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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。
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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 Medicine 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 Medicine 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
Intervening in the Premonitory Phase to Prevent Migraine: Prospects for Pharmacotherapy. 干预偏头痛的前驱期,预防偏头痛:药物疗法的前景。
IF 7.4 2区 医学 Q1 Medicine Pub Date : 2024-07-01 Epub Date: 2024-05-31 DOI: 10.1007/s40263-024-01091-2
Nazia Karsan, Peter J Goadsby

Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT1B/1D] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorous than modern day treatment studies, of small sample size, and have not since been replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.

偏头痛是一种常见的脑部疾病,其特点是发作时头痛伴有感觉敏感,令人丧失能力。尽管人们对偏头痛的神经生物学及其对治疗发展的影响有了越来越多的了解,但仍需要为现有疗法无法满足的患者提供治疗选择。首批开发的用于急性偏头痛治疗的特效药物--5-羟色胺[5-HT1B/1D]受体激动剂(三苯氧胺)似乎需要头痛发作时才能产生疗效,而在头痛升级前的轻微疼痛期间进行早期治疗可改善短期和长期疗效。有些患者发现,在头痛开始但未升级的早期窗口期进行治疗很困难,偏头痛可能在睡眠中或凌晨发作,因此在疼痛发作后及时治疗具有挑战性。有血管疾病的患者和年龄较大的患者可能不适合使用曲坦类药物,而且可能对一部分患者无效。人们越来越认识到,头痛只是偏头痛发作的众多症状之一,对一些患者来说,头痛并不是最严重的致残症状。在许多患者中,无痛症状可在头痛发作前出现,并能可靠地发出即将发生头痛的警告。因此,有必要确定可在发作过程中尽早使用的治疗目标和药物,以便在头痛发作前就加以预防,并减轻头痛和与头痛无关的发作负担。早期使用多潘立酮、那拉曲普坦和双氢麦角胺进行的小型研究表明,这种方法可能是有用的;这些研究在方法上不如现代治疗研究严谨,样本量也较小,而且后来没有进行过重复研究。最近出现的新型偏头痛靶向治疗方法,特别是降钙素基因相关肽(CGRP)受体拮抗剂(gepants),重新点燃了人们对这一策略的兴趣,并取得了令人鼓舞的结果。本综述总结了这一领域的历史数据和新出现的数据,支持利用偏头痛的前驱期作为尽早干预的机会,以预防发作相关的发病率。
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引用次数: 0
Targeting Biometals in Alzheimer's Disease with Metal Chelating Agents Including Coumarin Derivatives. 用包括香豆素衍生物在内的金属螯合剂靶向阿尔茨海默病中的生物金属。
IF 6 2区 医学 Q1 Medicine Pub Date : 2024-07-01 Epub Date: 2024-06-03 DOI: 10.1007/s40263-024-01093-0
Adrián Gucký, Slávka Hamuľaková

Numerous physiological processes happening in the human body, including cerebral development and function, require the participation of biometal ions such as iron, copper, and zinc. Their dyshomeostasis may, however, contribute to the onset of Alzheimer's disease (AD) and potentially other neurodegenerative diseases. Chelation of biometal ions is therefore a therapeutic strategy against AD. This review provides a survey of natural and synthetic chelating agents that are or could potentially be used to target the metal hypothesis of AD. Since metal dyshomeostasis is not the only pathological aspect of AD, and the nature of this disorder is very complex and multifactiorial, the most efficient therapeutics should target as many neurotoxic factors as possible. Various coumarin derivatives match this description and apart from being able to chelate metal ions, they exhibit the capacity to inhibit cholinesterases (ChEs) and monoamine oxidase B (MAO-B) while also possessing antioxidant, anti-inflammatory, and numerous other beneficial effects. Compounds based on the coumarin scaffold therefore represent a desirable class of anti-AD therapeutics.

人体的许多生理过程,包括大脑的发育和功能,都需要铁、铜和锌等生物金属离子的参与。然而,它们的失衡可能会导致阿尔茨海默病(AD)和其他潜在的神经退行性疾病的发生。因此,螯合生物金属离子是一种针对阿尔茨海默病的治疗策略。本综述对目前或可能用于针对 AD 金属假说的天然和合成螯合剂进行了调查。由于金属失衡并不是 AD 的唯一病理方面,而且这种疾病的性质非常复杂,具有多因素性,因此最有效的治疗方法应尽可能多地针对神经毒性因素。各种香豆素衍生物符合这一描述,除了能够螯合金属离子外,它们还具有抑制胆碱酯酶(ChEs)和单胺氧化酶 B(MAO-B)的能力,同时还具有抗氧化、抗炎和许多其他有益作用。因此,基于香豆素支架的化合物是一类理想的抗逆转录酶治疗药物。
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引用次数: 0
Sex Differences Between Female and Male Individuals in Antipsychotic Efficacy and Adverse Effects in the Treatment of Schizophrenia. 在治疗精神分裂症的抗精神病药疗效和不良反应方面,女性和男性的性别差异。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-07 DOI: 10.1007/s40263-024-01089-w
Megan Galbally, Karen Wynter, Dan Siskind, Christoph U Correll, Korinne Northwood, Susanna Every-Palmer

Background and objective: Antipsychotics are core treatments for people living with psychotic disorders. Understanding individualised factors that influence both efficacy and adverse responses will improve outcomes. The objective of this study was to examine sex differences in antipsychotic-related efficacy and tolerability.

Methods: This was a secondary analysis of data from phase 1 and 1a of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE); participants with schizophrenia were randomly assigned to double-blinded treatment with oral olanzapine, quetiapine, risperidone, ziprasidone or perphenazine. Measures included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions (CGI) scale and Calgary Depression Rating Scale, as well as self-reported side effects, medication compliance, dosage, weight measurements and various blood parameters.

Results: There were 1460 participants including 380 female and 1080 male individuals. Very few differences existed between male and female participants in response, adverse reactions, compliance or antipsychotic dosage. However, significantly more female participants than male participants reported constipation (28% vs 16%), dry mouth (50% vs 38%), gynecomastia/galactorrhea (11% vs 3%), incontinence/nocturia (16% vs 8%) and self reported weight gain (37% vs 24%) [all p < 0.001]. Within the risperidone treatment group, there was a significantly greater increase in prolactin levels (p < 0.001) among female participants (n = 61) than male participants (n = 159). No overall differences in clinician-rated measures, weight gain or other laboratory indicators were found.

Conclusions: While overall sex differences were limited across efficacy and tolerability for antipsychotic treatment, there were some specific findings with risperidone. Further examination of sex differences within antipsychotic trials will be important to improve efficacy and reduce adverse responses across as well as individualising care for people with schizophrenia.

背景和目的:抗精神病药物是治疗精神病患者的核心药物。了解影响疗效和不良反应的个体化因素将有助于改善治疗效果。本研究旨在探讨抗精神病药物相关疗效和耐受性方面的性别差异:这是对临床抗精神病药物干预效果试验(CATIE)第1期和第1a期数据的二次分析;精神分裂症患者被随机分配接受口服奥氮平、喹硫平、利培酮、齐拉西酮或奋乃静的双盲治疗。测量指标包括阳性和阴性综合量表(PANSS)、临床总体印象量表(CGI)和卡尔加里抑郁量表,以及自我报告的副作用、服药依从性、剂量、体重测量和各种血液参数:共有 1460 名参与者,包括 380 名女性和 1080 名男性。男性和女性参与者在反应、不良反应、依从性或抗精神病药物剂量方面几乎没有差异。然而,报告便秘(28% 对 16%)、口干(50% 对 38%)、妇科炎症/乳腺增生(11% 对 3%)、尿失禁/夜尿(16% 对 8%)和自我报告体重增加(37% 对 24%)的女性参与者明显多于男性参与者[均为 p 结论:虽然抗精神病药物治疗的疗效和耐受性方面的性别差异总体有限,但利培酮有一些特殊的发现。进一步研究抗精神病药物试验中的性别差异对于提高疗效、减少不良反应以及为精神分裂症患者提供个体化治疗非常重要。
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引用次数: 0
FcRn Inhibitor Therapies in Neurologic Diseases. 神经系统疾病中的 FcRn 抑制剂疗法。
IF 6 2区 医学 Q1 Medicine Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI: 10.1007/s40263-024-01090-3
Nouf Alfaidi, Salama Karmastaji, Alexandria Matic, Vera Bril

In the last decade, the landscape of treating autoimmune diseases has evolved with the emergence and approval of novel targeted therapies. Several new biological agents offer selective and target-specific immunotherapy and therefore fewer side effects, such as neonatal Fc receptor (FcRn)-targeting therapy. Neonatal Fc receptor-targeted therapies are engineered to selectively target FcRn through various methods, such as Fc fragments or monoclonal anti-FcRn antibodies. These approaches enhance the breakdown of autoantibodies by blocking the immunoglobulin G recycling pathway. This mechanism reduces overall plasma immunoglobulin levels, including the levels of pathogenic autoantibodies, without affecting the other immunoglobulin class immunoglobulin A, immunoglobulin E, immunoglobulin M, and immunoglobulin D levels. Drugs that inhibit FcRn include efgartigimod, rozanolixizumab, batoclimab, and nipocalimab. These medications can be administered either intravenously or subcutaneously. Numerous clinical trials are currently underway to investigate their effectiveness, safety, and tolerability in various neurological conditions, including myasthenia gravis and other neurological disorders such as chronic inflammatory demyelinating polyneuropathy, myositis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein antibody disease. Positive results from clinical trials of efgartigimod and rozanolixizumab led to their approval for the treatment of generalized myasthenia gravis. Additional clinical trials are still ongoing. Neonatal Fc receptor inhibitor agents seem to be well tolerated. Reported adverse events include headache (most commonly observed with efgartigimod and rozanolixizumab), upper respiratory tract infection, urinary tract infection, diarrhea, pyrexia, and nausea. Additionally, some of these agents may cause transient hypoalbuminemia and hypercholesterolemia notably reported with batoclimab and nipocalimab. In this review, we discuss the available clinical data for FcRN inhibitor agents in treating different neurological autoimmune diseases.

近十年来,随着新型靶向疗法的出现和获批,治疗自身免疫性疾病的格局发生了变化。一些新型生物制剂提供了选择性和靶向特异性免疫疗法,因此副作用较少,例如新生儿 Fc 受体(FcRn)靶向疗法。新生儿 Fc 受体靶向疗法通过各种方法,如 Fc 片段或单克隆抗 FcRn 抗体,选择性地靶向 FcRn。这些方法通过阻断免疫球蛋白 G 的循环途径来加强自身抗体的分解。这种机制可降低血浆免疫球蛋白的总体水平,包括致病性自身抗体的水平,而不会影响其他免疫球蛋白类免疫球蛋白 A、免疫球蛋白 E、免疫球蛋白 M 和免疫球蛋白 D 的水平。抑制 FcRn 的药物包括依加替莫德(efgartigimod)、罗扎尼珠单抗(rozanolixizumab)、巴妥珠单抗(batoclimab)和尼泊卡单抗(nipocalimab)。这些药物可以静脉注射或皮下注射。目前正在进行大量临床试验,以研究这些药物对各种神经系统疾病的有效性、安全性和耐受性,包括重症肌无力和其他神经系统疾病,如慢性炎症性脱髓鞘性多发性神经病、肌炎、神经性视脊髓炎和髓鞘少突胶质细胞糖蛋白抗体病。依加替莫德(efgartigimod)和罗扎尼珠单抗(rozanolixizumab)的临床试验结果良好,因此被批准用于治疗全身性重症肌无力。其他临床试验仍在进行中。新生儿 Fc 受体抑制剂似乎耐受性良好。已报告的不良反应包括头痛(最常见于依加替莫德和罗扎尼单抗)、上呼吸道感染、泌尿道感染、腹泻、发热和恶心。此外,这些药物中的一些可能会导致一过性低白蛋白血症和高胆固醇血症,巴妥珠单抗和尼泊卡珠单抗的报道尤为明显。在本综述中,我们将讨论 FcRN 抑制剂治疗不同神经系统自身免疫性疾病的现有临床数据。
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