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Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections. 苯二氮卓类药物和 Z 类药物的使用与随后的严重感染风险。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-01 DOI: 10.1007/s40263-024-01108-w
Xinchen Wang, Kayoko Isomura, Paul Lichtenstein, Ralf Kuja-Halkola, Brian M D'Onofrio, Isabell Brikell, Patrick D Quinn, Nanbo Zhu, Nitya Jayaram-Lindström, Zheng Chang, David Mataix-Cols, Anna Sidorchuk
<p><strong>Background and objectives: </strong>Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections.</p><p><strong>Methods: </strong>This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients.</p><p><strong>Results: </strong>In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections.</p><p><strong>Conclusions: </strong>BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confoundi
背景和目的:动物研究表明,苯并二氮杂卓和相关 Z 类药物 (BZDR) 的使用与免疫功能障碍之间存在联系。人类的相应证据有限,且主要集中在肺炎方面。本研究旨在评估使用苯二氮卓类药物与随后发生严重感染之间的关系:这项基于瑞典登记册的研究包括一个人口统计学匹配队列、一个同卵双胞对照队列和一个积极的参照队列。在 2007 年之前未使用过 BZDR 的 7362979 名 65 岁以下人群中,有 713896 名在 2007 年至 2019 年期间使用过任何 BZDR 的 BZDR 受试者与 713896 名未使用过 BZDR 的普通人群进行了 1:1 匹配;9197 名 BZDR 受试者与其 9298 名未接触过 BZDR 的同卵双胞胎/同卵多胞胎进行了比较;434900 名 BZDR 受试者与 428074 名选择性血清素再摄取抑制剂 (SSRI) 受试者进行了比较。研究结果通过全国患者登记册中首次住院或专科门诊严重感染的诊断,或死因登记册中作为根本原因记录的任何感染导致的死亡来确定。Cox比例危害回归模型已被拟合,并控制了多种混杂因素,包括家族混杂因素和适应症混杂因素。为了研究可能存在的剂量-反应关系,对每位BZDR接受者在随访期间的BZDR累积配药剂量进行了估算,并将其建模为时变暴露,剂量类别为三等分[≤20定义日剂量(DDDs),>20DDDs≤65,>65DDDs]。与人口统计学上匹配的非受试者相比,评估了BZDR受试者在每个累积BZDR剂量类别中的感染风险:在人口统计学匹配队列(使用 BZDR 的平均年龄为 42.8 岁,56.9% 为女性)中,BZDR 受试者和匹配的非受试者在 1 年随访期间任何严重感染的粗发病率分别为每 100 人年 4.18 例 [95% 置信区间 (CI) 4.13-4.23] 和 1.86 例 (95% CI 1.83-1.89)。在控制了人口、社会经济、临床和药物等混杂因素后,使用 BZDR 与任何感染风险相对增加 83% 有关[危险比 (HR) 1.83,95% CI 1.79-1.89]。在同卵双胞队列(HR 1.55,95% CI 1.23-1.97)和积极的比较队列(HR 1.33,95% CI 1.30-1.35)中,风险仍然增加,但有所减弱。在不同类型的初始 BZDR 和不同的 BZDR 中观察到的风险相似,风险随开始服用 BZDR 时的年龄而增加。我们还观察到,BZDR累积剂量与严重感染风险之间存在剂量反应关系:结论:即使考虑到未测量的家族混杂因素和适应症混杂因素,BZDR 的使用也与严重感染风险的增加有关。然而,BZDR 影响免疫功能的确切途径仍不清楚。需要进一步研究探索使用BZDR与严重感染之间关联的神经生物学机制,以便为需要使用BZDR的患者制定更安全的治疗策略。
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引用次数: 0
Effects of Trazodone on Sleep: A Systematic Review and Meta-analysis. 曲唑酮对睡眠的影响:系统回顾与元分析》。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-09 DOI: 10.1007/s40263-024-01110-2
Maria Kokkali, Elisavet Pinioti, Andreas S Lappas, Nikolaos Christodoulou, Myrto T Samara

Background and objectives: Sleep problems and insomnia are common, challenging to treat, and transcend specific diagnoses. Although trazodone is a popular choice, robust meta-analytic evidence is lacking. This systematic review and meta-analysis investigates the efficacy and safety of trazodone for sleep disturbances, reflecting recent updates in insomnia diagnosis and treatment.

Methods: We searched Medline, Embase, APA PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) up to 1 May 2024, for Randomized Controlled Trials (RCTs) comparing trazodone with placebo and reporting sleep-related outcomes. The minimum pharmacotherapy duration was 5 days. Included were all RCTs regardless of blinding (open-label or single- or double-blind), while quasi-randomized studies were excluded. The Cochrane Risk of Bias Tool for Randomized Trials assessed bias. Analyses used a random-effects model on an intention-to-treat (ITT) basis. Risk ratio (RR) was used for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes. When different units or scales were used, Hedge's adjusted g standardized mean difference (SMD) was calculated. Subgroup and preplanned sensitivity analyses explored heterogeneity and evaluated findings' strength and consistency.

Results: In total, 44 RCTs with 3935 participants were included. Trazodone did not significantly impact subjective total sleep time (TST) [WMD = 0.73 min, 95% confidence interval (CI) - 24.62; 26.07, p = 0.96] but improved sleep quality (SQ) (SMD = - 0.58, 95% CI - 0.87; - 0.28, p < 0.01) and secondary outcomes. These included the number of nocturnal awakenings (SMD = - 0.57, 95% CI - 0.85; - 0.30], p < 0.01), nocturnal time awake after sleep onset (WMD = - 13.47 min, 95% CI - 23.09; - 3.86], p < 0.01), objective TST by polysomnography (WMD = 27.98 min, 95% CI 4.02; 51.95, p = 0.02), and sleep efficiency (WMD = 3.32, 95% CI 0.53; 1.57, p = 0.02). Tolerability issues included more dropouts owing to adverse effects (RR = 2.30, 95% CI 1.45; 3.64, p < 0.01), any sleep-related adverse effects (RR = 3.67, 95% CI 1.07; 12.47, p = 0.04), more adverse effects in general (RR = 1.18, 95% CI 1.03; 1.33, p = 0.02), and more sleep-related adverse effects (RR = 4.31, 95% CI 2.29; 8.13, p < 0.01).

Conclusion: Trazodone extends total sleep time but does not affect perceived sleep duration. It may improve sleep quality and continuity but has minor effects on sleep latency, efficiency, and daytime impairment. Trazodone is associated with adverse effects, necessitating a careful risk-benefit assessment. Limited data restrict generalizability, underscoring the need for more research.

Registration: PROSPERO registration number,CRD42022383121.

背景和目的:睡眠问题和失眠症很常见,治疗起来具有挑战性,并且超越了特定的诊断。虽然曲唑酮(Trazodone)是一种常用药物,但目前尚缺乏可靠的荟萃分析证据。本系统综述和荟萃分析调查了曲唑酮治疗睡眠障碍的有效性和安全性,反映了失眠诊断和治疗的最新进展:我们检索了Medline、Embase、APA PsycINFO、Cochrane对照试验中央注册中心(CENTRAL)、ClinicalTrials.gov和世界卫生组织(WHO)国际临床试验注册平台(ICTRP)截至2024年5月1日的随机对照试验(RCT),比较了曲唑酮与安慰剂,并报告了睡眠相关结果。最短药物治疗时间为 5 天。纳入的所有 RCT 均不考虑盲法(开放标签、单盲或双盲),但排除了准随机研究。科克伦随机试验偏倚风险工具对偏倚进行了评估。分析采用随机效应模型,以意向治疗(ITT)为基础。二分结果采用风险比(RR),连续结果采用加权平均差(WMD)。如果使用不同的单位或量表,则计算 Hedge's 调整 g 标准化平均差 (SMD)。亚组分析和预先计划的敏感性分析探讨了异质性,并评估了研究结果的强度和一致性:结果:共纳入 44 项 RCT,3935 名参与者。曲唑酮对主观总睡眠时间(TST)没有明显影响[WMD = 0.73 min,95% 置信区间(CI)- 24.62; 26.07,p = 0.96],但改善了睡眠质量(SQ)(SMD = - 0.58,95% CI - 0.87; - 0.28,p 结论:曲唑酮能延长患者的总睡眠时间:曲唑酮可延长总睡眠时间,但不会影响感知睡眠时间。曲唑酮可改善睡眠质量和连续性,但对睡眠潜伏期、睡眠效率和日间障碍的影响较小。曲唑酮会产生不良反应,因此有必要进行谨慎的风险效益评估。有限的数据限制了该药物的普遍性,因此需要进行更多的研究:注册:PROSPERO 注册号:CRD42022383121。
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引用次数: 0
Antiseizure Medications and Sudden Unexpected Death in Epilepsy: An Updated Review. 抗癫痫药物与癫痫患者的意外猝死:最新综述。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI: 10.1007/s40263-024-01112-0
Anemoon T Bosch, Josemir W Sander, Roland D Thijs

Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic-clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence.

癫痫意外猝死(SUDEP)是大多数癫痫相关死亡的原因。它主要与未经目击的夜间惊厥(从局灶到双侧或全身强直阵挛发作(TCS))有关。由于基本机制尚不清楚,目前还缺乏有针对性的预防策略。抗癫痫药物(ASMs)通过减少癫痫发作来调节 SUDEP 风险,但个别 ASMs 或其他药物是否也会影响 SUDEP 的内部级联尚未确定。癫痫发作检测设备(SDD)可提供一种替代策略,防止三联征(TCS)在无人目击的情况下发生。在此,我们对 ASM、非癫痫伴随药物和 SDD 对 SUDEP 发生的影响的现有证据进行了严格评估。我们没有发现任何有力的证据表明,开始使用 ASMs 会对 TCS 控制以外的 SUDEP 产生影响,但我们发现一些迹象表明,多药治疗具有保护作用。我们没有发现任何迹象表明特定的 ASM 会对 SUDEP 产生风险。一项研究表明,左乙拉西坦可能具有保护作用,这需要进一步调查。只有少数几项小型研究探讨了非癫痫并发症药物与 SUDEP 之间的关联,其中精神药物没有一致的影响,而一项更广泛的研究表明他汀类药物使用者的风险较低。我们只发现了间接证据表明加强夜间监护具有保护作用,而没有明确探讨 SDD 对 SUDEP 发生的影响。我们需要进一步开展工作,探索 ASM 和其他干预措施在调节 SUDEP 风险方面的潜力,并应准确考虑 TCS 频率、多重用药情况和不依从性指标。
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引用次数: 0
Early Disease-Modifying Treatments for Presymptomatic Multiple Sclerosis 针对无症状多发性硬化症的早期疾病调节疗法
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-16 DOI: 10.1007/s40263-024-01117-9
Burcu Zeydan, Christina J. Azevedo, Naila Makhani, Mikael Cohen, Melih Tutuncu, Eric Thouvenot, Aksel Siva, Darin T. Okuda, Orhun H. Kantarci, Christine Lebrun-Frenay

Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The 2009 and revised 2023 RIS criteria were developed for diagnosis. Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3–4 of 4 dissemination in space McDonald 2005 MS criteria are still diagnosed with RIS using the revised 2023 RIS criteria. In presymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers, CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance.

放射学孤立综合征(RIS)是多发性硬化症(MS)疾病连续过程中的最早阶段。RIS是在无症状但大脑和/或脊髓有典型病变提示脱髓鞘的患者中偶然发现的。2009 年和修订后的 2023 年 RIS 诊断标准已经制定。符合 2009 年 RIS 标准的无症状患者,如果在麦当劳 2005 MS 标准的 4 个播散点中有 3-4 个播散点,则仍可根据修订后的 2023 年 RIS 标准诊断为 RIS。对于不符合2009年RIS标准的无症状患者,修订后的2023年RIS标准旨在确保准确及时的诊断:除了(a)在四个部位(脑室周围、皮质/皮质并区、脑室下、脊髓)中的两个部位有一个病变外,(b)还应符合三个特征(脊髓病变、脑脊液(CSF)限制性寡克隆带、新的T2或钆增强病变)中的两个特征。在实验室生物标志物中,脑脊液无卡帕轻链也能提高诊断的准确性。一旦确诊,应评估已有的危险因素,包括人口统计学、影像学和实验室生物标志物,以确定无症状多发性硬化的转归和预后。年龄较小、男性、神经丝光链增加、脑脊液异常以及影像学上存在幕下、脊髓或钆增强病变是向无症状多发性硬化症转变的主要危险因素。两项随机临床试验显示,改变病情的治疗在延迟或预防 RIS 首次临床事件的发生方面具有显著疗效。然而,由于部分患者仍为 RIS,因此必须识别出具有较多风险因素的患者,以便通过早期干预优化疾病预后,同时最大限度地减少不良事件的发生。建议与 MS 专家团队讨论每个 RIS 病例,因为目前仍缺乏临床指南来改善护理、咨询和监测。
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引用次数: 0
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。
{"title":"Rett Syndrome: The Emerging Landscape of Treatment Strategies","authors":"Alan K. Percy, Amitha Ananth, Jeffrey L. Neul","doi":"10.1007/s40263-024-01106-y","DOIUrl":"https://doi.org/10.1007/s40263-024-01106-y","url":null,"abstract":"&lt;p&gt;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 (&lt;i&gt;MECP2&lt;/i&gt;) 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 &lt;i&gt;MECP2&lt;/i&gt; 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","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"2 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
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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
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CNS drugs
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