更新于：2024-11-15

Topiramate

托吡酯

更新于：2024-11-15

概要

概要

基本信息

简介托吡酯以商品名Topamax ® 销售，是一种抗惊厥药物，于1995年在英国由Janssen Services 首次推上市场。其作用机制为 GABAAR 激动剂。主要用于治疗癫痫，也被批准用于预防和治疗偏头痛。托吡酯通过稳定大脑中的电活动起作用，从而降低癫痫发作的可能性。已发现它可有效降低癫痫患者癫痫发作的频率和严重程度，以及减少偏头痛的频率。托吡酯有片剂形式，通常按照医疗保健提供者的指示每天口服一次或两次。

药物类型

小分子化药

别名

2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate、2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate、Topiramate (JAN/USP/INN)

+ [19]

靶点

AMPA receptor x CAs x GABAA receptor x VGSCs

作用机制

AMPA receptor拮抗剂(离子型谷氨酸受体AMPA拮抗剂)、CAs抑制剂(碳酸酐酶家族抑制剂)、GABAA receptor激动剂(γ-氨基丁酸 A 受体激动剂)

治疗领域

神经系统疾病遗传病与畸形其他疾病

在研适应症

癫痫偏头痛Lennox-Gastaut综合征+ [4]

非在研适应症

精神病性情感障碍酗酒暴食症+ [24]

原研机构

Janssen Global Services LLC

在研机构

Azurity Pharmaceuticals, Inc.

Kyowa Kirin Co., Ltd.

Supernus Pharmaceuticals, Inc.

+ [5]

非在研机构

Janssen Pharmaceutica NVJohnson & Johnson Pharmaceutical Research & Development LLCOrtho-mcneil Neurologics, Inc.

+ [3]

最高研发阶段批准上市

首次获批日期

美国 (1996-12-24),

癫痫部分性发作强直阵挛性癫痫

最高研发阶段(中国)批准上市

特殊审评孤儿药 (美国)

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结构

分子式C12H21NO8S

InChIKeyKJADKKWYZYXHBB-XBWDGYHZSA-N

CAS号97240-79-4

关联

329

项与托吡酯相关的临床试验

NCT05209984 / Not yet recruiting临床3期

A Phase 3, Randomized, Double-blind, Double-dummy, Parallel-group, Active Drug and Placebo-controlled, Safety, Efficacy and Superiority of Sibutramine IR/Topiramate XR in Overweight Adults With Comorbidities/Obesity

A phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, active-drug- and placebo-controlled clinical trial to assess the safety, efficacy and superiority of the new fixed-dose combination sibutramine IR/topyramat XR in weight reduction in overweight adults with comorbidity(ies) or obesity

开始日期2025-10-30

申办/合作机构

Eurofarma Laboratórios SA

TCTR20240527003 / Not yet recruiting临床1期IIT

A Bioequivalence study of a randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence of Topiramate 100 mg tablets relative to Topamax 100 mg tablets, in healthy Thai volunteers under fasting condition

开始日期2025-02-11

申办/合作机构

Bio-innova Co., Ltd

NCT06499116 / Not yet recruiting临床4期IIT

Comparison of the Effectiveness of First-line Preventive Treatment of Migraine in Primary Care: a Pragmatic Clinical Trial [PREMI Study]

This study, which is aimed at comparing the effectiveness of the most frequently used drugs in the first line in primary care for the preventive treatment of migraine (amitriptyline, flunarizine, topiramate and propranolol), is a multicentre, pragmatic, parallel group, open randomised trial. Adults (≥18) candidates for preventive treatment for migraine; those with a frequency of ≥4 monthly migraine days, and who agree to participate in the clinical trial, will be randomised to one of the 4 groups. Sample: 460 patients. The primary outcome will be the reduction in monthly migraine days, comparing amitriptyline, flunarizine and topiramate with propranolol.

开始日期2024-10-01

申办/合作机构

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

[+1]

100 项与托吡酯相关的临床结果

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100 项与托吡酯相关的转化医学

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100 项与托吡酯相关的专利（医药）

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5,785

项与托吡酯相关的文献（医药）

2024-12-01·Molecular biology reports

Comparison of neuroprotective effects of a topiramate-loaded biocomposite based on mesoporous silica nanoparticles with pure topiramate against methylphenidate-induced neurodegeneration

Article

作者: Khalilzadeh, Mina ; Mir, Saeedeh ; Pari, Erfan ; Motevalian, Manijeh ; Moazam, Ashrafsadat ; Sheibani, Mohammad ; Sazegar, Mohammad Reza

BACKGROUND:

Methylphenidate (MPH) abuse has been criticized for its role in neurodegeneration. Also, a high risk of seizure was reported in the first month of MPH treatment. Topiramate, a broad-spectrum Antiepileptic Drug (AED), has been used as a neuroprotective agent in both aforementioned complications. Nanotechnology is introduced to increase desirable neurological treatment with minimum side effects. We aimed to investigate the potential neuroprotective activity of topiramate loaded on nanoparticles.

METHODS AND RESULTS:

MTT assay was performed to evaluate the cellular cytotoxicity of Mesoporous Silica Nanoparticles (MSN). Male rats were randomly divided into eight groups. Rats received an intraperitoneal (i.p) MPH (10 mg/kg) injection and a daily oral dose of topiramate (TPM, 30 mg/kg), MSN with Zn core (10 and 30 mg/kg), and MSN with Cu core (10 and 30 mg/kg) for three weeks. On day 21, a seizure was induced by a single injection of pentylenetetrazole (PTZ) to evaluate the protective effects of TPM-loaded nanoparticles on seizure latency and duration following MPH-induced neurotoxicity. Moreover, the hippocampal content of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and the anti-oxidant enzymes (SOD, GPx, and GR) activities were assessed. Also, BAX and Bcl-2 as two main apoptotic markers were evaluated.

RESULTS:

MPH neurotoxicity was observed as a raised duration and reduced latency in PTZ-induced seizure. However, TPM-loaded MSN with Zn species (NE) treatment reduced the duration and improved the latency time. Also, NE and, somewhat, TPM-loaded MSN with Cu species (NM) administration reduced inflammatory cytokines, MDA, and Bax levels and increased activities in the rat hippocampus.

CONCLUSION:

TPM-loaded nanoparticles could be used as neuroprotective agents against MPH-induced neurodegeneration by improving seizure parameters and reducing inflammatory, oxidant, and apoptotic factors.

2024-12-01·Pain and Therapy

Cerebral Artery Vasoconstriction After Galcanezumab Loading Dose for Migraine Prevention: A Case Report

Article

作者: Blumenfeld, Andrew ; Asawavichienjinda, Thanin ; Jittapiromsak, Nutchawan

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies that target CGRP ligands or receptors, may cause a very rare side effect of reversible cerebral vasoconstriction syndrome (RCVS). This study is a case report of a patient who developed cerebral artery vasoconstriction documented on serial brain magnetic resonance angiography (MRA) scans without the typical manifestations of RCVS following galcanezumab loading dose. Case report: A 40-year-old female patient with high-frequency episodic migraine with visual aura on topiramate 100 mg/day developed transient numbness of the right upper and lower extremities and right face without headache and a normal neurological examination 10 min after a loading dose of galcanezumab, which resolved over the next 2 days. Magnetic resonance angiography brain imaging showed segmental arterial constriction of both middle cerebral arteries in the M1-2 segments and both posterior cerebral arteries in the P1-2 segments, which partial resolved in a subsequent study by the end of 6 months. There were no other supporting examination data, such as transcranial Doppler, which might provide additional information on the progression and improvement of the vasoconstriction. Her differential diagnosis included prolonged migraine sensory aura without headache, RCVS, or cerebral vasoconstriction secondary to the effect of an anti-CGRP monoclonal antibody. Further research needs to be conducted.

2024-12-01·PEDIATRIC NEUROLOGY

Rare CCND2 (p.Thr280Ile) Variant Associated With Infantile Spasms in a Patient With Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

Article

作者: Erdemir, Gozde ; Carpenter, Jessica L ; Mok, Kent M ; Mok, Kent M. ; Yazbek, Sandrine ; Herrada, Pamela ; Greene, Carol ; Carpenter, Jessica L.

BACKGROUND:

This report describes a pediatric case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome, a rare neurodevelopmental disorder caused by pathogenic variants in the AKT3, CCND2, or PIK3R2 genes. We present a patient with a rare CCND2 variant (c.839C>T, p.Thr280Ile), associated with infantile spasms, ventriculomegaly, polymicrogyria, and intraventricular hemorrhage (IVH).

METHODS:

A retrospective chart review and literature search were performed using PubMed.

RESULTS:

Our patient was found to have ventriculomegaly, grade 3 IVH, bilateral polymicrogyria, and restricted diffusion in the caudate nuclei prenatally. No polydactyly was observed. The patient developed infantile spasms at age 5 months. While high-dose prednisone treatment failed to control the spasms, they resolved with topiramate. By age 2 years, the patient continued to have significant developmental delays, including having poor tone and being nonverbal.

CONCLUSION:

MPPH syndrome remains a rare and challenging diagnosis, with fewer than 100 cases reported. This case highlights the importance of early genetic testing and neuroimaging in the diagnosis and management of MPPH. The unique presentation of IVH and restricted diffusion warrants further investigation into the syndrome's variable phenotypic spectrum. Early intervention and targeted therapy may help manage seizure activity and improve outcomes.

109

项与托吡酯相关的新闻（医药）

2024-11-08

·丁香园

近千万女性服下的「保胎神药」，让癌症延续了 3 代人

本文作者：方婧玉有一项癌症研究，历时 50 余年，开展了六轮，纳入超 21000 名志愿者，贡献了 40 余篇高质量研究论文，是全球范围内少有的横跨三代人的癌症研究之一。然而，这项研究却被称为「医学历史上最大规模的亡羊补牢」。它就是美国国立癌症研究院（NCI）开展的己烯雌酚随访研究（DES Follow-up Study）。己烯雌酚，这种如今已被熟知的 I 类致癌物，在 70 年前却被近千万女性当做「保胎药」服用。其灾难性的后果，在 21 世纪的今天仍然持续。「保胎神药」的诞生己烯雌酚诞生在 1938 年，英国化学家查尔斯·多兹在偶然中，合成出了一种不具有雌激素的典型结构，却依然有着明显雌激素活性的物质。自 1942 年发现的结合雌激素（倍美力）被正式用于临床治疗更年期综合征等疾病后，雌激素补充治疗（ERT）被越来越多被妇女接受。但天然来源的雌激素需要从胎盘或马尿中提取，常受到原材料供应短缺的限制，而结构简单、合成成本低廉的己烯雌酚的出现，让医疗界看到了雌激素缺乏的新希望。经过了简单的临床研究后，1941 年美国食品药品监督管理局（FDA）批准己烯雌酚用于治疗更年期综合征。然而，登上市场后，己烯雌酚的销量并不好。这是因为，虽然更年期综合征是一种常见病，但保守的社会风气使得女性对这一疾病的认知度并不高，而若将这本就不大的市场平摊到数十家药企上，就更加显得可怜了。转机很快出现了。有药企发现，一些妇产科医生会把雌激素制剂处方开给孕妇，以此来「保胎」。在当时，医疗界普遍认为流产和早产与妊娠期间的雌激素和孕激素水平失调有关，而补充雌激素则成为了医生们「预防流产和早产」的一种手段。 1946 年，妇产科学界权威、哈佛大学的史密斯夫妇在《美国妇产科学杂志》（AJOG）上发表研究[2]，表示己烯雌酚可以纠正胎盘内孕激素水平的异常，从而可能起到「预防早产」的作用。而这项研究，则是由生产己烯雌酚的药企资助完成的。彼时，美国的药品监管制度正处于一片混乱之中，尽管 1937 年发生的磺胺酏剂中毒事件催生了《1938 年联邦食品、药品及化妆品法案》的诞生[3]，但当时对处方药的上市要求仍然流于形式。 1947 年，FDA 批准了己烯雌酚用于预防流产和早产。次年，奥利弗·史密斯再次在 AJOG 上发表文章[4]，表示在自己的研究中有 72% 的孕妇在服用己烯雌酚后成功娩出健康婴儿，并提出了此后被妇产科医生沿用了数十年的「史密斯方案」。己烯雌酚片剂，在当时有数十家药企在生产和推广己烯雌酚（图源：wonderdrugthemovie.com）出于对监管部门和医学权威的信任，从 20 世纪 50 年代开始，医生们开出大量己烯雌酚处方给孕妇，一度被奉为「保胎神药」。据统计，在己烯雌酚获批后的三十余年内，共有近千万女性曾在妊娠期服用过己烯雌酚。是神药，还是安慰剂？在 20 世纪中期，美国法律禁止了直接面向消费者的处方药推广行为。于是，药企转向医生宣传：在专业期刊上刊登己烯雌酚的广告，派遣医药代表向医生推销己烯雌酚，或直接为己烯雌酚相关的论文提供赞助。己烯雌酚的主要生产药企曾经派出大量医药代表，协助全美各地的产科医生和家庭保健医生工作，并在专业期刊上刊登了一则医药代表的广告，宣传其医药代表是医生的得力助手。药企打出了「我们为他付工资，而他则只为你服务」（We Pay Him But He Works for You！）的广告词，希望让医生与医药代表建立紧密的利益关系。医药史上少有的没有宣传具体产品的药企广告（图源：desaction.org）然而，并不是所有的妇产科医生都对己烯雌酚持欢迎态度。芝加哥产科医院的妇产科主任威廉姆·迪克曼教授认为，史密斯夫妇进行的开放性研究和病例回顾分析，很可能产生了强大的安慰剂效应，从而营造出了「己烯雌酚有效」的假象。更何况，史密斯夫妇涉及了己烯雌酚的研究都接受了药企的资助，这一利益关联也使得研究的含金量大打折扣。很快，迪克曼教授拿到了美国国立卫生研究院的资助，开展了一项针对己烯雌酚预防早产的随机、双盲、安慰剂对照临床试验。为了表示公正，迪克曼教授还在研究中特意采用了「史密斯方案」来完成己烯雌酚治疗——结果不出所料，在校正了诸多混杂因素之后，己烯雌酚预防流产和早产的效果和安慰剂毫无区别。 1953 年，迪克曼教授将研究结果拿到了第 76 届美国妇产科学会年会上和史密斯夫妇「当面对质」[5]。史密斯先生表示，自己的研究受年代和条件限制未能如愿以偿地完善，并质疑迪克曼教授的研究存在方法学重大缺陷；史密斯夫人则认为迪克曼教授的研究没有考虑到人和人之间的生理差异，并表示己烯雌酚治疗的理论基础妙过哲学（something more than a philosophy）。最终，尽管迪克曼教授的研究内容得到了在场多位专家的认可，但他在和史密斯夫妇的争论中并没有占据上风，这项研究结果最终也未能得到医疗界注意，己烯雌酚依旧在继续它的「神话」。被千万女性服用，影响横跨三代人「神药」终于跌下神坛的一天。 1970 年，17 岁的纽约州女孩希拉·斯通被确诊为阴道腺癌。这是一种极其罕见的生殖系统肿瘤，根据当时的资料，阴道腺癌几乎不会发生于 30 岁以下的女性。希拉一直以来健康状况良好，家族中并没有类似的癌症病史，也没有接触过已知的任何致癌物，不过，她的母亲曾经在怀孕期间服用过数月的己烯雌酚。希拉认为自己患病可能和己烯雌酚有关，并数次向医生提到自己的这一想法，主治医生随后将她的病历转交给哈佛大学麻省总医院的亚瑟·赫布斯特医生。希拉的故事随后被公益组织 DES Action 所报道（图：DES Action）收到希拉的病例前，赫布斯特医生刚刚在著名医学杂志 Cancer 上发表了一篇文章，介绍了自己从 1966～1969 年收到的 7 例年轻阴道腺癌患者[6]。在听到了希拉的病史之后，赫布斯特也赶忙去调阅了自己手上患者的资料，发现其中 6 例患者的母亲都在怀孕期间服用过己烯雌酚。为了验证自己的想法，赫布斯特开展了一项病例对照研究，将自己收集到的 8 例阴道腺癌（包括 1 例同事转交的病例）患者母亲的资料与 32 例同时期出生的健康女性的母亲的资料进行了对比，结果发现母亲孕期服用己烯雌酚与女儿患阴道腺癌具有明确关联。赫布斯特的研究随后于 1971 年 4 月发表于 NEJM 上[7]，并很快引起了纽约州卫生署的彼得·格林沃德医生的注意。格林沃德也去火速调阅了纽约州癌症登记系统上的资料，发现了包括希拉在内的 5 例年轻阴道腺癌患者，病例对照研究同样显示，她们的肿瘤与母亲孕期服用己烯雌酚类药物明确相关，这项研究也于 1971 年 8 月发表于 NEJM[8]。赫布斯特和格林沃德的研究相继发表，引起了 FDA 的注意。由于证据确凿，FDA 于 1971 年 11 月下达通报，正式对孕妇禁用己烯雌酚，并强制要求所有雌激素制剂（包括己烯雌酚和天然雌激素制剂）的说明书中列明己烯雌酚与癌症的相关性资料[9]。 FDA 发布的通报（图源：参考文献[9]）然而，FDA 的通报还是来的太迟了。在这份通报生效之前，仅美国就有约 500 万女性在孕期服用过己烯雌酚，且己烯雌酚还一度被作为兽用生长促进剂，用于畜禽的「增肥」，所以实际暴露人数可能还要更多。另一方面，很多医生已经把处方己烯雌酚变成了和吃饭喝水一样平常的事情，而 FDA 的通报并没有要求己烯雌酚撤市（在美国，己烯雌酚直到 2000 年才正式被注销批文），因此直到 20 世纪 80 年代，仍有医生继续给孕妇处方己烯雌酚，直到药企因诉讼而被迫主动停产药物为止。在 FDA 发布了己烯雌酚禁令之后，美国成立了多个由己烯雌酚受害者组成的维权团体，在它们的推动下，整个社会开始重视起了这场灾难性的药害事件。 1975 年，由 NCI 牵头的己烯雌酚腺病计划（DESAD）正式启动[10]，4000 余名己烯雌酚暴露者和 1000 余名健康女性共同参与了研究；1992 年，DESAD 计划正式扩展为己烯雌酚随访研究。然而，随着研究的不断深入，科学界发现己烯雌酚的影响早已超出预期。己烯雌酚的销量（黑线）与对应20年后的阴道腺癌发病数（紫线）的对比（图源：参考文献[10]）根据最近的己烯雌酚随访研究的数据，除了直接导致阴道透明细胞腺癌外，己烯雌酚还可影响多个与生殖系统发育有关的基因[11]，可诱发女性生殖道发育异常。此外，己烯雌酚还可能通过表观遗传机制改变受暴露女性子代（第三代己烯雌酚婴儿）的部分基因[12]，从而使其对人体的不利影响波及三代人，例如关于尿道下裂的风险升高，关于卵巢癌的风险升高。亡羊补牢纵观历史，己烯雌酚事件与欧洲同时期的「反应停事件」颇为类似，二者均为开发用于孕妇的药物，均在临床证据不明的情况下被推向市场，并都导致了灾难性的结局。然而，己烯雌酚事件受到的关注度远不如反应停事件。也许是因为反应停事件的后果更为直观惨重，而己烯雌酚的危害往往缓慢暴露；也可能是因为 FDA 拒绝沙利度胺上市成为了医学史上的一次「功勋事件」，在一定程度上掩盖了随后己烯雌酚事件的恶劣影响，电影《Wonder Drug》甚至称己烯雌酚为「隐形的沙利度胺」。但毫无疑问的是，己烯雌酚事件对FDA造成了深远影响。由于己烯雌酚的滥用很大程度上源于监管不作为，FDA 在此后制定了非常严格的妊娠期用药体系，强制性要求药物在上市前开展动物生殖研究，并建立了妊娠用药分级，即 ABCDX 制度。 FDA 的「五字母系统」，已在 2015 年废除。新规要求药品说明书中提供详细信息，由医生自主决定用药。（图源：丁香园临床用药指南）此外，FDA 也建设了常态化的药物相关出生缺陷报告与评估网络，该机制帮助 FDA 陆续发现了数种具有强致畸效应的药物，有效避免了大量出生缺陷的发生。例如，治疗银屑病的阿维 A 酯于 1986 年在美国上市，但后来有证据表明阿维 A 酯会导致严重的先天畸形，而且在人体内很难被代谢，会存留 3 年以上甚至是终生。因此阿维 A 酯在 1998 年被撤出了市场。再如，托吡酯在 1996 年获批时是妊娠 C 级，后北美抗癫痫药妊娠期注册项目（NAAED）发现此药会导致唇腭裂，FDA 便调整它为妊娠 D 级，并且建议在妊娠早期不要使用[14]。还有治疗艾滋病的多替拉韦，获批后经观察性研究证明多替拉韦会导致神经管畸形，FDA 随即在说明书里增加了多替拉韦致畸的内容，并且建议在妊娠中晚期不要使用该药。时至今日，己烯雌酚随访研究仍在继续自己的步伐，根据 NCI 的计划，待疫情平稳后，第七轮己烯雌酚随访研究将按原计划开展。而对于世界，这项研究更像是一口警钟，时刻提醒着，不要让悲剧重演。致谢：本文经天津市武清区人民医院妇产科副主任医师赵天皎专业审核【注】天津市武清区人民医院妇产科副主任医师赵天皎审核意见：中国有句老话——是药三分毒。药既可以治病，也可以致病。本文讨论的雌激素替代物乙烯雌酚，目前已经广泛应用于临床。它可以补充体内雌激素不足，如萎缩性阴道炎、女性性腺发育不良、绝经期综合征、老年性外阴干枯症及阴道炎、卵巢切除后、原发性卵巢缺如。预防产后泌乳、退（或回）乳等。可以说给众多患者带来福音。但是用药的前提是排除禁忌。禁忌证： A) 乳腺癌(除了选定的接受转移性疾病治疗的患者外)患者禁用 B) 患有雌激素依赖性肿瘤患者禁用 C) 妊娠患者禁用 D) 存在未确诊的异常生殖器出血者禁用 E) 血栓性静脉炎，血栓形成或血栓栓塞性疾病患者禁用。药物治疗就是用化学物质来改变人体内的某个特定的生物过程，不能离开剂量、不能忽视禁忌症谈药效，否则良药也会成毒药。策划：z_popeye 监制：carollero 题图来源：视觉中国参考文献： [1]Dodds E, Goldburg L, Lawson W, et al. OEstrogenic Activity of Certain Synthetic Compounds. Nature. 1938;141.3562:247-248. doi:10.1038/141247b0 [2]SMITH OW, SMITH GV, HURWITZ D. Increased excretion of pregnanediol in pregnancy from diethylstilbestrol with special reference to the prevention of late pregnancy accidents. Am J Obstet Gynecol. 1946;51:411-5. doi: 10.1016/s0002-9378(16)40020-7 [3]Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122(6):456-61. doi: 10.7326/0003-4819-122-6-199503150-00009 [4]SMITH OW. Diethylstilbestrol in the prevention and treatment of complications of pregnancy. Am J Obstet Gynecol. 1948;56(5):821-34. doi: 10.1016/0002-9378(48)90440-2 [5]DIECKMANN WJ, DAVIS ME, RYNKIEWICZ LM, et al. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol. 1953;66(5):1062-81. doi: 10.1016/s0002-9378(16)38617-3 [6]Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer. 1970;25(4):745-57. doi: 10.1002/1097-0142(197004)25:4<745::aid-cncr2820250402>3.0.co;2-2 [7]Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(15):878-81. doi: 10.1056/NEJM197104222841604 [8]Greenwald P, Barlow JJ, Nasca PC, et al. Vaginal cancer after maternal treatment with synthetic estrogens. N Engl J Med. 1971;285(7):390-2. doi: 10.1056/NEJM197108122850707 [9]Selected item from the FDA drug bulletin-november 1971: diethylstilbestrol contraindicated in pregnancy. Calif Med. 1972;116(2):85-6. [10]Labarthe D, Adam E, Noller KL, et al. Design and preliminary observations of National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. Obstet Gynecol. 1978;51(4):453-8. doi: 10.1097/00006250-197804000-00014 [11]Bromer JG, Wu J, Zhou Y, et al. Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic mechanism for altered developmental programming. Endocrinology. 2009;150(7):3376-82. doi: 10.1210/en.2009-0071 [12]Titus L, Hatch EE, Drake KM, et al. Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. Reprod Toxicol. 2019;84:32-38. doi: 10.1016/j.reprotox.2018.12.008 [13]Gee D, MacGarvin M, Stirling A, et al. Late lessons from early warnings: the precautionary principle 1896-2000. Ed. Poul Harremoës. Luxembourg: Office for Official Publications of the European Communities, 2001.[14]https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-risk-oral-clefts-children-born-mothers-taking-topamax-topiramate 丁香园是面向医疗从业者的专业平台，以「助力中国医生」为己任。在丁香园，可以和同行讨论病例，在线学习公开课，使用用药助手等临床决策工具，在丁香人才找可靠医疗岗位。

2024-11-04

·生物制药小编

癫痫药物的春天来了？

癫痫治疗领域再次迎来重磅交易。近日，灵北制药宣布以26亿美元的价格，收购Longboard Pharmaceuticals。后者的核心管线是bexicaserin，一款高选择性的5-HT2C超级激动剂，用于治疗难治性癫痫DEE，已完成二期临床并获得突破疗法认证。收购消息传出后，Longboard股价大涨超50%。年初至今，由于公布bexicaserin 1b/2a期研究的积极顶线数据，其股价一路上涨，涨幅超过888%。灵北制药是丹麦精神疾病与神经系统疾病领域先驱，也是为数不多专注于CNS疾病的制药公司之一。大手笔收购Longboard，也意味着其在神经学和罕见疾病这片充满挑战却又极具潜力的领域中，更进一步。尽管失败如影随形，但是，随着越来越多药企尝试征服这一CNS研发高地，或许，正如阿尔兹海默症般，经历数十载漫长黑夜，癫痫药物的开发正在迎来春天。严重未满足的临床需求癫痫是最常见的中枢神经系统疾病（CNS）之一，影响着全球5000多万人。作为一种高致残性的慢性神经系统疾病，癫痫以其发作的不可预测性对患者生活造成极大影响。对于患者来说，治疗首选方案是抗癫痫发作药物（ASMs），这也是最基础、最重要的治疗手段。过去几十年，已有超过20种ASMs问世，从第一代演变至第三代，然而，疗效有限、副作用明显等问题依然影响着癫痫患者的治疗效果，是目前ASMs亟待解决的问题。比如，第一代ASMs包括苯巴比妥、苯妥英钠、卡马西平、丙戊酸、氯硝西泮等。这些药物在早期的癫痫治疗中发挥了重要作用，但其副作用较为明显，如嗜睡、头晕、恶心等，并且药物之间的相互作用较多，需要严格控制剂量和监测不良反应。而第二代ASMs如加巴喷丁、拉莫三嗪、托吡酯、左乙拉西坦、普瑞巴林等。相比第一代药物，副作用有所减少，药物间的相互作用也较少，是目前治疗的主流。但是，在过去的30年中，二代ASMs的广泛使用似乎并未使癫痫药物治疗的整体疗效和耐受性得到提高。近几年上市的三代ASMs，能否打破目前的停滞状态还有待于进一步观察。与之相比，还有一类患者的治疗困境尤为突出。尽管WHO指出70%的癫痫患者通过ASMs治疗可达到消除癫痫发作，但仍有约30%的患者对现有ASMs不敏感，癫痫发作无法得到有效控制，称为难治性癫痫。这类患者由于异质性、耐药性导致可选择的药物十分匮乏。典型如全球神经系统疾病负担的第三大元凶——DEEs。这也是灵北制药此次收购布局的领域。 DEEs是一组罕见的神经系统疾病，通常在婴儿期发作，具有难治性癫痫发作和发育迟缓和/或倒退的特征。同时DEEs涵盖了超过25种不同的综合征，包括Dravet综合征（DS）、Lennox-Gastaut综合征（LGS）、结节性硬化症（TSC）、CDKL5缺乏症（CDD）等，其中仅有4种有获批药物。虽然这些综合征单独被认为是孤儿病，但据估计在美国大约有22万患者受到DEEs综合征的影响。作为一组疾病，其总体发病率达到（0.27～0.54）/1000例新生儿，癫痫发作的影响还伴随到他们的儿童、成年时期，甚至可能导致过早死亡或者避免死亡但留下严重的神经系统残疾。而在治疗方面，大多数DEE患者采用多种药物联合治疗，并随时间更换药物。然而，几乎所有患者都经历了多次癫痫发作和治疗相关的副作用。换句话说，DEEs治疗领域存在严重未满足的临床需求，需要更多更好的治疗选择。潜在破局者bexicaserin 灵北制药此次收购Longboard，看中的就是bexicaserin有成为DEEs领域破局者的潜力。 Bexicaserin是由Longboard研发的新型口服、高选择性、中枢作用的5-HT2C超级激动剂，正在开发用于治疗与DEE相关的癫痫发作，例如Dravet综合征、Lennox-Gastaut综合征、结节性硬化症、CDKL5缺乏症和其他癫痫性疾病。 5-HT是一种重要的脑内神经递质，与神经元的兴奋-抑制平衡密切相关，其受体包含多种亚型。其中5-HT2C受体，是一种G蛋白偶联受体，这也是Longboard一直专注的成药靶点，已被确定为治疗肥胖和其他CNS疾病(如精神分裂症和药物成瘾)的有效药物靶点。但是，由于5-HT2C受体与其他两个5-HT2亚型(5-HT2A和5-HT2B)具有约50%的序列相似性，因此导致大量药物存在脱靶效应，或因选择性差从而与5-HT2A、5-HT2B结合，产生幻觉和心脏瓣膜病等副作用。比如2020年获批用于治疗Dravet综合征的5-HT2激动剂Fintepla，其药物标签上有一个黑框警告，该药物的活性成分与瓣膜性心脏病和肺动脉高压的风险有关。因此，开发高选择性5-HT2C受体激动剂，作为潜在治疗DEEs药物更具前景。临床前试验已经验证了bexicaserin的5-HT2C受体高选择性以及相比内源性5-HT能诱导更强的细胞反应。与Fintepla相比，bexicaserin对5-HT2C受体的选择性增加，从而减少了与5-HT2A和5-HT2B激动剂相关的潜在不良反应的可能性。今年1月，Longboard公布了bexicaserin 1b/2a期研究的积极顶线数据，结果显示：在主要疗效终点方面，在DEE研究人群中，bexicaserin使可数运动性癫痫发作的中位数减少53.3%，远高于安慰剂组的20.8%。另外，Longboard还公布了在DS、LGS和其他DEE亚组中的数据，癫痫发作的中位数降低分别为72.1%、48.1%和61.2%。这一数据，与此前Fintepla治疗DS的三期临床数据不相上下。而在安全性方面，bexicaserin表现似乎更优。此前Fintepla各组患者经历了至少一次严重TEAE，bexicaserin最常见的不良事件则是嗜睡、食欲下降、便秘、腹泻和嗜睡。数据公布后，Longboard的股价一路上涨，截至收购消息公布前，涨幅已经接近600%，而年初至今，其股价涨幅超过888%。 7月，bexicaserin获得FDA突破性疗法认定，用于2岁以上DEEs患者的治疗。9月以来，Longboard正式开启了bexicaserin针对DS的Ⅲ期试验。优秀的临床表现也成功吸引了灵北制药入局，并对其报以厚望，计划在2028年第四季度正式推出，预计bexicaserin全球销售额达到15-20亿美元。灵北制药总裁Charl van Zyl表示，此次收购是“变革型的交易”，将成为灵北神经罕见病的基石，有可能推动未来十年的发展。癫痫药物的春天来了？由于血脑屏障阻碍、致病机制不明、缺乏有效疾病模型等原因，包括癫痫在内的CNS疾病新药研发困难重重。幸运的是，包括Longboard在内的biotech在不断努力，包括灵北制药、艾伯维、武田等大药企的加入，也在不断增强我们对于征服该领域的信心。去年底，艾伯维宣布以87亿美元收购Cerevel，后者管线较多，其中之一包括Darigabat，用于治疗难治性癫痫和恐慌症，已经进入2期临床。整体来看，除了前文提及的bexicaserin、Fintepla，还有一些已上市以及很多处于研究中的新型抗癫痫药物。根据DelveInsight公司提供的数据，目前有超过75家药企在开发癫痫药物，在研药物超过90个。可以说，这些新一代ASMs的研究和开发为癫痫患者提供了更多治疗选择。而去年以来，癫痫领域在基础、临床研究方面取得了诸多进展。比如加拿大药企Xenon，其核心管线XEN1101是一款新型小分子Kv7.2/Kv7.3钾通道开放剂，主要开发适应症是癫痫和抑郁症。 Kv7.2/Kv7.3电压门控钾通道在大脑神经元轴突周围和轴突上的表达，是一个特别有吸引力的靶点。这些抑制性离子通道在靠近动作电位阈值的神经膜去极化对抗癫痫的过度兴奋起着制约作用，增强Kv7.2/Kv7.3通道开放的药物已被证明能减少癫痫发作。2011年，瑞替加滨被FDA批准为治疗癫痫的抗惊厥药物，但由于存在严重的皮肤及视网膜色素沉积等毒副作用，已经退市。与之相比，XEN1101有更高的体外和体内活性，瑞替加滨需要每天给药三次，而XEN1101每天给药一次，且没有色素沉积等问题。临床二期数据显示，XEN1101高剂量组癫痫发作频率相比基线降低52.8%，而安慰剂组只有18.2%。国内方面，上海药物所研发的派恩加滨同样瞄准这一靶点。而与瑞替加滨相比，派恩加滨的化学性质、活性、药代和安全性特征均显著优化，没有色素沉积风险。临床一期试验证明其具有良好的安全和代谢特性，目前出于二期阶段。再比如，Epidiolex是一种首创运用大麻成分的抗癫痫疗法，也是首个获批用于DS的药物，其主要成分大麻二酚（CBD）是一种多靶点分子，被证实具有明显抗癫痫活性。不过，CBD抗癫痫作用的分子机制仍不清楚，其可能的治疗靶点包括离子通道、转运体和跨膜信号蛋白，具体抗癫痫作用的机制仍有待研究。而最新研究显示，LPI-GPR55信号传导通路是CBD抗癫痫靶点的潜在调节因子，在联合用药方面，CBD也为对GABAAR调节剂（例如苯二氮卓类药物）无效的难治性癫痫患者提供了一种潜在的治疗选择。而在新机制研究方面，武田制药8.65亿美元收购而来的胆固醇24羟化酶（CH24H）抑制剂soticlestat，属于一个全新的抗癫痫作用机制，是通过抑制CH24H活性，减少胆固醇转化为24S-羟基胆固醇，从而降低谷氨酸能通路的兴奋性，减少癫痫发作。积极的二期试验结果为DS和LGS患者提供了新的药物选择的可能性，尤其是那些对现有药物不敏感的患者。然而，三期试验双双折戟。总体来看，目前在研治疗方法主要针对遗传学、离子通道和其他神经递质，以及其他潜在性FIC干预措施，比如干细胞、肠道微生物组、AAV9基因疗法等在进行早期研究，也为患者带来了更多新希望。从趋势来看，癫痫新疗法的研究不再局限于发作的控制，而是包括从发病机制的根源上改变癫痫发作的治疗及预后情况。总结需要承认的是，尽管新的突破每天都有可能发生，但这尚无法彻底改变CNS疾病新药研发的困境。就在上半年，一些药企在研癫痫新药遭遇失败。4月份，Addex宣布ADX71149在治疗对左乙拉西坦或布瓦西坦反应不佳的局灶性癫痫发作的2期研究失败；6月份，Marinus公司口服抗癫痫药物Ztalmy的静脉制剂ganaxolone治疗难治性癫痫持续状态开展的试验失败；武田的soticlestat，在治疗LGS及DS这两种难治性癫痫综合征的三期试验均未达主要终点；对此，武田表示，在16周的治疗中，治疗应答率、护理人员和临床医生对病情改善的总体印象以及癫痫发作强度和持续时间尺度都发生了显著变化。总体数据呈积极趋势，希望与监管机构商讨下一步行动。在号称“研发黑洞”的CNS领域，也的确需要武田这种屡败屡战的精神。期待新的革命性突破，早日到来。

并购临床2期

2024-10-30

·GlobeNewswire-Health Care

VIVUS and UpScriptHealth Announce Launch of ChooseQ.online for Access to Advanced Weight Management Solutions

Collaborative telehealth platform will provide patients with immediate access to QSYMIA®, a chronic weight loss medication, enhancing their healthcare journey CAMPBELL, Calif., Oct. 30, 2024 (GLOBE NEWSWIRE) -- VIVUS LLC, a biopharmaceutical company committed to the development and commercialization of innovative therapies that focus on advancing treatments for patients with serious unmet medical needs, and UpScriptHealth, a leading, nationwide, direct-to-consumer telemedicine company, today announced the launch of ChooseQ.online. This robust online telemedicine platform is designed specifically for distributing QSYMIA® (phentermine and topiramate extended-release capsules CIV), the leading non-injectable branded weight loss medication in the U.S. for adults. Under this collaboration, QSYMIA is now accessible to patients through UpScript LLC’s proprietary Telehealth Platform. QSYMIA is indicated as an FDA-approved adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in some adults and certain pediatric patients aged 12 years and older. “The launch of ChooseQ.online represents a significant milestone in our commitment to enhancing patient care and accessibility. We are thrilled to offer our patients the convenience they deserve,” said John Amos, CEO of VIVUS. “By leveraging UpScriptHealth’s expertise, within just a few clicks patients can now access medications, like QSYMIA, and consult with a physician from anywhere, ensuring that quality health care is always within reach.” ChooseQ.online offers the ability to: Access high quality health care and directly communicate with a healthcare providerHave medication mailed directly to patients through a mail order pharmacy, which offers patients a time-saving solution, or sent to a retail pharmacyProvide patient assistance with managing the coverage administration process through UpScriptHealth’s benefit support capabilities “Partnering with VIVUS marks a significant milestone in our joint commitment to technological innovation in healthcare. Together, we are redefining telehealth standards, offering patients nationwide a convenient, efficient, and personalized approach to managing their weight and health,” said Peter Ax, CEO and founder of UpScriptHealth. With over 20 years of experience and more than one million patients served, UpScriptHealth specializes in creating effective web-based campaigns for pharmaceutical companies. Its comprehensive services include virtual prescribing, coverage and benefit support, as well as long-term adherence support. For patients actively seeking online support and solutions, UpScriptHealth offers a fast and convenient option. “Our collaboration with UpScriptHealth ensures that patients receive the highest standard of care at a convenient time and location,” added Santosh T. Varghese, MD, President VIVUS Global Pharmaceutical Development and Chief Medical Officer at VIVUS LLC. “This initiative, paired with our recent labeling update, not only expands access to QSYMIA, but also empowers patients to proactively engage in their treatment plans, fostering long-term health outcomes.” The label update for QSYMIA removed specific body mass index (BMI) requirements and warnings or precautions regarding increase in heart rate, risk of hypoglycemia in people with type 2 diabetes taking anti-diabetic therapy, and risk of hypotension in people taking antihypertensive medication. The projected global impact of obesity is staggering, with an estimated one billion people expected to be affected by 2030. This marks nearly a twofold increase from around 511 million in 2020. Significantly, obesity escalates the risk of type 2 diabetes, hypertension, and dyslipidemia. Consequently, this heightened risk contributes to an overall increased susceptibility to cardiovascular disease and mortality. Achieving and maintaining healthy weight goals can play a crucial role in mitigating this risk. QSYMIA was approved by the U.S. Food and Drug Administration in 2012 for chronic weight management. The once-daily pill is covered by the majority (81%) of commercial healthcare plans and is indicated for long-term use. QSYMIA is designed to help patients manage hunger and reduce cravings throughout the day. Combined with a healthy diet and exercise, it has been proven to help patients lose weight and maintain weight loss. About VIVUS VIVUS is a biopharmaceutical company committed to the development and commercialization of innovative therapies that focus on advancing treatments for patients with serious unmet medical needs. For more information about the Company, please visit http://www.vivus.com. About UpScriptHealthUpScriptHealth provides a fully compliant direct-to-consumer Telemedicine platform for pharmaceutical companies and consumer products companies. This unique platform allows for convenient access to high quality health care including state of the art medicines. In 2002 UpScriptHealth was the first company in the US to be licensed to write prescriptions on the internet through an online physician consultation. Since then, we’ve treated more than a million patients in all fifty states. Learn more at www.UpScriptHealth.com. About QSYMIA QSYMIA is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 12 years and older with obesity, and in adults with overweight in the presence of at least one weight-related comorbid condition The effect of QSYMIA on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of QSYMIA in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. For more information on QSYMIA, please visit https://QSYMIA.com/ Important Safety Information for QSYMIA Do not take QSYMIA if you are pregnant, planning to become pregnant, or become pregnant during QSYMIA treatment; have glaucoma; have thyroid problems (hyperthyroidism); are taking certain medicines called monoamine oxidase inhibitors (MAOIs) or have taken MAOIs in the past 14 days; are allergic to topiramate, sympathomimetic amines such as phentermine, or any of the ingredients in QSYMIA. QSYMIA can cause serious side effects, including birth defects (cleft lip/cleft palate), serious eye problems (secondary angle closure glaucoma), visual field defects (independent of elevated intraocular pressure), suicidal thoughts or actions, and severe rash with blisters and peeling skin. QSYMIA may slow the increase in height in children 12 years and older. Common side effects of QSYMIA in adults include numbness or tingling in the hands, arms, feet, or face (paraesthesia), dizziness, changes in the way foods taste or loss of taste (dysgeusia), trouble sleeping (insomnia), constipation, and dry mouth. Common side effects of QSYMIA in children aged 12 years and older include depression, dizziness, joint pain, fever, flu, and ankle sprain. For more information please read the QSYMIA Medication Guide, Full Prescribing Information, and Risk of Birth Defects with QSYMIA patient brochure. Forward-Looking Statements Important Information and Cautionary Note Regarding Forward-Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, and/or covered by the “Bespeaks Caution” doctrine applied by the courts under the antifraud provisions of the federal securities laws, and other applicable provisions of the federal securities laws. Such forward-looking statements are based on current expectations, management’s beliefs and certain assumptions made by the Company’s management. These statements may be identified by the use of forward-looking words such as “will,” “shall,” “may,” “believe,” “expect,” “forecast,” “intend,” “anticipate,” “predict,” “should,” “plan,” “likely,” “opportunity,” “estimated,” and “potential,” and/or the negative use of these words or other similar words. All forward-looking statements included in this document are based on our current expectations, and the Company assumes no obligation to update any such forward-looking statements except to the extent otherwise required by law. Forward-looking information about QSYMIA, including its potential beneﬁts, approvals in potential markets outside the U.S. and anticipated product availability, involve substantial risks and uncertainties that could cause actual results to diﬀer materially from those expressed or implied in this press release. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to diﬀering interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisﬁed with the design of and results from our clinical studies; whether and when drug applications may be ﬁled in any other markets or approved, whether QSYMIA will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could aﬀect the availability or commercial potential of QSYMIA; uncertainties regarding the impact of COVID-19 on our business, operations, and ﬁnancial results; and competitive developments. The above factors, risks and uncertainties are difficult to predict, contain uncertainties that may materially affect actual results and may be beyond the Company’s control. New factors, risks and uncertainties emerge from time to time, and it is not possible for management to predict all such factors, risks and uncertainties. Although the Company believes that the assumptions underlying the forward-looking statements contained herein are reasonable, any of the assumptions could be inaccurate, and therefore any of these statements may prove to be inaccurate. In light of the significant uncertainties inherent in the forward-looking statements included herein, the inclusion of such information should not be regarded as a representation or warranty by the Company or any other person that the Company’s objectives and plans will be achieved. These forward-looking statements speak only as of the date such statements were made or any earlier date indicated, and the Company does not undertake any obligation to update or revise any forward-looking statements, whether as a result of new information, future events, changes in underlying assumptions or otherwise, unless otherwise required by law. Contacts VIVUS LLCT: +1 (650) 934-5200 Media – FINN Partners Glenn Silver glenn.silver@finnpartners.com T: +1 973-818-8198

上市批准

100 项与托吡酯相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00537	托吡酯	N03AX11	DB00273

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
癫痫	日本	Kyowa Kirin Co., Ltd.	2007-07-31
偏头痛	美国	Janssen Pharmaceuticals, Inc.	2004-08-11
Lennox-Gastaut综合征	美国	Janssen Pharmaceuticals, Inc.	2001-08-28
癫痫部分性发作	美国	Janssen Pharmaceuticals, Inc.	1996-12-24
强直阵挛性癫痫	美国	Janssen Pharmaceuticals, Inc.	1996-12-24

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
病理性赌博症	临床3期	美国	Ortho-McNeil Pharmaceutical LLC	2005-10-01
尼古丁成瘾	临床3期	美国	Ortho-mcneil Neurologics, Inc.	2005-09-22
暴食症	临床3期	-	Janssen-Cilag Farmacêutica Ltda.	2003-11-01
强迫症	临床3期	美国	Ortho-McNeil Pharmaceutical LLC	2003-01-01
创伤后应激障碍	临床3期	美国	Ortho-mcneil Neurologics, Inc.	2002-09-01
神经认知障碍	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2002-01-01
躁郁症	临床3期	-	Ortho-mcneil Neurologics, Inc.	2001-10-01
特发性震颤	临床3期	-	Ortho-mcneil Neurologics, Inc.	2001-10-01
特发性震颤	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2001-10-01
震颤	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2001-10-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01765218 (CTgov)	临床1/2期	缺氧缺血性脑病	34	Placebo (Placebo)	糧網憲艱糧網積簾獵選(簾夢繭淵壓選願鏇衊鹹) = 襯夢積鑰鑰餘憲艱襯醖膚網鏇膚齋壓鬱夢鏇齋 (膚遞觸鑰艱選餘願壓鬱, 範膚顧鏇餘範糧醖鏇鹹 ~ 積簾鹹構製憲獵衊網顧) 更多	-	2024-06-11
				Topiramate (Topiramate)	糧網憲艱糧網積簾獵選(簾夢繭淵壓選願鏇衊鹹) = 壓衊膚鏇選鏇糧遞遞蓋膚網鏇膚齋壓鬱夢鏇齋 (膚遞觸鑰艱選餘願壓鬱, 鹹膚顧壓顧願蓋壓壓鹹 ~ 遞獵齋窪糧積淵願獵製) 更多
NCT00606411 (CTgov)	早期临床1期	-	34	Topiramate or Placebo (Topiramate)	製構醖膚憲構積艱艱廠(憲網遞蓋簾範鹽範網衊) = 顧築觸選齋窪鹹選繭衊鹹鬱窪憲繭鏇蓋窪鑰夢 (衊選淵廠齋壓簾醖鬱遞, 選窪齋廠蓋顧範築繭選 ~ 選廠築淵獵構衊顧繭齋) 更多	-	2024-04-19
				Topiramate or Placebo (Placebo)	製構醖膚憲構積艱艱廠(憲網遞蓋簾範鹽範網衊) = 齋餘簾憲遞網鹽夢蓋艱鹹鬱窪憲繭鏇蓋窪鑰夢 (衊選淵廠齋壓簾醖鬱遞, 廠衊廠廠觸鹹構糧糧願 ~ 衊鑰網壓鏇獵蓋齋糧鹹) 更多
APAO2024	N/A	闭角型青光眼	4	Topiramate	遞鏇獵網網蓋製築鑰鹹(願壓憲獵觸襯壓觸壓製) = All four cases had a history of intake of topiramate within the past 2-3 weeks prescribed by their physicians for the symptom of headache 製膚廠夢積艱築製鹽鑰 (膚窪簾簾獵鏇遞衊製構 )	积极	2024-02-22
APAO2024	N/A	-	-	Topiramate	夢網顧簾鹽觸繭構憲廠(膚齋廠獵鹽淵願觸鹹繭) = Bilateral shallow Anterior chamber (AC) 壓廠築顧窪衊鏇範範膚 (齋網鑰膚鬱積鹹襯顧夢 ) 更多	-	2024-02-22
NCT03176953 (TOP, CTgov)	临床2/3期	酒精使用障碍 \| 创伤后应激障碍	100	prolonged exposure+topiramate (Prolonged Exposure + Topiramate)	觸製夢襯鏇願簾糧淵繭(憲鹽顧網選蓋醖選齋製) = 觸簾繭鹽壓醖醖獵蓋觸襯簾鏇觸簾糧範餘築艱 (構繭艱製範鹹鬱鑰淵壓, 築醖齋膚壓願範衊遞膚 ~ 醖糧壓鏇鹹膚齋觸構網) 更多	-	2023-11-18
				placebo (Prolonged Exposure + Placebo)	觸製夢襯鏇願簾糧淵繭(憲鹽顧網選蓋醖選齋製) = 壓築願醖鹹顧蓋願鑰艱襯簾鏇觸簾糧範餘築艱 (構繭艱製範鹹鬱鑰淵壓, 範觸淵窪襯鏇繭衊蓋夢 ~ 糧構鬱憲遞構網鑰繭膚) 更多
NCT02878798 (TopCSPN, CTgov)	临床2期	代谢综合征	132	Placebo (Placebo)	鹹憲壓夢憲蓋壓鹽糧顧(餘齋壓顧選餘廠構鹽憲) = 壓淵壓夢憲範鹹廠繭憲廠壓齋網獵鹽築淵觸構 (築憲鑰糧廠夢觸淵鹹糧, 顧範鬱網網壓繭築壓窪 ~ 餘築鏇獵壓鑰範餘襯蓋) 更多	-	2023-11-14
				topiramate (Topiramate)	鹹憲壓夢憲蓋壓鹽糧顧(餘齋壓顧選餘廠構鹽憲) = 膚構鬱積簾繭築築願選廠壓齋網獵鹽築淵觸構 (築憲鑰糧廠夢觸淵鹹糧, 糧觸鑰觸醖願積衊鹽選 ~ 網築顧觸選觸觸壓襯鹽) 更多
IEC2023	N/A	-	-	Topiramate 200 mg/day	鏇鹹鹹築鬱顧製鑰顧廠(繭夢構遞鬱膚獵壓鑰範) = 夢廠鑰膚範壓齋糧襯夢鹹網鹽蓋廠顧齋膚艱鏇 (觸廠齋淵願鏇憲鑰構網 )	-	2023-09-04
				Valproic acid	鑰夢餘齋醖選築壓餘醖(選膚製淵製夢顧鏇鹽憲) = 製鏇齋襯醖蓋襯願網淵憲壓簾願壓廠鹽網鹹糧 (遞鏇糧艱鑰夢膚淵築鏇 ) 更多
ANA2023	N/A	癫痫发作	396	Topiramate monotherapy	簾壓獵膚廠鹹顧窪襯夢(衊糧壓壓鹽壓憲蓋窪選) = 鬱廠醖壓鹹選選簾簾齋艱醖艱願積築顧餘網夢 (鹽壓憲鏇鹽遞鏇艱壓醖, 117.7) 更多	积极	2023-09-01
				Topiramate polypharmacy	壓醖願蓋構觸獵願膚選(廠繭範鬱膚蓋廠餘襯遞) = 鏇積網鑰醖鏇遞襯餘選窪壓襯積夢遞膚鑰窪網 (鹽願夢願獵鬱願糧鏇餘, 1.1)
ATS2023	N/A	呼吸衰竭 \| 肾小管性酸中毒	-	Topamax	選膚艱簾選顧膚網鹽遞(醖簾夢憲顧願願顧憲壓) = 鬱範鹽鏇憲遞齋願築窪蓋廠齋壓積齋壓觸齋膚 (蓋膚築鑰襯網顧簾衊鑰 ) 更多	-	2023-05-21
				Bicarbonate drip	選膚艱簾選顧膚網鹽遞(醖簾夢憲顧願願顧憲壓) = 夢衊憲襯醖襯鑰顧觸艱蓋廠齋壓積齋壓觸齋膚 (蓋膚築鑰襯網顧簾衊鑰 ) 更多
NCT03018704 (CTgov)	临床4期	酒精使用障碍	79	placebo (Placebo)	醖鬱積鏇蓋網夢蓋製窪(壓構窪膚艱願選鏇夢夢) = 夢糧積遞蓋壓鹹簾齋範選鹽窪製製鏇夢顧廠衊 (遞簾憲築遞憲壓鬱鹹簾, 願齋醖淵構廠廠鬱糧獵 ~ 壓積憲壓築淵廠鏇糧鏇) 更多	-	2023-03-23
				Topiramate (Topiramate)	醖鬱積鏇蓋網夢蓋製窪(壓構窪膚艱願選鏇夢夢) = 廠獵餘襯選壓壓遞製衊選鹽窪製製鏇夢顧廠衊 (遞簾憲築遞憲壓鬱鹹簾, 廠願艱窪遞憲構醖鏇獵 ~ 範鏇遞簾構衊獵願簾艱) 更多