项III期临床研究在全球多个国家展开,计划在2022年结束。

07 crenezumab

本品是一种单克隆抗体,可以结合到不同形式淀粉样蛋白。分别在2015年7月开始第一项III期临床研究,计划招募750人,预计2020年结束。第二项III期临床研究于2017年2月开始,同样招募750人。

08 elenbecestat

这也是一个BACE抑制剂。2016年10月,卫材开始两项III期临床研究,计划于2020年结束。

09 gantenerumab

本品是一种结合在Aβ的N-末端表位的单克隆抗体,可结合低聚和纤维状Aβ,从而导致小胶质细胞介导的吞噬细胞清除斑块。2015年罗氏宣布临床研究中主要终点和次要重点均未见疗效。但是在2017今年,罗氏再度开展针对早期阶段AD患者的III期临床研究。

10 verubecestat

这也是一种BACE抑制剂。2017年2月,美国默克宣布一项治疗轻/中度阿尔兹海默症患者临床II/III期研究终止。而另一项庞大的III期临床研究针对早期阿尔茨海默病,目前状态未在招募受试者。该研究原本计划招募1350人,于2013年11月开始,预计在2021年3月结束。试验分两部分,受试者需要服用本品104周以及260周。

11 右美沙芬、奎尼丁和氘

右美沙芬是止咳糖浆中的常用成分,这也是一种较弱的NMDA受体拮抗剂(如美金刚)。加入奎尼丁和氘的目的是提高右美沙芬生物利用度。

III期临床研究计划在2021年3月结束。

12 阿立哌唑

该化合物早在2002年批准用于治疗精神分裂症,后续也用于其他情感障碍。

早在2003年到2005年期间,一项III期临床研究招募了129位不同类型痴呆症患者,包括阿尔茨海默病、血管型和混合型,肌肉注射本品用于激越急性发作有效,但是和安慰剂相比,也带来更多副作用。2008年,有研究人员发现口服本品可以改善行为和精神症状,包括激越、焦虑和抑郁。

2014年6月,大冢在日本开始一项III期临床研究,计划招募880位MMSE评分在1~22分的阿尔茨海默病患者,目的是研究对激越症状的有效性和安全性。该研究计划在2017年7月结束。

13 Brexpiprazole

本品是阿立哌唑的后继产品,已经在多个国家批准用于精神分裂症和重度抑郁症的辅助治疗。

2017年5月公布了在北美、欧洲和俄罗斯进行的两项III期研究结果表明,本品对阿尔茨海默病患者的激越症状相比安慰剂有改善。不同国家之间的数据存在差异,这可能和护理水平有关,尤其是俄罗斯的数据显示本品与安慰剂差别不大。

两家公司尚未宣布下一步计划。

14 ITI-007

2016年6月开展的一项III期临床研究,目的是考察对于阿尔茨海默病患者激越症状的效果。计划招募360人,并于2018年8月结束。

15 Idalopirdine

本品是一种五羟色胺6(5-HT6)受体拮抗剂。这种受体亚型主要在大脑表达,尤其是大脑皮层和海马区,这与认知功能密切相关。

2016年7月,本品获得美国FDA快速审评资格。但在2016年9月,灵北宣布III期临床研究显示未达到主要终点,本品疗效不明显。

16 intepirdine

这也是一种五羟色胺6(5-HT6)受体拮抗剂。2015年10月开始一项III期临床研究,计划招募1150人,于2017年10月结束。本研究中轻微到中度阿尔茨海默病患者常规服用多奈哌齐基础上增加每天一次35mg本品,共6个月。公司计划基于本次研究结果提交上市申请。

17 masitinib

本品已经在欧盟批准用于胰腺癌和胃肠道间质瘤。本品也在研究用于多种神经退行性疾病。一项用于治疗阿尔茨海默病的III期临床研究,本品与胆碱酯酶抑制剂或美金刚联合使用,评价其疗效和安全性。原本计划于2016年12月结束,但时至今日未见任何消息。

18 nilvadipine

本品在欧洲和日本等国批准用于治疗高血压,是一种钙通道阻滞剂。另一款钙通道阻滞剂尼莫地平用于改善脑部血液循环,常用于认知症患者。一项研究在欧盟9个国家开展,计划招募500为轻微到中度阿尔茨海默病患者,研究工作于2017年结束。

国内在研新药

中国的科研人员也在努力攻克这一医学难题。目前在研的新药有以下6个,数量不多,有中药、天然产物和化学药。其中两款中药产品信息披露有限。

左黄皮酰胺是从芸香科植物黄皮叶中提取分离出的有效成分,经化学合成而得。

甘露寡糖二酸是从海洋褐藻中提取分离并经降解获得。而海正选择传统的胆碱酯酶抑制剂,成功的概率相对较高,但现有的此类药物也只是起到缓解作用。

另外哌哒甲酮十分少有的选择针对神经炎症,希望能尽早进入临床研究阶段进行验证。

阿尔茨海默病临床研究的用药周期一般设计18个月,另外加上研究需要招募受试者十分多,且入组标准也较高,导致入组完成也经历比较长时间。因此,这类临床研究在时间和资金上的投入都十分庞大。除了发病机制尚未清楚,疾病特征导致临床研究周期通常十分漫长,都使得新药难产。总体来看,虽然目前还是有不少新药处于研发后期,但下一个新药上市还是需要耐心等待,但愿这种等待不会太久。

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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160914/IMG57D82E721DB581755.jpg, createdBy=4fc81933929, createdName=明天会更好!, createdTime=Fri Jul 21 09:59:01 CST 2017, time=2017-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224545, encodeId=2f362245450d, content=学习了谢谢了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLPeNmuNF9ibgMfMOAs7Iic5MpiaU8RLmRH67xCKuk5wzfhb7G4ib7ia6z9lrnsTicj1nAUfEOMecZDtvvu/0, createdBy=d7f91939785, createdName=186****0580(小山羊), createdTime=Fri Jul 21 08:14:06 CST 2017, time=2017-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224291, encodeId=bbde22429193, content=希望能够改善症状, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, 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    2017-07-21 QQ25ed180f

    与年龄相关的神经退行性病变,但愿能研发出新药,减缓疾病的进展

    0

  4. 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encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, time=2017-07-19, status=1, ipAttribution=)]
    2017-07-21 明天会更好!

    学习过了,谢谢分享!

    0

  5. 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encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, time=2017-07-19, status=1, ipAttribution=)]
    2017-07-21 186****0580(小山羊)

    学习了谢谢了。

    0

  6. 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encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, time=2017-07-19, status=1, ipAttribution=)]
    2017-07-20 nannanxyy

    希望能够改善症状

    0

  7. 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encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, 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  8. 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encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, time=2017-07-19, status=1, ipAttribution=)]
    2017-07-19 李东泽

    很好,不错,以后会多学习

    0

  9. 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topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Sun Jan 28 07:39:00 CST 2018, time=2018-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224782, encodeId=6271224e827e, content=与年龄相关的神经退行性病变,但愿能研发出新药,减缓疾病的进展, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/1103841572/C3426ED027FF661B0C576A5B3127C2E8/40, createdBy=39dc1706090, createdName=QQ25ed180f, createdTime=Fri Jul 21 23:25:26 CST 2017, time=2017-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224592, encodeId=2cba22459223, content=学习过了,谢谢分享!, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160914/IMG57D82E721DB581755.jpg, createdBy=4fc81933929, createdName=明天会更好!, createdTime=Fri Jul 21 09:59:01 CST 2017, time=2017-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224545, encodeId=2f362245450d, content=学习了谢谢了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLPeNmuNF9ibgMfMOAs7Iic5MpiaU8RLmRH67xCKuk5wzfhb7G4ib7ia6z9lrnsTicj1nAUfEOMecZDtvvu/0, createdBy=d7f91939785, createdName=186****0580(小山羊), createdTime=Fri Jul 21 08:14:06 CST 2017, time=2017-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=224291, encodeId=bbde22429193, content=希望能够改善症状, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5KynZWiaZcw1J0lWhzLtT6ukInjVSRV4un6UrPrs68caGt3cNk2qhwctOqMFPWlvwF4wkvtn7bTIOQ/0, createdBy=cca998055, createdName=nannanxyy, createdTime=Thu Jul 20 16:00:41 CST 2017, time=2017-07-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470152, encodeId=1f2614e015242, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Jul 20 12:39:00 CST 2017, time=2017-07-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223885, encodeId=71422238855e, content=很好,不错,以后会多学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzUn81b5CF5ibVPib8jWI92iciaxmqGHlwruOnK4SVZykd4iahqo1hicklIibyZoxm55X7EM8BW9eX1h1hQ2/0, createdBy=8aa81937526, createdName=李东泽, createdTime=Wed Jul 19 11:37:21 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=223700, encodeId=a40e223e0070, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Wed Jul 19 05:22:58 CST 2017, time=2017-07-19, status=1, ipAttribution=)]
    2017-07-19 天涯183

    非常好的文章,学习了,很受益

    0

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