The introduction of felbamate into North America in 1993 heralded that market’s first new antiepileptic drug in 15 years. Its structure (2-phenyl-1,3-propanediol dicarbamate) is related to meprobamate (the minor tranquilizer), but it does not have significant sedative effects at treatment doses and has a positive effect on a wide range of seizure types. Among the mechanisms of action explored in animal models have been potentiation of gamma aminobutyric acid-mediated chloride conductance and inhibition of N-methyl-D-aspartate-induced calcium currents. Landmarks leading up to felbamate’s introduction included its being the first antiepileptic drug submitted to a double-blind monotherapy trial protocol, and its assessment in the first placebo-controlled trial of a treatment for Lennox–Gastaut syndrome. The treatment effects were considered impressive, and felbamate spent a year of highly successful marketing before it was found to have a relatively high risk of two serious adverse effects: severe liver and bone marrow toxicity. Although there was much uncertainty about the risks attributable to felbamate, for aplastic anaemia it was considered to be somewhere between 10 and 100 times the population risk, and so potentially as high as 1 in 4800. Given felbamate’s effectiveness in treating Lennox–Gastaut syndrome, which is an epilepsy syndrome that often evolves from infantile spasms, it is natural that investigators would also wish to explore its effects in treating spasms. There were some very small early studies, but Dozi eres-Puyravel et al. report a larger review of 29 patients who were treated with felbamate during periods between 2008 and 2019. These cases had failed earlier treatments, which variably included vigabatrin, oral corticosteroids, and the ketogenic diet. The authors observed that 8 out of 29 cases became spasm-free, but they did not define a strictly specified period within which spasm freedom had to occur in order for this to be considered a positive response to treatment. (The timing of the 1-month period defining treatment failure depended upon the rate of dose escalation and drug tolerability). Given that the natural history of infantile spasms is for spasms to remit, at some point, in most cases, the retrospective and descriptive study design means that it is not clear how much better this treatment fared relative to a control group or an alternative treatment. In addition, it seems that many cases were also on treatment with the ketogenic diet, which could have relatively late treatment effects in some cases, and this might act as a potential confounding factor. In their 2003 monograph, Frost and Hrachovy stated: ‘In view of the inconclusive evidence for a significant degree of efficacy, and the potential for severe side effects, the routine use of [felbamate] as a therapy for infantile spasms is not recommended’. Their opinion was based upon reviewing three very small studies, the largest of which, by Hosain et al., included only 11 cases. Dozi eresPuyravel et al. interpret the Hosain study more positively, noting that parents had reported a reduction in spasms in 10 of the 11 cases and that, based on data from the 2-hour video-electroencephalograms forming the primary endpoint of that study, felbamate was associated with a 72% median reduction in spasms relative to baseline.

中文翻译：

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非氨酯对耐药婴儿痉挛症的疗效

1993 年将 felbamate 引入北美预示着该市场 15 年来第一个新的抗癫痫药。其结构（2-苯基-1,3-丙二醇二氨基甲酸酯）与甲丙氨酯（次要镇静剂）有关，但在治疗剂量下没有显着的镇静作用，对多种癫痫发作类型有积极作用。在动物模型中探索的作用机制包括增强 γ 氨基丁酸介导的氯化物电导和抑制 N-甲基-D-天冬氨酸诱导的钙电流。导致非尔氨酯推出的里程碑包括它是第一个提交给双盲单药治疗试验方案的抗癫痫药物，以及它在第一个治疗 Lennox-Gastaut 综合征的安慰剂对照试验中的评估。治疗效果被认为是令人印象深刻的，felbamate 在被发现具有相对较高的两种严重不良反应：严重的肝脏和骨髓毒性之前，经过了一年的非常成功的营销。尽管非尔氨酯的风险存在很多不确定性，但对于再生障碍性贫血，它被认为是人群风险的 10 到 100 倍，因此可能高达 4800 分之一。 鉴于非尔氨酯在治疗 Lennox-Gastaut 综合征方面的有效性，这是一种通常由婴儿痉挛症演变而来的癫痫综合征，研究人员自然也希望探索其在治疗痉挛方面的作用。有一些非常小的早期研究，但 Dozi eres-Puyravel 等人。报告对 29 名在 2008 年至 2019 年期间接受非氨酯治疗的患者进行了更大规模的审查。这些​​病例早期治疗失败，其中包括氨己烯酸、口服皮质类固醇和生酮饮食。作者观察到 29 例中有 8 例不再出现痉挛，但他们没有定义一个严格规定的时间段，在该时间段内必须出现痉挛消失才能被视为对治疗的积极反应。（定义治疗失败的 1 个月时间段取决于剂量递增率和药物耐受性）。鉴于婴儿痉挛的自然病程是痉挛在某些时候缓解，在大多数情况下，回顾性和描述性研究设计意味着尚不清楚这种治疗相对于对照组或替代治疗的效果如何。此外，似乎许多病例也在接受生酮饮食治疗，在某些情况下可能会产生相对较晚的治疗效果，这可能是一个潜在的混杂因素。在他们 2003 年的专着中，Frost 和 Hrachovy 表示：“鉴于没有确凿的证据表明其显着程度的疗效和严重副作用的可能性，不推荐常规使用 [非氨酯] 作为治疗婴儿痉挛的方法”。他们的意见基于对三项非常小的研究的审查，其中最大的一项是 Hosain 等人的研究，仅包括 11 个案例。Dozi eresPuyravel 等。更积极地解释 Hosain 研究，注意到父母报告说在 11 例中有 10 例痉挛减少，并且根据构成该研究主要终点的 2 小时视频脑电图数据，