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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
<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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。
{"title":"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.","authors":"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","doi":"10.1007/s40263-024-01102-2","DOIUrl":"10.1007/s40263-024-01102-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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 (&lt; 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (&lt; 1%; ER, 1.02); q2m, n = 1 (&lt; 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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;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","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"625-636"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491171","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
Effectiveness of Anti-Calcitonin Gene-Related Peptide Medication in Vestibular Migraine: A Retrospective Cohort Study in an Asian Population. 抗降钙素基因相关肽药物对前庭性偏头痛的疗效:亚洲人群的回顾性队列研究》。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-29 DOI: 10.1007/s40263-024-01094-z
Teppei Kouga, Toru Miwa, Kishiko Sunami, Yoshiaki Itoh

Background: Migraine and dizziness often coexist, with vestibular migraine (VM) presenting with vestibular symptoms and headaches. Calcitonin gene-related peptide (CGRP) may be involved in motion-induced symptoms; however, studies on the use of anti-CGRP monoclonal antibodies (mAbs) for the treatment of VM have yielded conflicting results. This study aimed to clarify the effectiveness of anti-CGRP mAbs in VM treatment.

Methods: This retrospective observational cohort study, conducted between 1 January 2021 and 31 March 2023, assessed 12 Japanese patients with VM who were treated with anti-CGRP mAbs (CGRP group) for 6 months and 11 Japanese patients who received standard of care for VM and served as controls. Clinical questionnaires and equilibrium tests were administered, with primary outcomes including changes in Dizziness Handicap Inventory (DHI) scores compared with baseline values. Objective variables included the DHI score and explanatory variables included demographic data, balance test results, head-up tilt (HUT) test results, vestibular test results and questionnaire survey results. Analysis of variance was used to assess the treatment effects of anti-CGRP mAbs, and multivariate regression analysis was performed to identify mAb responders.

Results: After 6 months, the CGRP group showed significant improvements in DHI scores [0 versus 6 months, odds ratio (95% confidence interval): 22.01 (0.13-43.88)] and number of vertigo/dizziness attacks per month [0 versus 6 months: 10.28 (2.80-17.76)]. No significant difference was observed in the control group [DHI scores, 0 versus 6 months: 0.65 (-26.84 to 28.14); number of vertigo/dizziness attacks per month, 0 versus 6 months: - 8.07 (- 23.77 to 7.62)]. Multivariate regression analysis showed that autonomic function at baseline was associated with mAb response in patients [β estimates (95% confidence interval): 3.63 (0.21-7.06)].

Conclusions: Treatment with anti-CGRP mAbs was more effective than conventional treatment in preventing migraine in patients with VM. While the identified factors associated with treatment responsiveness offer valuable insights into personalised treatment approaches, further prospective studies are warranted to validate the findings due to our study's retrospective design and limited sample size.

背景:偏头痛和头晕常常同时存在,前庭性偏头痛(VM)表现为前庭症状和头痛。降钙素基因相关肽(CGRP)可能与运动诱发症状有关;然而,关于使用抗CGRP单克隆抗体(mAbs)治疗VM的研究结果却相互矛盾。本研究旨在明确抗 CGRP mAbs 在治疗血管瘤中的有效性:这项回顾性观察队列研究在 2021 年 1 月 1 日至 2023 年 3 月 31 日期间进行,评估了 12 名接受抗 CGRP mAbs(CGRP 组)治疗 6 个月的日本血管瘤患者,以及 11 名接受标准疗法治疗的日本血管瘤患者作为对照组。研究人员进行了临床问卷调查和平衡测试,主要结果包括头晕障碍量表(DHI)评分与基线值相比的变化。客观变量包括 DHI 分数,解释变量包括人口统计学数据、平衡测试结果、仰头倾斜(HUT)测试结果、前庭测试结果和问卷调查结果。方差分析用于评估抗CGRP mAb的治疗效果,多变量回归分析用于识别mAb应答者:6个月后,CGRP组的DHI评分[0与6个月相比,几率比(95%置信区间):22.01(0.13-43.88)]和每月眩晕/头晕发作次数[0与6个月相比:10.28(2.80-17.76)]均有显著改善。在对照组中未观察到明显差异[DHI 评分,0 对 6 个月:0.65 (-26.84)] :0.65 (-26.84 to 28.14);每月眩晕/头晕发作次数,0 对 6 个月:- 8.07(-23.77 至 7.62)]。多变量回归分析显示,基线时的自主神经功能与患者的mAb反应有关[β估计值(95%置信区间):3.63(0.21-7.06)]:抗CGRP mAb治疗在预防VM患者偏头痛方面比常规治疗更有效。虽然已确定的与治疗反应性相关的因素为个性化治疗方法提供了有价值的见解,但由于我们的研究是回顾性设计,样本量有限,因此有必要开展进一步的前瞻性研究来验证研究结果。
{"title":"Effectiveness of Anti-Calcitonin Gene-Related Peptide Medication in Vestibular Migraine: A Retrospective Cohort Study in an Asian Population.","authors":"Teppei Kouga, Toru Miwa, Kishiko Sunami, Yoshiaki Itoh","doi":"10.1007/s40263-024-01094-z","DOIUrl":"10.1007/s40263-024-01094-z","url":null,"abstract":"<p><strong>Background: </strong>Migraine and dizziness often coexist, with vestibular migraine (VM) presenting with vestibular symptoms and headaches. Calcitonin gene-related peptide (CGRP) may be involved in motion-induced symptoms; however, studies on the use of anti-CGRP monoclonal antibodies (mAbs) for the treatment of VM have yielded conflicting results. This study aimed to clarify the effectiveness of anti-CGRP mAbs in VM treatment.</p><p><strong>Methods: </strong>This retrospective observational cohort study, conducted between 1 January 2021 and 31 March 2023, assessed 12 Japanese patients with VM who were treated with anti-CGRP mAbs (CGRP group) for 6 months and 11 Japanese patients who received standard of care for VM and served as controls. Clinical questionnaires and equilibrium tests were administered, with primary outcomes including changes in Dizziness Handicap Inventory (DHI) scores compared with baseline values. Objective variables included the DHI score and explanatory variables included demographic data, balance test results, head-up tilt (HUT) test results, vestibular test results and questionnaire survey results. Analysis of variance was used to assess the treatment effects of anti-CGRP mAbs, and multivariate regression analysis was performed to identify mAb responders.</p><p><strong>Results: </strong>After 6 months, the CGRP group showed significant improvements in DHI scores [0 versus 6 months, odds ratio (95% confidence interval): 22.01 (0.13-43.88)] and number of vertigo/dizziness attacks per month [0 versus 6 months: 10.28 (2.80-17.76)]. No significant difference was observed in the control group [DHI scores, 0 versus 6 months: 0.65 (-26.84 to 28.14); number of vertigo/dizziness attacks per month, 0 versus 6 months: - 8.07 (- 23.77 to 7.62)]. Multivariate regression analysis showed that autonomic function at baseline was associated with mAb response in patients [β estimates (95% confidence interval): 3.63 (0.21-7.06)].</p><p><strong>Conclusions: </strong>Treatment with anti-CGRP mAbs was more effective than conventional treatment in preventing migraine in patients with VM. While the identified factors associated with treatment responsiveness offer valuable insights into personalised treatment approaches, further prospective studies are warranted to validate the findings due to our study's retrospective design and limited sample size.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"637-648"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161368","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
Alzheimer's Disease: Combination Therapies and Clinical Trials for Combination Therapy Development. 阿尔茨海默病:联合疗法和联合疗法开发的临床试验。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-27 DOI: 10.1007/s40263-024-01103-1
Jeffrey L Cummings, Amanda M Leisgang Osse, Jefferson W Kinney, Davis Cammann, Jingchun Chen

Alzheimer's disease (AD) is a complex multifaceted disease. Recently approved anti-amyloid monoclonal antibodies slow disease progression by approximately 30%, and combination therapy appears necessary to prevent the onset of AD or produce greater slowing of cognitive and functional decline. Combination therapies may address core features, non-specific co-pathology commonly occurring in patients with AD (e.g., inflammation), or non-AD pathologies that may co-occur with AD (e.g., α-synuclein). Combination therapies may be advanced through co-development of more than one new molecular entity or through add-on strategies including an approved agent plus a new molecular entity. Addressing add-on combination therapy is currently urgent since patients on anti-amyloid monoclonal antibodies may be included in clinical trials for experimental agents. Phase 1 information must be generated for each agent in combination drug development. Phase 2 and Phase 3 of add-on therapies may contrast the new molecular entity, the approved agent as standard of care, and the combination. More complex development programs including standard or modified combinatorial designs are required for co-development of two or more new molecular entities. Biomarkers are markedly affected by anti-amyloid monoclonal antibodies, and these effects must be anticipated in add-on trials. Examining target engagement biomarkers and comparing the magnitude and sequence of biomarker changes in those receiving more than one therapy, compared with those on monotherapy, may be informative. Using network-based medicine approaches, computational strategies may identify rational combinations using disease and drug effect network mapping.

阿尔茨海默病(AD)是一种复杂的多发性疾病。最近批准的抗淀粉样蛋白单克隆抗体可使疾病进展减缓约30%,而联合疗法似乎是预防阿尔茨海默病发病或进一步减缓认知和功能衰退所必需的。联合疗法可针对AD患者的核心特征、常见的非特异性共病理(如炎症)或可能与AD并发的非AD病理(如α-突触核蛋白)。联合疗法可通过共同开发一种以上的新分子实体或通过附加策略(包括一种已批准的药物加一种新分子实体)来推进。由于服用抗淀粉样蛋白单克隆抗体的患者可能会被纳入实验性药物的临床试验中,因此目前迫切需要解决附加联合疗法的问题。必须为联合用药开发中的每种药物提供第一阶段的信息。附加疗法的第 2 期和第 3 期可以对比新的分子实体、作为标准疗法的已批准药物以及联合用药。两种或两种以上新分子实体的联合开发需要更复杂的开发计划,包括标准或改进的组合设计。生物标志物会受到抗淀粉样蛋白单克隆抗体的明显影响,在附加试验中必须预见到这些影响。与接受单一疗法的患者相比,研究目标参与生物标志物并比较接受一种以上疗法的患者的生物标志物变化的幅度和顺序可能会有所启发。利用基于网络的医学方法,计算策略可通过疾病和药物效应网络图确定合理的组合。
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引用次数: 0
Sex Differences in the Dual Antiplatelet Therapy Versus Alteplase for Patients with Minor Nondisabling Acute Ischemic Stroke: A Secondary Analysis of the ARAMIS Study. 轻度非致残性急性缺血性卒中患者接受双重抗血小板疗法与阿替普酶治疗的性别差异:ARAMIS 研究的二次分析。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-28 DOI: 10.1007/s40263-024-01096-x
Hui-Ling Qu, Xiao-Yu Sun, Chao He, Hui-Sheng Chen

Background and purpose: Sex is associated with clinical outcome in stroke. The present study aimed to determine the effect of sex on efficacy of dual antiplatelet (DAPT) versus alteplase in ischemic stroke based on Antiplatelet versus recombinant tissue plasminogen activator (R-tPA) for Acute Mild Ischemic Stroke (ARAMIS) trial.

Methods: In this secondary analysis of the ARAMIS study, eligible patients aged 18 years or older with minor nondisabling stroke who received dual antiplatelet therapy or intravenous alteplase within 4.5 h of stroke onset were divided into two groups: men and women. The primary endpoint was an excellent functional outcome, defined as a modified Rankin Scale (mRS) 0-1 at 90 days. Binary logistic regression analyses and generalized linear models were used.

Results: Of the 719 patients who completed the study, 31% (223) were women, and 69% (496) were men. There were no significant sex differences in excellent functional outcome (unadjusted p = 0.304 for men and p = 0.993 for women; adjusted p = 0.376 for men and p = 0.918 for women) and favorable functional outcome (mRS score of 0-2; unadjusted p = 0.968 for men and p = 0.881 for women; adjusted p = 0.824 for men and p = 0.881 for women). But for the secondary outcomes, compared with alteplase, DAPT was associated with a significantly decreased proportion of early neurological deterioration within 24 h in men {unadjusted odds ratio [OR] = 0.440 [95% confidence interval (CI), 0.221-0.878]; p = 0.020; adjusted OR = 0.436 [95% CI, 0.216-0.877]; p = 0.020}, but not in women [unadjusted OR = 0.636 (95% CI, 0.175-2.319), p = 0.490; adjusted OR = 0.687 (95% CI, 0.181-2.609), p = 0.581]. For the safety outcomes, compared with the DAPT group, alteplase was associated with a significantly increased proportion of any bleeding events in men [unadjusted OR = 3.110 (95% CI, 1.103-8.770); p = 0.032], but not in women [unadjusted OR = 5.333 (95% CI, 0.613-46.407), p = 0.129; adjusted OR = 5.394 (95% CI, 0.592-49.112), p = 0.135].

Conclusion: Sex did not influence the effect of dual antiplatelet therapy versus intravenous alteplase in minor nondisabling stroke, but more early neurological deterioration and bleeding events occurred in men who received alteplase.

背景和目的:性别与中风的临床预后有关。本研究旨在根据急性轻度缺血性卒中抗血小板与重组组织纤溶酶原激活剂(R-tPA)试验(ARAMIS)确定性别对缺血性卒中双联抗血小板(DAPT)与阿替普酶疗效的影响:在这项 ARAMIS 研究的二次分析中,符合条件的 18 岁及以上非致残性轻微脑卒中患者在脑卒中发生后 4.5 小时内接受了双联抗血小板疗法或静脉注射阿替普酶后,被分为两组:男性组和女性组。主要终点是良好的功能预后,即 90 天时改良 Rankin 量表(mRS)为 0-1。研究采用了二元逻辑回归分析和广义线性模型:在完成研究的 719 名患者中,31%(223 人)为女性,69%(496 人)为男性。在优良功能预后(未经调整的男性 p = 0.304,女性 p = 0.993;调整后男性 p = 0.376,女性 p = 0.918)和良好功能预后(mRS 评分 0-2 分;未经调整的男性 p = 0.968,女性 p = 0.881;调整后男性 p = 0.824,女性 p = 0.881)方面没有明显的性别差异。但就次要结果而言,与阿替普酶相比,DAPT与男性24小时内早期神经功能恶化的比例显著降低相关{未经调整的几率比[OR] = 0.440 [95% 置信区间 (CI),0.221-0.878];p = 0.020;调整后 OR = 0.436 [95% CI,0.216-0.877];p = 0.020},但在女性中没有相关性[未调整 OR = 0.636 (95% CI,0.175-2.319),p = 0.490;调整 OR = 0.687 (95% CI,0.181-2.609),p = 0.581]。在安全性结果方面,与DAPT组相比,阿替普酶与男性[未调整OR = 3.110 (95% CI, 1.103-8.770); p = 0.032]显著增加的任何出血事件比例相关,但与女性[未调整OR = 5.333 (95% CI, 0.613-46.407), p = 0.129; 调整OR = 5.394 (95% CI, 0.592-49.112), p = 0.135]无关:性别并不影响双联抗血小板疗法与静脉注射阿替普酶治疗轻度非致残性卒中的效果,但接受阿替普酶治疗的男性患者早期神经功能恶化和出血事件发生率更高。
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引用次数: 0
The Use of Ketamine for the Treatment of Anhedonia in Depression. 使用氯胺酮治疗抑郁症患者的失神症。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-23 DOI: 10.1007/s40263-024-01099-8
Liliana Patarroyo-Rodriguez, Stefanie Cavalcanti, Jennifer L Vande Voort, Balwinder Singh

Anhedonia, a complex symptom rooted in deficits across reward processes, is primarily linked to depression and schizophrenia but transcends diagnostic boundaries across various mental disorders. Its presence correlates with poorer clinical outcomes, including an increased risk of suicide and diminished response to treatment. The neurobiological underpinnings of anhedonia remain incompletely understood despite advancements in biomarkers and imaging that contribute to deeper insights. Ketamine, known for its rapid-acting antidepressant properties, appears to possess antianhedonic effects through a mechanism of action not fully elucidated. This effect appears to be independent of its antidepressant properties. Explorations into alternative antianhedonic treatments have been underway, yet lingering questions persist, underscoring the imperative need for ongoing research to advance the field.

失乐症是一种复杂的症状,其根源在于奖赏过程的缺陷,主要与抑郁症和精神分裂症有关,但它超越了各种精神障碍的诊断界限。它的存在与较差的临床结果相关,包括自杀风险增加和对治疗的反应减弱。尽管生物标记物和成像技术的进步有助于深入了解厌食症的神经生物学基础,但人们对它的了解仍然不够全面。氯胺酮因其速效抗抑郁特性而闻名,它似乎通过一种尚未完全阐明的作用机制而具有抗失神作用。这种作用似乎与其抗抑郁特性无关。对其他抗失眠治疗方法的探索一直在进行,但仍有一些问题挥之不去,这突出表明迫切需要不断进行研究,以推动这一领域的发展。
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引用次数: 0
A Framework for the Administration of Anti-amyloid Monoclonal Antibody Treatments in Early-Stage Alzheimer's Disease. 早期阿尔茨海默氏症抗淀粉样蛋白单克隆抗体治疗的管理框架。
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-06-05 DOI: 10.1007/s40263-024-01097-w
Michael H Rosenbloom, Tricia O'Donohue, Domi Zhou-Clark, Deepashni Mala, Andrew Frazier, Michael Tarrant, Michelle Modrijan, Melora Riveira, Darla Chapman, Yvonne Griffin, Lauren Shakalis, Thomas J Grabowski

The US Food and Drug Administration (FDA) approval of lecanemab for early-stage Alzheimer's disease (AD) represents an exciting new chapter in the management of neurodegenerative disease, but likewise presents numerous clinical, technical, and financial logistical challenges for both academic and non-academic medical institutions hoping to administer this drug. Minimal resources exist that provide guidance for establishing and maintaining a lecanemab treatment program at the institutional level. The current report aims to provide healthcare institutions a framework for the planning, onboarding, and longitudinal treatment of AD with anti-amyloid monoclonal antibody treatments. We present an implementation study involving three stages: (1) feasibility assessment, (2) operations and going live, and (3) monitoring assessment. We found that implementation of lecanemab in clinical practice was feasible due to the assignment of an enterprise-wide project manager to facilitate the planning phase, a cost analysis showing that lecanemab was financially sustainable, and the development of electronic medical record tools to support operational efficiency.

美国食品和药物管理局(FDA)批准将莱卡尼单抗用于早期阿尔茨海默病(AD)的治疗,为神经退行性疾病的治疗揭开了激动人心的新篇章,但同时也给希望使用这种药物的学术和非学术医疗机构带来了许多临床、技术和财务后勤方面的挑战。目前只有极少的资源可为在机构层面建立和维护莱卡奈单抗治疗项目提供指导。本报告旨在为医疗机构提供一个框架,用于抗淀粉样蛋白单克隆抗体治疗的规划、入职和纵向治疗。我们介绍了一项实施研究,包括三个阶段:(1) 可行性评估;(2) 运行和上线;(3) 监测评估。我们发现,在临床实践中实施莱卡尼单抗是可行的,因为我们指派了一名企业级项目经理来推动规划阶段的工作,成本分析表明莱卡尼单抗在财务上是可持续的,而且还开发了电子病历工具来支持运营效率。
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引用次数: 0
Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics. 健康非吸烟志愿者体内氯氮平和诺氯氮平半生理学药代动力学模型:种族和遗传的影响。
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-06-05 DOI: 10.1007/s40263-024-01092-1
Orwa Albitar, Sabariah Noor Harun, Siti Maisharah Sheikh Ghadzi

BACKGROUND AND OBJECTIVES: Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors.

Methods: Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography-ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism.

Results: A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis.

Conclusions: This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials.

背景和目的:氯氮平是治疗耐药性精神分裂症的首选药物。然而,氯氮平的代谢过程复杂,个体间的差异性无法解释。目前的研究旨在建立非吸烟者服用氯氮平和诺氯氮平的药代动力学模型,并评估人口统计学和遗传学预测因素的影响。在服用单剂量氯氮平(12.5 毫克)后的 30 分钟、1、2、3、5 和 8 小时采集血液样本。通过高效液相色谱-紫外法测定氯氮平和诺氯氮平的浓度。利用非线性混合效应模型建立了氯氮平与诺氯氮平的半生理学药代动力学模型。利用限制性片段长度多态性评估了临床和遗传预测因素,包括 CYP1A2 (rs762551) 和 ABCB1 (rs2032582):共收集了 33 名参与者的 270 份样本。使用氯氮平的二室模型和诺氯氮平的二室模型(一阶吸收、消除和系统前代谢)对数据进行了最佳描述。氯氮平和诺氯氮平的估计清除率(相对标准误差)分别为 27 升/小时(31.5%)和 19.6 升/小时(30%)。与亚洲人(20 人)相比,撒哈拉以南非洲人(4 人)和白种人(9 人)的氯氮平清除率较低。在单变量分析中,CYP1A2(rs762551)(n = 18)和ABCB1(rs2032582)(n = 12)突变等位基因参与者的氯氮平清除率较低:这是首次建立氯氮平和诺氯氮平的半生理学药代动力学模型的研究,该模型考虑了前系统代谢。与白种人相比,亚洲人所需的氯氮平剂量较低,而撒哈拉以南非洲人的氯氮平药代动力学应在更大规模的试验中进一步研究。
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引用次数: 0
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