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章华:临床应用Zonisamide(唑尼沙胺)治疗帕金森症的最新机制解释  邮箱:drdanielcheung@hotmail.com  IP:183.63.47.183  日期:2012-8-21 [回复1楼]

  临床应用Zonisamide(唑尼沙胺)治疗帕金森症的最新机制解释
  Zonisamide(唑尼沙胺)是一种新型的治疗帕金森症药物,在经历2001-2009年的临床后,日本卫生部已于2009年1月批准唑尼沙胺正式用于帕金森症的治疗,在这几年的研究及临床中,唑尼沙胺对于帕症的治疗中,发现有30%-40%的患者运动功能显著恢复,特别是应用左旋多巴制剂时间比较长,而有剂末和开关现象的患者。由于这只药物的治疗机制完全不同于现有的帕症药物,所以有必要做一个跟进,这只药物的主要功能在于二个方面。
  一:神经保护,帕症的疾病进展牵涉到Tau蛋白介导的细胞毒性,异常的Tau蛋白聚集即过度表达和高度磷酸化是疾病不断进展的一个主要因素,而唑尼沙胺治疗帕金森症的机制是通过通过提高Hrd1泛素连接酶的水平而介导Tau蛋白的降解从而提供神经保护和解除疾病进展的诱因,从而彻底减缓疾病的进展。
  二:在日本爱媛大学的一项研究中发现,Zonisamide可以诱导多巴胺能神经元的恢复,这一点比第一点更为重要,也就是揭示了一种积极的治疗方式,而不是对症的消极治疗。Zonisamide可能比雷沙吉兰这只目前最为有效的神经保护剂更为接近严格意义上讲的治疗二个字。
  Zonisamide目前的一般治疗指引是每天25mg-75mg,最佳剂量为50mg,不建议每天用多于100mg,原厂是Eisai公司,即以前讨论过的VitK2的原厂厂家。
  需要注意的是,如果病人有磺胺类药物过敏的是不适合用唑尼沙胺的。
  
  
  J Mol Neurosci. 2012 Mar;46(3):527-35. Epub 2011 Sep 3.
  HRD1 levels increased by zonisamide prevented cell death and caspase-3 activation caused by endoplasmic reticulum stress in SH-SY5Y cells.
  Omura T, Asari M, Yamamoto J, Kamiyama N, Oka K, Hoshina C, Maseda C, Awaya T, Tasaki Y, Shiono H, Shimizu K, Matsubara K.
  SourceDepartment of Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.
  
  Abstract
  Zonisamide, which is commonly prescribed at high doses (200-400 mg/day) for the treatment of partial seizures, has recently been used at a low dose (25 mg/day) for improving parkinsonian syndrome. However, the molecular mechanisms that underlie the antiparkinsonian effects of zonisamide have not been clarified. Here we show that low micromolar concentrations of zonisamide prevented cleavage of caspase-3 and cell death in human dopaminergic SH-SY5Y neuroblastoma cells that were subjected to endoplasmic reticulum stress induced by tunicamycin or 6-hydroxydopamine. Hypodense zonisamide increased the expression levels of SEL1L, which is known to stabilize the ubiquitin ligase HRD1. Indeed, upregulation of HRD1 protein was observed. Thus, the results of this study strongly suggest that low concentrations of zonisamide inhibit neuronal cell death by increasing HRD1 protein levels in patients with Parkinson’s disease. Consequently, in addition to the treatment of Parkinson’s disease, the therapeutic potential of zonisamide should be considered for the treatment of several neurodegenerative disorders with pathophysiological mechanisms involving endoplasmic reticulum stress.
  
  PMID:21892618[PubMed - in process]
  
  
  
  
  
  Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity.
  Choudhury ME, Moritoyo T, Kubo M, Kyaw WT, Yabe H, Nishikawa N, Nagai M, Matsuda S, Nomoto M.
  SourceDepartment of Therapeutic Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon-Shi, Ehime 791-0295, Japan.
  
  Abstract
  Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinson’s disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg×4 every 2h; 3) MPTP and zonisamide, 40 mg/kg×1, 1h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100β-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP-induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100β secretion.
  
  Copyright © 2011 Elsevier B.V. All rights reserved.
  
  PMID:21320474[PubMed - indexed for MEDLINE]
  
  
  
  这是2007年的文章,有必要再重温一下,发表在当年美国神经学会会刊上的文章。
  Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study.
  Murata M, Hasegawa K, Kanazawa I; Japan Zonisamide on PD Study Group.
  SourceDepartment of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan. mihom@ncnp.go.jp
  
  Erratum in
  Neurology. 2007 Jul 3;69(1):120.
  Abstract
  OBJECTIVE: To evaluate the efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of zonisamide (ZNS) administered as adjunctive treatment in patients with Parkinson disease (PD).
  
  METHODS: We conducted a multicenter, randomized, double-blind, parallel-treatment, placebo-controlled study in Japan. Patients with PD who showed insufficient response to levodopa treatment were given placebo for 2 weeks and then treated for 12 weeks with 25, 50, or 100 mg/day of ZNS or placebo, in addition to levodopa, followed by a 2-week dose-reduction period. The primary endpoint was change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at the final assessment point. Secondary endpoints included changes from baseline in total daily "off" time; total scores of UPDRS Parts I, II, and IV; and Modified Hoehn and Yahr Scale score. Safety analysis was based on the incidence of adverse events.
  
  RESULTS: There was significant improvement in the primary endpoint in the 25-mg and 50-mg groups vs placebo. The duration of "off" time was significantly reduced in the 50-mg and 100-mg groups vs placebo. Dyskinesia was not increased in ZNS groups. The incidence of adverse effects was similar between the 25-mg, 50-mg, and placebo groups but higher in the 100-mg group.
  
  CONCLUSIONS: Zonisamide is safe, effective and well tolerated at 25 to 100 mg/day as an adjunctive treatment in patients with Parkinson disease.
  
  
   

沙漠胡杨:章医生的消息使我们看到了曙光给了我们活下去的信心  邮箱:nclaodongbaozhang@163.com  IP:222.62.90.225  日期:2012-8-21 [回复2楼]

  章医生的消息使我们看到了曙光给了我们活下去的信心
  章医生的消息使我们看到了曙光给了我们活下去的信心,不知这个药中国什么时候推广应用? 

沙漠胡杨:可以买到Zonisamide(唑尼沙胺)试试吗?  邮箱:nclaodongbaozhang@163.com  IP:222.62.90.225  日期:2012-8-21 [回复3楼]

  可以买到Zonisamide(唑尼沙胺)试试吗?
  不知道能否自己买到Zonisamide(唑尼沙胺)试试吗? 

章华:回复2楼 沙漠胡杨  邮箱:drdanielcheung@gmail.com  IP:183.63.47.221  日期:2012-8-21 [回复4楼]

  回复2楼 沙漠胡杨
  回复2楼 沙漠胡杨:章医生的消息使我们看到了曙光给了我们活下去的信心
  
  唑尼沙胺目前的状态是:日本临床帕金森一线用药,欧洲最后临床进行中,在中国、美国及其他国家只批准用于癫癎症新药,用量在每天100mg-300mg。
  此药在国内用于帕症治疗我估计需要5年以上,而日本原产Eisai的不易取得,我也是托了很多人才从欧洲购得此药。薛老介绍的印度雷公司有每片25mg的仿制药,非常便宜,和国内生产的100mg一样,我并不推荐购买并应用。 

莫菲:谢谢章医生带来的最新信息  邮箱:37595552@qq.com  IP:123.68.104.123  日期:2012-8-21 [回复5楼]

  谢谢章医生带来的最新信息
    很高兴的看到章医生带来的这则关于治疗帕金森的最新信息,尽管目前我们还不能接受使用,但是又多了许些希望和信心!期盼在我国能早日应用到临床,解除帕金森病人的痛苦。谢谢你,章医生~
  
  
   

沙漠胡杨:请问:为什么不推荐并购买?  邮箱:nclaodongbaozhang@163.com  IP:222.62.84.247  日期:2012-8-22 [回复6楼]

  请问:为什么不推荐并购买?
  回复4楼 章华:回复2楼 沙漠胡杨
  
  请问章医生:好的技术和好的药应该推广应用~! 

章华:回复6楼 沙漠胡杨  邮箱:drdanielcheung@gmail.com  IP:220.246.74.155  日期:2012-8-23 [回复7楼]

  回复6楼 沙漠胡杨
  回复6楼 沙漠胡杨:请问:为什么不推荐并购买?
  
  唑尼沙胺作为一种新型的帕金森症药物,在国内研究很少,这里有一个,可以参考。
  
  [作者] 王晔; [作者单位] 沈阳军区总医院神经内科,辽宁省沈阳市,110015; [文献出处] 国际神经病学神经外科学杂志.2010;37(5): 450-454 [关键词] 帕金森病; 运动障碍; 唑尼沙胺; [文章摘要] 帕金森病(PD)患病率随着人口老化逐渐升高,PD早期运动特征可见震颤、强直和运动缓慢,姿位不稳常见于疾病晚期.非运动特征包括认知功能和精神改变,自主神经功能障碍和睡眠紊乱.现在推荐早期应用的一线药物,如左旋多巴、多巴胺受体激动剂和单胺氧化酶B抑制剂(MAO-B)等,均町增强多巴胺能神经传递.随着时间延续,出现疗效衰减和运动障碍,影响生活质量.近年发现抗癫痫药物唑尼沙胺添加治疗可明显改善PD病人临床症状,确切作用机制未明.
  因为当时作用机制未明,所以没有重视和研究推广。前几天我贴出来的一个研究人员Omura T的研究,既唑尼沙胺通过提高HRD1泛素连接酶而导致Tau蛋白降解,可能是提供一个神经保护和解除疾病进展的重要途径。
  但这个研究是用Eisai原产的Zonegran的产品做的,因此一切疗效数据以此为准。
  我不是反对帕友们用国产的唑尼沙胺片(目前已经有100mg的国产药用于癫痫症,30片是210元左右),而是基于疗效和副作用的考虑,建议尽量购买Eisai原产的Zonegran来治疗,在临床上,每天50mg和100mg的用量是最好的,而副作用在25mg和50mg的治疗组没有大的差异,但在100mg的治疗组开始上升。
  如果确实购买Eisai原产的Zonegran有困难,也不妨可以买国产的唑尼沙胺片(100mg)试试效果,但要留意副作用,包括头痛,困倦,嗜睡,眩晕等,但这些副作用在用于癫痫症每天200mg-400mg才会出现,而25mg-100mg的副作用表现是比较少的,还有就是磺胺类过敏的病人不建议使用,包括SMZ磺胺甲恶唑,复方新诺明,可能会有嘴唇长疱等过敏症状。
  最新的消息是Zonegran已经在中国申请唑尼沙胺专利,申请的标题就是(治疗神经变性药物),但什么时候用于临床我想还不会那么快,但迟早会上市。
   

章华:唑尼沙胺在帕金森症治疗上异动症的处理  邮箱:drdanielcheung@gmail.com  IP:220.246.74.155  日期:2012-8-28 [回复8楼]

  唑尼沙胺在帕金森症治疗上异动症的处理
  
  帕金森症治疗上异动症的处理
  帕金森症治疗上始终有一个严重问题的存在,即异动。
  目前在异动症治疗上,除了减低左旋多巴的用量,金刚烷胺和氯氮平也有一定效果,最近发现唑尼沙胺在迟发性运动障碍上包括帕金森症后期由于美多巴或息宁引起的异动症也有独特的效果,用量在每天50mg-100mg,下面的研究就显示在应用唑尼沙胺后,异动症病人的AIMS(异常不自主运动量表)的评分明显下降,揭示唑尼沙胺在异动症方面的应用前景,而且可以用在早期帕金森患者出现的或者由于运用受体激动剂如森福罗而加重的晚间快动眼睡眠行为障碍(RMD),表现为夜间发恶梦及大声说梦话,以及手足抽动甚至踢打的情况。所以,唑尼沙胺这只药物在整体帕金森症的治疗上值得关注。
  
  Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial.
  Iwata Y, Irie S, Uchida H, Suzuki T, Watanabe K, Iwashita S, Mimura M.
  SourceDepartment of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan. youske0221@ybb.ne.jp
  
  Abstract
  Once developed, tardive dyskinesia (TD) is a challenging condition to treat. The recent evidence has indicated that zonisamide, an antiepileptic drug indicated for partial-onset seizures, may also have beneficial effects for ameliorating dyskinesia in Parkinson’s disease. However, this finding has not systematically been tested in psychiatric patients with TD associated with antipsychotic treatment. The objective of this study was to examine the efficacy, tolerability, and safety of zonisamide against TD in these patients. In this 4-week open-label study, subjects who suffered TD were given 50-100 mg/day of add-on zonisamide. Severity of TD was evaluated at the baseline and endpoint, using the Abnormal Involuntary Movement Scale (AIMS). Eleven subjects (6 females; mean±SD age, 75.5±4.7 years; schizophrenia [N=6], bipolar affective disorder [N=2], schizoaffective disorder [N=1], mental retardation [N=1], mental retardation with epilepsy [N=1]; 6 were antipsychotic free at baseline) participated in this study. The AIMS total score (mean±SD) was significantly decreased from 24.1±5.5 to 19.5±5.9, with 36.4% of the subjects (N=4) demonstrating 20% or more decrease in the AIMS total score. Treatment with zonisamide was well-tolerated and no participants dropped out prematurely. In conclusion, zonisamide may be safe and effective for the treatment of TD associated with antipsychotic treatment. These preliminary findings need to be further explored by larger well-designed trials.
  
  Copyright © 2012 Elsevier B.V. All rights reserved.
  
  PMID:22285275[PubMed - in process]  

hyh883:有疑问请教章医生  邮箱:123456  IP:124.90.182.147  日期:2012-8-29 [回复9楼]

  有疑问请教章医生
  章医生,你在这个网站上发的每篇文字我都反复阅读。内地象你样的医生堪为绝无仅有。我先生发病两年半,因有幸拜读你的文字,我一直不让我先生吃一切西药,就是中药调理和针灸,维持还可以,最近才开吃金思平和长春胺。我先生现症状是行动慢,左手摆动不好,左手指就是起床时是好的,过几分钟后就不灵了,左脚有拖步,不明显,这种情况已两年,吃过每多巴四分之一颗三天无效,象这种情况就吃金思平和长春胺行不,他有查出过椎动脉供血不足,还有他有时有抑郁情绪,累了声音会轻下来。把金思平改唑尼沙胺需要不,谢谢。体检的其它所有指标都好,人偏瘦 

章华:回复9楼 hyh883  邮箱:drdanielcheung@gmail.com  IP:220.246.74.155  日期:2012-8-29 [回复10楼]

  回复9楼 hyh883
  回复9楼 hyh883:有疑问请教章医生
  首先从经济层面讲,金思平应该是药保药物,所以不用多花钱,但如果本身经济条件还可以,不妨用进口雷沙吉兰,因雷沙吉兰目前是最顶尖的神经保护剂,薛老己经解释的再清楚不过了,等以后国产雷进入医保后再转。
  至于长春胺(长春西汀)除了有抑制炎症反应外,还能扩张血管,抗凝(血液的高凝状态促生很多疾病包括心脑疾病),所以用长春胺可以对椎动脉供血不足导致的缺氧症有好处,如果长春胺缓释胶囊对胃部有刺激的话可以选用长春西汀片10mg的剂型,最近有个病人告诉我他自己加到了每天40mg,以前的肌肉僵硬和痛楚都有改善。
  而轻度抑郁症完全可以用SAMe(S-腺苷蛋氨酸)治疗,每天二次,每次400-500mg,安全有效。
  现在治疗帕症的药物选择很少,总是在几种药物上打转,远远不够。而且左旋多巴类药物虽然可以明显改善帕症症状,但是可以通过诱导细胞凋亡促进多巴胺神经元变性坏死,所以是作为最后选择。
  唑尼沙胺并不为人所熟悉,本身是抗癫癎症药物,但用于帕症的治疗剂量大约是癫癎症的十分之一,每天在25mg起步,到100mg为止,当然25mg的副作用最小,100mg的最大。
  如果把DBS手术的治疗机制讲一讲可能会加深对唑尼沙胺治疗帕症的认识,DBS手术的治疗机制还不是太确定,但可以肯定DBS并不是作用于产生多巴胺细胞上,所以不会改变多巴胺的浓度,但DBS可以纠正可能因为多巴胺缺乏而导致STN(丘脑下核)和GPI(苍白球内核)的不正常放电,而使大脑电流回复正常,不正常的肌肉运动得到矫正达到治疗目的,癫癎症也是大脑内部异常放电引起,所以从这个方面来讲唑尼沙胺用于治疗帕金森症完全可以理解。而剂量只需要十分之一是因为癫癎症的异常生物电比较强,需要大剂量。
  但我的看法唑尼沙胺的治疗机制应该远远不止仅仅是抑制异常生物电,重在一个抑制MPTP神经毒性,提高HRD1泛素连接酶水平降解Tau蛋白而阻止多巴胺神经元坏死阻止疾病进展,在一些研究中䂳尼沙胺甚至是诱导多巴胺神经元复原,这和左旋多巴诱导多巴胺神经元坏死是大相径庭。而唑尼沙胺目前是在日本广泛应用,虽然在美国FDA还只是批准用于癫癎症,但越来越多的医学界人士留意到唑这只药物,包括美国罗马林达大学运动障碍临床部神经内科的Jack J.Chen最近八月写的「最新的帕金森病循证医学评论概述」中把唑尼沙胺和雷沙吉兰并提为有效(efficacious),反而司来吉兰(金思平)的评定状态是证据不足(insufficient evidence)。
  治疗帕症不能停留在目前的治疗水准上,从八月份开始我己经选择性地开展人类胎盘干细胞疗法,希望对帕症治疗开发一些新的实践与方法。
  
   

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