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Current Landscape of NTRK Inhibition for Pediatric CNS Tumors NTRK抑制剂治疗小儿中枢神经系统肿瘤的现状
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-15 DOI: 10.1007/s40263-024-01121-z
Daniel C. Moreira, Margit Mikkelsen, Giles W. Robinson

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

过去十年间,随着分子平台对小儿中枢神经系统(CNS)肿瘤基因组特征的描述,小儿神经肿瘤学发生了巨大变化。NTRK 融合是一种致癌驱动基因改变,已在包括小儿中枢神经系统肿瘤在内的多种肿瘤类型中发现。近年来,NTRK抑制剂已成为治疗NTRK基因融合的小儿中枢神经系统肿瘤的一类前景广阔的靶向疗法。拉罗替尼(larotrectinib)和恩替替尼(entrectinib)用于治疗复发的小儿中枢神经系统肿瘤,已使相当一部分患者产生了快速、稳健的反应。这些药物的耐受性良好,但有近 20% 的患者出现自发性骨折。鉴于复发患者的现有数据,在前期使用 NTRK 抑制剂进行临床试验是疗效测试的下一个自然进展,目前许多临床试验正在进行中。要优化 NTRK 抑制剂的使用并确定最有可能从中获益的 NTRK 融合阳性中枢神经系统肿瘤患者,仍有一些难题需要解决。随着这些药物得到更广泛的应用,耐药性将成为一个更加普遍的问题,因此需要针对这种情况确定相应的策略。本文总结了NTRK抑制剂治疗小儿中枢神经系统肿瘤的现状,并讨论了未来扩大使用的机遇和挑战。
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引用次数: 0
Rett Syndrome: The Emerging Landscape of Treatment Strategies 雷特综合征:新出现的治疗策略
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-09 DOI: 10.1007/s40263-024-01106-y
Alan K. Percy, Amitha Ananth, Jeffrey L. Neul
<p>Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (<i>MECP2</i>) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation—IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype–genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal <i>MECP2</i> gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editi
雷特综合征(RTT)在特定疗法方面取得了显著进展。雷特综合征是一种独特的神经发育障碍,于 1966 年首次被描述,在哈格伯格及其同事于 1983 年发表具有里程碑意义的论文之前,该病一直进展缓慢。此后,该病取得了突飞猛进的发展,包括制定了具体的诊断标准,并积极寻找遗传病因,结果在 16 年后发现了位于 Xq28 的甲基-CpG 结合蛋白(MECP2)基因的变异。此后不久,美国国立卫生研究院罕见病办公室于 2003 年资助了 RTT 自然史研究(NHS),开始从大量 RTT 患者中获取有关临床特征的自然史数据。这些信息对于推进临床试验,为该疾病提供特异性疗法至关重要。在此过程中,成立了国际雷特综合征协会(IRSA)(现为国际雷特综合征基金会-IRSF),该协会直接参与了鼓励和扩大 NHS 注册人数的工作,随后又参与了 SCOUT 计划的开发,以促进在 RTT 小鼠模型中测试潜在的治疗药物。会议的总体目标是回顾从 NHS 研究中得出的临床特征,并讨论针对这种进行性神经发育障碍的特定疗法的现状。NHS 研究提供了有关 RTT 的关键信息:生长、人体测量学、寿命、主要合并症(包括癫痫、呼吸异常、胃食管功能障碍、脊柱侧凸和其他矫形问题)、青春期、行为和焦虑以及进行性运动退化(包括出现帕金森病特征)。研究还注意到表型与基因型的相关性,包括 X 染色体失活的作用。临床严重程度和生活质量测量方法的开发对于后续的临床试验也至关重要。此外,生化和神经生理学生物标志物的开发为临床试验提供了更多终点。国家医疗服务体系之前的最初临床试验效果不佳,但国家医疗服务体系和全球其他研究取得的进展引起了制药公司的极大兴趣,并促成了多项临床试验。虽然其中一些临床试验没有取得成果,如沙立唑坦,但其他一些临床试验却很有希望,包括美国食品和药物管理局(FDA)于 2023 年批准了特罗菲奈肽(trofinetide),这是第一种可用于专门治疗 RTT 的药物。Blarcamesine 已在 3 期试验中试用,14 种药物已在 2 期试验中研究,7 种药物正在临床前/横向研究中评估。盖伊等人在 2007 年进行的一项具有里程碑意义的研究表明,在无效小鼠模型中激活正常的 MECP2 基因可显著改善病情。基因替代疗法已通过转化研究推进到目前的两项 1 / 2 期临床试验(Taysha102 和 Neurogene-401)。其他基因疗法也在研究之中,包括基因编辑、RNA 编辑和 X 染色体再激活。总之,在过去的 40 年中,人们在了解和治疗 RTT 方面取得了显著进展。这表明,进一步的进步是可以期待的。
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引用次数: 0
Patterns of Pregabalin Users from Substance Abuse Treatment Facilities: Results from the French OPPIDUM Program from 2008 to 2022. 来自药物滥用治疗机构的普瑞巴林使用者模式:2008 年至 2022 年法国 OPPIDUM 计划的结果。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-11 DOI: 10.1007/s40263-024-01095-y
Clément Garnier, Martin Schein, Clémence Lacroix, Elisabeth Jouve, Thomas Soeiro, Gaétan Gentile, Maryse Lapeyre Mestre, Joëlle Micallef

Introduction: In recent years, pregabalin has received growing attention due to its abuse liability. The aim of this study was to further characterize patterns of pregabalin users from substance abuse treatment facilities and detect changes in users profile over the study period.

Methods: The data source was the Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse (OPPIDUM) program, an annual, repeated, cross-sectional, nationwide, multicenter survey that collects consumption data from patients with substance use disorders. First, we described the characteristics of pregabalin users and their consumption patterns. We compared these data between 2008 and 2018 (P1) and 2019 and 2022 (P2). Second, we conducted a multiple correspondence analysis to identify profiles of users.

Results: From 2008 to 2022, 291 pregabalin users (0.37% of all users) from 116 substance abuse treatment facilities were identified. The number of pregabalin users was lower than 15 per year in P1 (n = 89) and between 40 and 60 per year in P2 (n = 202). The number of users who reported pregabalin as the first substance leading to dependence increased significantly in P2 compared with P1 (p < 0.005). When comparing P2 with P1, there was a significant increase in precarity (p < 0.001), users in prison (p = 0.002), withdrawal symptoms (p < 0.001), dependence (p < 0.001), use of higher dose of pregabalin (p = 0.029), and acquisition by deal/street market (p < 0.001). The multiple correspondence analysis allowed for the identification of distinct profiles of pregabalin users: (i) a cluster with mainly users from P1, who presented a simple use of pregabalin, and were older (> 45 years), were involved in opioid agonist treatment (OAT), and obtained pregabalin legally; and (ii) a cluster with mainly users from P2, who presented pregabalin dependence, and were younger (< 26 years), reported pregabalin as the first substance leading to dependence, used doses higher than the market authorization, were in severe precarity, and were in prison.

Conclusions: These data showed that the profile of pregabalin users has changed in the last years. Pregabalin use disorders also affect users without history of addiction.

简介近年来,普瑞巴林因其易被滥用而受到越来越多的关注。本研究旨在进一步描述药物滥用治疗机构中普瑞巴林使用者的模式,并检测研究期间使用者情况的变化:数据来源于 "OPPIDUM(Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse)"项目,该项目是一项每年重复进行的横断面全国性多中心调查,旨在收集药物使用障碍患者的消费数据。首先,我们描述了普瑞巴林使用者的特征及其消费模式。我们比较了 2008 年至 2018 年(P1)和 2019 年至 2022 年(P2)的这些数据。其次,我们进行了多重对应分析,以确定使用者的特征:从 2008 年到 2022 年,我们从 116 家药物滥用治疗机构中确定了 291 名普瑞巴林使用者(占所有使用者的 0.37%)。普瑞巴林使用者的数量在 P1(n = 89)中低于每年 15 人,在 P2(n = 202)中介于每年 40 到 60 人之间。与 P1 相比,P2 中报告普瑞巴林是导致依赖的第一种药物的使用者人数显著增加(p < 0.005)。与 P1 相比,P2 的不稳定性(p < 0.001)、监狱中的使用者(p = 0.002)、戒断症状(p < 0.001)、依赖性(p < 0.001)、使用更大剂量的普瑞巴林(p = 0.029)以及通过交易/街头市场获取(p < 0.001)均有显著增加。通过多重对应分析,可以确定普瑞巴林使用者的不同特征:(i) 一个主要由 P1 用户组成的群组,他们表现为普瑞巴林的简单使用,年龄较大(大于 45 岁),参与阿片激动剂治疗(OAT),并通过合法途径获得普瑞巴林;(ii) 一个主要由 P2 用户组成的群组,他们表现为普瑞巴林依赖,年龄较小(小于 26 岁),报告普瑞巴林是导致依赖的第一种药物,使用剂量高于市场授权剂量,处于严重不稳定状态,并在监狱服刑。结论这些数据表明,普瑞巴林使用者的情况在过去几年中发生了变化。普瑞巴林使用障碍也会影响到没有成瘾史的使用者。
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引用次数: 0
Caregiver Perspective of Benefits and Side Effects of Anti-Seizure Medications in CDKL5 Deficiency Disorder from an International Database. 从国际数据库看护理人员对 CDKL5 缺乏症患者服用抗癫痫药物的益处和副作用的看法。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI: 10.1007/s40263-024-01105-z
Kingsley Wong, Mohammed Junaid, Solomon Alexander, Heather E Olson, Elia M Pestana-Knight, Rajsekar R Rajaraman, Jenny Downs, Helen Leonard

Background and objective: CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database.

Methods: Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population.

Results: The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits.

Conclusions: The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management.

背景和目的:CDKL5 缺乏症是一种具有挑战性的疾病,患者早期会出现难治性癫痫发作、严重发育迟缓以及一系列其他神经系统症状。我们的研究旨在利用CDKL5缺乏症国际数据库的数据,探讨抗癫痫药物(ASM)在控制CDKL5缺乏症患者癫痫发作方面的益处和副作用:这项回顾性队列研究的数据来自国际CDKL5障碍数据库,该数据库包含2012年至2022年期间进行的基线问卷调查和2018年至2019年期间进行的后续问卷调查的答复。符合条件者的家属被要求提供有关以前和现在服用的 ASMs、处方剂量、开始服药的年龄以及过去停药的年龄等信息。我们关注的结果变量是当前和过去使用的 ASMs 对癫痫发作的相关益处以及护理人员报告的副作用。分析中不包括急救药物和不经常使用的 ASM。描述性统计用于总结研究人群的特征:该研究纳入了399名患有CDKL5缺乏症的儿童和成人,根据护理人员的报告,对23种独特的ASM的益处和副作用进行了描述性分析。研究发现,左乙拉西坦、托吡酯、丙戊酸钠、维格巴曲林、苯巴比妥和氯巴扎姆是使用最多的ASMs。值得注意的是,大麻二酚的疗效显著且副作用较小,而左乙拉西坦和苯巴比妥的疗效与副作用比率则不太理想。丙戊酸钠和左乙拉西坦的双重疗法只使用了少量(n = 5),但似乎能有效减少癫痫发作活动,且副作用相对较少。与单药疗法相比,多药疗法的副作用报告率相对高于益处报告率:这项研究的样本量超过了以往研究的样本量,强调了 CDKL5 缺乏症癫痫发作治疗的复杂性。我们的研究结果突出表明,有必要持续开展研究,以优化治疗策略,同时考虑癫痫发作控制的疗效和潜在的不良反应。这项研究还指出,今后有必要对新出现的治疗方法(如甘纳唑酮)的治疗潜力以及大麻产品在癫痫发作控制方面尚未解决的疗效进行调查。
{"title":"Caregiver Perspective of Benefits and Side Effects of Anti-Seizure Medications in CDKL5 Deficiency Disorder from an International Database.","authors":"Kingsley Wong, Mohammed Junaid, Solomon Alexander, Heather E Olson, Elia M Pestana-Knight, Rajsekar R Rajaraman, Jenny Downs, Helen Leonard","doi":"10.1007/s40263-024-01105-z","DOIUrl":"10.1007/s40263-024-01105-z","url":null,"abstract":"<p><strong>Background and objective: </strong>CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database.</p><p><strong>Methods: </strong>Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population.</p><p><strong>Results: </strong>The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits.</p><p><strong>Conclusions: </strong>The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis. 患有心肌炎的精神分裂症患者何时、为何以及如何再次使用氯氮平?
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-01 DOI: 10.1007/s40263-024-01100-4
Mishal Qubad, Gabriele Dupont, Martina Hahn, Simon S Martin, Valentina Puntmann, Eike Nagel, Andreas Reif, Robert A Bittner

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

氯氮平诱发的心肌炎(CIM)是限制氯氮平作为精神分裂症最有效治疗药物使用的最重要不良反应之一。氯氮平诱发的心肌炎需要立即停用氯氮平,通常会导致永久性停药,对患者的精神病理学和长期疗效产生相当大的不利影响。因此,越来越多的人认为在 CIM 后重新使用氯氮平是一种可行的替代方法,已发表的报告显示成功率约为 60%。然而,已发表的 CIM 后再次用药的病例仍然有限。在此,我们对有关 CIM 的流行病学、病理生理学、风险因素、诊断和临床管理的研究现状进行了叙述性综述,并对目前有关 CIM 后重新挑战患者的建议进行了总结。其中包括根据目前有关 CIM 病理生理学和风险因素的证据,为这一关键程序提供分步指南。缓慢的剂量滴定方案以及应对包括同时服用丙戊酸钠和奥氮平在内的风险因素,对于预防 CIM 和确保安全、成功的再挑战至关重要。此外,我们还讨论了 C 反应蛋白、肌钙蛋白、N-末端丙种球蛋白、脑钠肽、治疗药物监测和心脏磁共振成像在 CIM 筛查和诊断以及 CIM 后再挑战中的作用。
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引用次数: 0
Psychotropic Drugs Reemerging as Headache Medicines. 精神药物重新成为头痛药物。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI: 10.1007/s40263-024-01107-x
Emmanuelle A D Schindler

Scientific and public attention on the therapeutic effects of psychedelics and other psychoactive compounds in headache disorders has recently grown. The use and reported therapeutic effects of such treatments have long been reported, though formal clinical trials are only recently taking place. When considering how these substances might be further studied and eventually applied, it is important to consider the specific headache disorder, the particular drug, and the mode of use. No singular protocol will be applicable across all headache disorders and drugs. In this leading article, the nuance required to consider the value of classic psychedelics, ketamine, and cannabinoids as headache medicines is presented.

最近,科学界和公众越来越关注迷幻药和其他精神活性化合物对头痛疾病的治疗效果。此类疗法的使用和治疗效果早有报道,但正式的临床试验最近才开始进行。在考虑如何进一步研究并最终应用这些物质时,重要的是要考虑特定的头痛疾病、特定的药物和使用方式。没有一种方案适用于所有头痛疾病和药物。在这篇主要文章中,将介绍考虑经典迷幻药、氯胺酮和大麻素作为头痛药物的价值所需的细微差别。
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引用次数: 0
Cenobamate as an Early Adjunctive Treatment in Drug-Resistant Focal-Onset Seizures: An Observational Cohort Study 塞诺巴马特作为药物耐药性局灶性发作的早期辅助治疗:观察性队列研究
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-03 DOI: 10.1007/s40263-024-01109-9
Yaroslav Winter, Raya Abou Dargham, Susana Patiño Tobón, Sergiu Groppa, Sven Fuest

Background and Objectives

Cenobamate (CNB) is a new antiseizure medication (ASM) to treat drug-resistant, focal-onset seizures. Data on its use in early therapy lines are not yet available, and clinicians frequently consider CNB to be a later ASM drug choice. We investigated the efficacy and safety of CNB as an early adjunctive treatment in drug-resistant, focal-onset seizures.

Methods

The study population were patients with drug-resistant, focal-onset seizures who were initiated with CNB after they did not respond to two or three lifetime ASMs, including all prior and concomitant ASMs. These patients were matched (1:2) by sex, age, and seizure frequency to controls who were initiated with any ASM other than CNB. All participants participated in the Mainz Epilepsy Registry. We evaluated the retention rate after 12 months of CNB and after each new adjunctive ASM in the control group. In addition, seizure freedom and the response rate (reduction of seizure frequency by ≥ 50% from baseline) after 12 months were estimated.

Results

We included 231 patients aged 44.4 ± 15.8 years. Of these, 33.3% (n = 77) were on CNB, 19.0% (n = 44) on valproate (VPA), 17.3% (n = 40) on lacosamide (LCS), 16.4% (n = 38) on levetiracetam (LEV), and 13.9% (n = 32) on topiramate (TPM). The highest retention rate after 12 months since the beginning of the early adjunctive therapy was observed on CNB (92.0%), compared with LCS (80.0%), LEV (73.3%), VPA (68.2%), or TPM (62.5%) (p < 0.05). Seizure freedom and response rate were also the best on CNB (19.5% and 71.4%, respectively) compared with other ASMs (8.3% and 52.5%, respectively; p < 0.05). No significant differences in adverse events between CNB and other ASMs were observed.

Conclusions

Our study provides evidence that CNB is an effective ASM with a good safety profile in the early therapy lines of drug-resistant, focal-onset seizures. This data should support medical decision making in the management of patients with refractory epilepsy.

Clinical Trial ID

NCT05267405.

背景和目的塞诺巴马特(CNB)是一种新型抗癫痫药物(ASM),用于治疗耐药的局灶性癫痫发作。目前还没有关于该药在早期治疗方案中使用的数据,临床医生通常将 CNB 作为后期抗癫痫药物的选择。我们研究了 CNB 作为耐药、局灶性发作的早期辅助治疗药物的有效性和安全性。研究对象为耐药、局灶性发作患者,他们在接受了两到三次终生 ASM(包括所有先前和伴随的 ASM)治疗无效后开始使用 CNB。这些患者按性别、年龄和癫痫发作频率与对照组进行了配对(1:2),对照组患者开始使用除 CNB 以外的任何 ASM。所有参与者都参加了美因茨癫痫登记。我们评估了对照组患者在接受 CNB 治疗 12 个月后以及每次使用新的辅助 ASM 后的保留率。此外,我们还估算了 12 个月后的发作自由度和反应率(发作频率比基线降低≥50%)。其中,33.3%(n = 77)服用 CNB,19.0%(n = 44)服用丙戊酸钠(VPA),17.3%(n = 40)服用拉科萨胺(LCS),16.4%(n = 38)服用左乙拉西坦(LEV),13.9%(n = 32)服用托吡酯(TPM)。早期辅助治疗开始 12 个月后,CNB(92.0%)的保留率最高,而 LCS(80.0%)、LEV(73.3%)、VPA(68.2%)或 TPM(62.5%)的保留率最低(p <0.05)。与其他 ASMs(分别为 8.3% 和 52.5%;p < 0.05)相比,CNB 的癫痫发作自由度和反应率也是最好的(分别为 19.5% 和 71.4%)。结论我们的研究提供了证据,证明 CNB 是一种有效的 ASM,在耐药、局灶性癫痫发作的早期治疗中具有良好的安全性。这些数据应能为难治性癫痫患者的医疗决策提供支持。
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引用次数: 0
Pharmacological Treatment of Binge Eating Disorder and Frequent Comorbid Diseases 暴食症和常见并发症的药物治疗
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-03 DOI: 10.1007/s40263-024-01111-1
Hubertus Himmerich, Jessica Bentley, Susan L. McElroy

Binge eating disorder (BED) is the most common specific eating disorder (ED). It is frequently associated with attention deficit hyperactivity disorder (ADHD), depression, bipolar disorder (BD), anxiety disorders, alcohol and nicotine use disorder, and obesity. The aim of this narrative review was to summarize the evidence for the pharmacological treatment of BED and its comorbid disorders. We recommend the ADHD medication lisdexamfetamine (LDX) and the antiepileptic and antimigraine drug topiramate for the pharmacological treatment of BED. However, only LDX is approved for the treatment of BED in some countries. Medications to treat diseases frequently comorbid with BED include atomoxetine and LDX for ADHD; citalopram, fluoxetine, sertraline, duloxetine, and venlafaxine for anxiety disorders and depression; aripiprazole for manic episodes of BD; lamotrigine, lirasidone and lumateperone for depressive episodes of BD; naltrexone for alcohol use disorder; bupropion for nicotine use disorder; and liraglutide, semaglutide, and the combination of bupropion and naltrexone for obesity. As obesity is a frequent health consequence of BED, weight gain-inducing medications, such as the atypical antipsychotics olanzapine or clozapine, the novel antidepressant mirtazapine and tricyclic antidepressants, and the mood stabilizer valproate should be avoided where possible. It is currently unclear whether the novel and promising glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptor agonists like tirzepatide and retatrutide help with BED and its comorbidities. However, these compounds have been reported to reduce binge eating in individuals with obesity or overweight.

暴饮暴食症(BED)是最常见的特殊饮食失调症(ED)。它经常与注意力缺陷多动障碍(ADHD)、抑郁症、双相情感障碍(BD)、焦虑症、酒精和尼古丁使用障碍以及肥胖症相关联。本综述旨在总结 BED 及其合并症的药物治疗证据。我们推荐多动症药物利司他敏(LDX)和抗癫痫及抗偏头痛药物托吡酯用于 BED 的药物治疗。不过,在一些国家,只有 LDX 被批准用于治疗 BED。治疗 BED 常见合并症的药物包括:治疗多动症的阿托西汀和 LDX;治疗焦虑症和抑郁症的西酞普兰、氟西汀、舍曲林、度洛西汀和文拉法辛;治疗 BD 躁狂发作的阿立哌唑;治疗 BD 抑郁发作的拉莫三嗪、利拉西酮和卢马替丙酮;治疗酒精使用障碍的纳曲酮;治疗尼古丁使用障碍的安非他酮;以及治疗肥胖症的利拉鲁肽、赛马鲁肽和安非他酮与纳曲酮的复方制剂。由于肥胖是 BED 常见的健康后果,应尽可能避免使用导致体重增加的药物,如非典型抗精神病药物奥氮平或氯氮平、新型抗抑郁药物米氮平和三环类抗抑郁药物,以及情绪稳定剂丙戊酸钠。目前还不清楚新型和前景看好的胰高血糖素、葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样肽 1(GLP-1)受体激动剂(如替泽帕肽和雷他曲肽)是否有助于治疗 BED 及其合并症。不过,有报道称这些化合物可减少肥胖或超重患者的暴饮暴食。
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引用次数: 0
The State of Synthetic Cannabinoid Medications for the Treatment of Pain. 合成大麻素药物治疗疼痛的现状。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-01 DOI: 10.1007/s40263-024-01098-9
Anca Maglaviceanu, Miki Peer, Jason Rockel, Robert P Bonin, Mary-Ann Fitzcharles, Karim S Ladha, Anuj Bhatia, Timothy Leroux, Lakshmi Kotra, Mohit Kapoor, Hance Clarke

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

合成大麻素是在实验室中制成的化合物,在结构上和功能上模仿来自大麻(Cannabis sativa L.)植物的植物大麻素,包括δ-9-四氢大麻酚(THC)。合成大麻素(SCs)可通过经典的内源性大麻素系统(ECS)和更大的内源性大麻素网络发出信号,突出了其信号的复杂性和深远影响。屈大麻酚和纳比隆模拟四氢大麻酚信号,已被美国食品药品管理局(FDA)批准用于治疗癌症化疗和/或获得性免疫缺陷综合征(艾滋病)引起的恶心。然而,人们对这两种药物作为潜在镇痛剂治疗其他各种临床病症的兴趣也在不断增长,包括神经性疼痛、痉挛相关疼痛、非痉挛性疼痛综合征(包括纤维肌痛、骨关节炎和术后疼痛等)。在这篇综述中,我们将重点介绍经 FDA 批准的合成大麻素的信号机制,讨论研究其镇痛潜力的主要临床试验,并说明将合成大麻素应用于临床时所面临的挑战。
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引用次数: 0
A Long-Term Safety and Tolerability Study of TV-46000 for Subcutaneous Use in Patients with Schizophrenia: A Phase 3, Randomized, Double-Blinded Clinical Trial. 精神分裂症患者皮下注射 TV-46000 的长期安全性和耐受性研究:3期随机双盲临床试验。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1007/s40263-024-01102-2
John M Kane, Roy Eshet, Eran Harary, Orna Tohami, Anna Elgart, Helena Knebel, Nir Sharon, Mark Suett, Kelli R Franzenburg, Glen L Davis, Christoph U Correll

Background: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia.

Methods: Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning.

Results: Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction.

Conclusion: Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous stu

背景:TV-46000是一种利培酮长效皮下抗精神病药(LASCA)制剂,已获美国食品药品管理局批准用于治疗成人精神分裂症。在利培酮皮下缓释剂(RISE)3 期随机双盲研究中,与安慰剂相比,每月一次(q1m)和每两个月一次(q2m)的 TV-46000 能显著延长即将复发的时间[5.0 倍(q1m)和 2.7 倍(q2m)]。这项TV-46000皮下注射人体安全性评估(SHINE)的3期随机双盲研究旨在评估TV-46000在精神分裂症患者中的长期安全性、耐受性和暴露情况:完成 RISE 而未复发(滚动)或新招募(从头开始)的患者有资格参加 SHINE 研究。患者最初使用利培酮口服药物稳定治疗12周(完成RISE的患者为转期患者,新招募的患者为SHINE患者)。在SHINE研究中,新患者队列中的患者和在RISE研究中接受安慰剂治疗的患者按1:1比例随机接受TV-46000 q1m或q2m治疗,疗程长达56周。SHINE的主要终点是报告的不良事件(AEs)频率;事件发生率[ER;每100患者年(PYs)的事件发生率]由患者根据一般询问计算得出:共有 336 名患者随机接受了 SHINE 治疗[TV-46000 q1m,n = 174;TV-46000 q2m,n = 162;其中,新患者,n = 109;滚转患者,n = 227(n = 172 名患者接受治疗,n = 55 名患者接受安慰剂治疗)]。共对 334 名患者进行了安全性评估[q1m,n = 172(PY = 97.8);q2m,n = 162(PY = 104.5)]。出现≥1次AE和≥1次治疗相关AE的患者(ER)比例分别为:TV-46000 q1m为37%(180.0)和21%(84.9),TV-46000 q2m为46%(157.9)和20%(70.8)。与治疗相关的常见不良反应[两组中均≥3%;患者比例(ER)]为注射部位疼痛[q1m,5%(24.5);q2m,4%(22.0)]和注射部位结节[q1m,2%(9.2);q2m,6%(12.4)]。TV-46000 q1m和TV-46000 q2m出现严重AEs的患者比例分别为5%和7%;总体上报告的严重AEs≥2例的患者为精神分裂症恶化[q1m,n = 1(< 1%;ER,1.02); q2m, n = 2 (1%; ER, 1.91)] 和高血糖 [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]。在报告的三例死亡病例中,没有一例与治疗有关。总体而言,有8名患者因AE停止了治疗。与之前未接受过TV-46000治疗的患者相比,从TV-46000治疗中转入治疗的患者(新转入和安慰剂转入)的AEs发生率相似或略低。大多数与注射部位反应有关的不良反应都很轻微,没有患者出现严重反应:这项长期安全性研究的结果进一步证实了 TV-46000 q1m 和 q2m 具有良好的安全性,这与利培酮的其他制剂以及之前的 TV-46000 研究结果一致:注册:ClinicalTrials.gov,NCT03893825;2019年3月27日。
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