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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 CLINICAL NEUROLOGY 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
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 CLINICAL NEUROLOGY 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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引用次数: 0
The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations. 与酶诱导型抗癫痫药物相比,左乙拉西坦对阿哌沙班和利伐沙班血浆峰浓度的影响
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-01 Epub Date: 2024-03-23 DOI: 10.1007/s40263-024-01077-0
Rachel Goldstein, Natalie Rabkin, Noa Buchman, Aviya R Jacobs, Khaled Sandouka, Bruria Raccah, Tamar Fisher Negev, Ilan Matok, Meir Bialer, Mordechai Muszkat

Background and objective: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM.

Methods: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups.

Results: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression.

Conclusions: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

背景和目的:中风后癫痫是一项重要的临床挑战,因为它通常需要同时使用直接口服抗凝剂(DOACs)和抗癫痫药物(ASMs)进行治疗。左乙拉西坦(LEV)是一种已知不会诱导代谢酶的 ASM,有人建议它在接受 DOACs 治疗的患者中作为酶诱导 (EI) ASMs 的更安全替代品;然而,由于可能存在 P 糖蛋白诱导和竞争(基于临床前研究),目前的临床指南建议左乙拉西坦与 DOACs 合用时要谨慎。我们研究了 LEV 是否会影响阿哌沙班和利伐沙班的浓度,并与两个对照组进行了比较:(a) 接受 EI-ASMs 治疗的患者;(b) 未接受任何 ASM 治疗的患者:在这项回顾性观察研究中,我们监测了接受 LEV(n = 28)和 EI-ASM (n = 33)治疗的 203 名患者以及未接受任何 ASM 治疗的患者(n = 142)的阿哌沙班和利伐沙班峰值血浆浓度(Cmax)。酶诱导 ASM 包括卡马西平、苯妥英、苯巴比妥、普立米通和奥卡西平。我们收集了临床和实验室数据进行分析,并将服用 LEV 患者的 DOAC Cmax 与其他两组患者进行了比较:在203名患者中,55%为女性,平均年龄为78±0.8岁。186名患者服用阿哌沙班,17名患者服用利伐沙班。LEV 组 DOAC Cmax 低于治疗范围的患者比例为 7.1%,非 ASM 组为 10.6%,EI-ASM 组为 36.4%(p < 0.001)。服用 LEV 的患者 DOAC Cmax 低于治疗范围的几率(与对照组相比)没有显著差异(调整后的几率比 0.70,95% 置信区间 0.19-2.67,p = 0.61),但服用 EI-ASM 的患者的几率比对照组高 12.7 倍(p < 0.001)。在对接受阿哌沙班治疗的患者进行的分析中,接受LEV治疗的患者与非ASM对照组的阿哌沙班Cmax没有差异,在多变量线性回归中,LEV的临床使用与阿哌沙班Cmax的变化无关:在这项研究中,我们发现与 EI-ASMs 不同,LEV 的临床应用与阿哌沙班 Cmax 的降低无明显关联,与未接受任何 ASM 治疗的患者相似。我们的研究结果表明,LEV 与阿哌沙班和利伐沙班联用可能与阿哌沙班和利伐沙班 Cmax 降低无关。因此,需要进行前瞻性对照研究,以探讨 LEV-apixaban 或 LEV-rivaroxaban 联合用药对患者预后影响的可能非药代动力学机制。
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引用次数: 0
Sex Differences in Adverse Effects of Antiseizure Medications in Adults with Epilepsy: A Systematic Review 成人癫痫患者服用抗癫痫药物不良反应的性别差异:系统回顾
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-30 DOI: 10.1007/s40263-024-01088-x
Loretta Giuliano, Vania Durante, Giulia Battaglia, Sara Gasparini, Elena Zambrelli, Caterina Ermio, Angela La Neve, Barbara Mostacci

Background

Sex differences in epilepsy have been described in prevalence, seizure propensity and response to treatment. Therefore, taking into account sex-based differences in epilepsy is important for both diagnostic purposes and therapeutic considerations. However, little is known about sex differences in adverse effects of antiseizure medications (ASMs).

Objectives

We performed a systematic review searching for sex differences in adverse effects of ASMs in adult persons with epilepsy (PWE) as part of a wider project aimed to assess sex-based differences in efficacy and adverse effects of ASMs in PWE.

Methods

We conducted a comprehensive literature search in the PubMed database. The search was conducted with no restriction on publication date, and all results up to April 2020 were included. We included articles written in English, Italian, Spanish, or French that evaluated adverse effects of one or more ASMs in PWE, with specific mention of the two sexes. When appropriate, Newcastle-Ottawa or Jadad scales were used to assess study quality.

Results

Of 5164 identified studies, only 167 considered sex in the analysis and were therefore included. Significant sex-related differences were found in 58 of those studies. We found a consistently higher frequency of cutaneous adverse effects in females; higher risk of developing general adverse effects on different ASMs in females; stronger risk of adverse effects on bone metabolism in females, mainly on treatment with enzyme-inducing ASMs; a concordant higher risk of visual field loss was noted in males on vigabatrin; an overall worse lipid profile in males; as well as higher leptin levels and higher body mass index in females treated with various ASMs.

Conclusions

Our analysis has identified some important sex differences in the adverse effects of ASMs. Clinicians should be aware of these differences when informing patients about the risks associated with ASM treatment in PWE.

背景癫痫在发病率、发作倾向和对治疗的反应方面存在性别差异。因此,考虑癫痫的性别差异对于诊断和治疗都很重要。作为旨在评估抗癫痫药物在成年癫痫患者(PWE)中疗效和不良反应的性别差异的更广泛项目的一部分,我们对抗癫痫药物在成年癫痫患者(PWE)中不良反应的性别差异进行了系统性综述。我们在 PubM 数据库中进行了全面的文献检索,检索不限制发表日期,并纳入了截至 2020 年 4 月的所有结果。我们收录了以英语、意大利语、西班牙语或法语撰写的文章,这些文章评估了一种或多种 ASMs 对 PWE 的不良影响,并特别提到了两种性别。在适当的情况下,我们使用纽卡斯尔-渥太华或贾达德量表来评估研究质量。结果 在 5164 篇已确定的研究中,只有 167 篇在分析中考虑了性别因素,因此被纳入其中。其中 58 项研究发现了与性别相关的显著差异。我们发现女性出现皮肤不良反应的频率一直较高;女性出现不同 ASMs 一般不良反应的风险较高;女性出现骨代谢不良反应的风险较高,主要是在接受酶诱导 ASMs 治疗时;男性接受维格巴曲林治疗时出现视野缺损的风险较高;男性血脂状况总体较差;女性接受各种 ASMs 治疗时瘦素水平较高,体重指数较高。结论我们的分析发现了 ASMs 不良反应中的一些重要性别差异。临床医生在告知患者ASM治疗对PWE的相关风险时应注意这些差异。
{"title":"Sex Differences in Adverse Effects of Antiseizure Medications in Adults with Epilepsy: A Systematic Review","authors":"Loretta Giuliano, Vania Durante, Giulia Battaglia, Sara Gasparini, Elena Zambrelli, Caterina Ermio, Angela La Neve, Barbara Mostacci","doi":"10.1007/s40263-024-01088-x","DOIUrl":"https://doi.org/10.1007/s40263-024-01088-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Sex differences in epilepsy have been described in prevalence, seizure propensity and response to treatment. Therefore, taking into account sex-based differences in epilepsy is important for both diagnostic purposes and therapeutic considerations. However, little is known about sex differences in adverse effects of antiseizure medications (ASMs).</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>We performed a systematic review searching for sex differences in adverse effects of ASMs in adult persons with epilepsy (PWE) as part of a wider project aimed to assess sex-based differences in efficacy and adverse effects of ASMs in PWE.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We conducted a comprehensive literature search in the PubMed database. The search was conducted with no restriction on publication date, and all results up to April 2020 were included. We included articles written in English, Italian, Spanish, or French that evaluated adverse effects of one or more ASMs in PWE, with specific mention of the two sexes. When appropriate, Newcastle-Ottawa or Jadad scales were used to assess study quality.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of 5164 identified studies, only 167 considered sex in the analysis and were therefore included. Significant sex-related differences were found in 58 of those studies. We found a consistently higher frequency of cutaneous adverse effects in females; higher risk of developing general adverse effects on different ASMs in females; stronger risk of adverse effects on bone metabolism in females, mainly on treatment with enzyme-inducing ASMs; a concordant higher risk of visual field loss was noted in males on vigabatrin; an overall worse lipid profile in males; as well as higher leptin levels and higher body mass index in females treated with various ASMs.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Our analysis has identified some important sex differences in the adverse effects of ASMs. Clinicians should be aware of these differences when informing patients about the risks associated with ASM treatment in PWE.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"25 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140829367","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
Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data 非典型抗精神病药物在氯氮平治疗前血清中低于治疗水平的快速代谢:真实世界数据的回顾性分析
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-18 DOI: 10.1007/s40263-024-01079-y
Hasan Çağın Lenk, Robert Løvsletten Smith, Kevin S. O’Connell, Ole A. Andreassen, Espen Molden

Introduction

Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment.

Methods

Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups.

Results

Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005).

Conclusion

LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

导言:在诊断出耐药性精神分裂症并开始氯氮平治疗之前,需要适当的抗精神病治疗强度。我们的目的是研究氯氮平治疗前非氯氮平非典型抗精神病药物低剂量调整血清浓度(CD)的潜在快速药物代谢原因。方法2005年至2023年期间,挪威奥斯陆的一家治疗药物监测服务机构纳入了在开始使用氯氮平前1年内使用非氯氮平非典型抗精神病药物(阿立哌唑、利培酮、奥氮平或喹硫平)的患者。患者被分为低 CD (LCD) 和正常 CD (NCD) 亚组。使用包含 147,964 次抗精神病药物测量值的参考样本,LCD 被定义为低于第 25 百分位数的 CD,而 NCD 患者的 CD 值介于各自参考测量值的第 25 百分位数和第 75 百分位数之间。比较了 LCD 组和 NCD 组非氯氮平类抗精神病药物的代谢比率、剂量和治疗水平以下的频率。与 NCD 组相比,LCD 患者的奥氮平(1.5 倍;p <;0.001)、喹硫平(3.0 倍;p <;0.001)和利培酮(6.0 倍;p <;0.001)代谢比率较高。奥氮平(p = 0.008)和利培酮(p = 0.016)的代谢比率差异分别与吸烟和 CYP2D6 基因型无关。尽管 LCD 患者的奥氮平剂量(1.25 倍;p = 0.054)和喹硫平剂量(1.6 倍;p = 0.001)高于 NCD 患者,但前者的代谢速度更快,同时奥氮平达不到治疗水平的频率更高(3.结论在开始氯氮平治疗前,LCD 和相关的非氯氮平类抗精神病药物的快速代谢很常见。对于奥氮平和喹硫平,这与治疗浓度不足的风险显著增加有关。
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引用次数: 0
Ticagrelor Versus Clopidogrel in Acute Large-Vessel Ischemic Stroke: A Randomized Controlled Single-Blinded Trial 替卡格雷与氯吡格雷治疗急性大血管缺血性卒中:单盲随机对照试验
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-15 DOI: 10.1007/s40263-024-01080-5
Mohamed G. Zeinhom, Ahmed Elbassiouny, Ahmed Mahmoud Mohamed, Sherihan Rezk Ahmed

Background

Large-vessel ischemic stroke represents about 25–40% of all ischemic strokes. Few clinical trials compared ticagrelor versus clopidogrel in ischemic stroke patients; all these studies included only patients with a transient ischemic attack or minor stroke; moreover, none of these studies included patients from North Africa.

Objectives

We aimed to compare ticagrelor versus clopidogrel in the first-ever large-vessel occlusion (LVO) acute ischemic stroke in Egypt.

Methods

Our trial involved 580 first-ever LVO ischemic stroke patients who were randomly assigned to administer loading and maintenance doses of ticagrelor or clopidogrel. Screening, randomization, and start of treatment occurred during the first 24 hours of the stroke.

Results

580 patients were included in the intention-to-treat analysis. Thirty patients in the ticagrelor group and 49 patients in the clopidogrel group experienced a new ischemic or hemorrhagic stroke at 90 days (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.38–0.98; p-value = 0.04), 36 patients in the ticagrelor group, and 57 in the clopidogrel group experienced composite of a new stroke, myocardial infarction, or death due to vascular insults (HR 0.56; 95% CI 0.37–0.87; = 0.009). Patients who received ticagrelor had better clinical outcomes regarding National Institutes of Health Stroke Scale (NIHSS) reduction and a favorable modified Rankin scale (mRS) score. There were no differences between ticagrelor and clopidogrel regarding hemorrhagic and non-hemorrhagic complications.

Conclusion

Patients with acute large-vessel ischemic stroke who received ticagrelor within the first 24 hours after ischemic stroke had better clinical outcomes based on recurrent stroke rates, NIHSS reduction, and favorable mRS rates compared with those who received clopidogrel. There were no differences between ticagrelor and clopidogrel regarding hemorrhagic and non-hemorrhagic complications.

Trial Registration

Clinical trials.gov (NCT06120725).

背景大血管缺血性卒中约占所有缺血性卒中的 25-40%。很少有临床试验对缺血性卒中患者进行替卡格雷与氯吡格雷的比较;所有这些研究都只纳入了短暂性脑缺血发作或轻微卒中患者;此外,这些研究都没有纳入北非患者。我们的试验涉及 580 名首次发生大血管闭塞(LVO)的缺血性卒中患者,他们被随机分配服用负荷和维持剂量的替卡格雷或氯吡格雷。筛选、随机分配和开始治疗均在中风发生后的 24 小时内进行。噻格瑞洛组和氯吡格雷组分别有 30 名和 49 名患者在 90 天后发生新的缺血性或出血性脑卒中(危险比 [HR] 0.61;95% 置信区间 [CI]0.38-0.98;P 值 = 0.04),接受替卡格雷治疗的患者中有36人出现新发中风、心肌梗死或因血管损伤死亡的复合情况,而接受氯吡格雷治疗的患者中有57人(HR 0.56; 95% CI 0.37-0.87; p = 0.009)。接受替卡格雷治疗的患者在美国国立卫生研究院卒中量表(NIHSS)降低和改良Rankin量表(mRS)评分方面的临床疗效更好。结论与接受氯吡格雷治疗的急性大血管缺血性卒中患者相比,在缺血性卒中发生后 24 小时内接受替卡格雷治疗的急性大血管缺血性卒中患者在卒中复发率、NIHSS 降低率和良好的 mRS 评分方面具有更好的临床预后。在出血性和非出血性并发症方面,ticagrelor和氯吡格雷没有差异。试验注册Clinical trials.gov (NCT06120725)。
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引用次数: 0
Impulse Control Disorders in Parkinson’s Disease: An Overview of Risk Factors, Pathogenesis and Pharmacological Management 帕金森病的冲动控制障碍:风险因素、发病机制和药物治疗概述
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-13 DOI: 10.1007/s40263-024-01087-y
Federico Carbone, Atbin Djamshidian

Impulse control disorders in Parkinson’s disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson’s disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson’s disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.

帕金森病的冲动控制障碍是一种相对常见的由药物诱发的成瘾行为,通常由多巴胺激动剂普拉克索、罗匹尼罗和罗替戈汀引发。这篇叙述性综述旨在全面概述目前有关帕金森病冲动控制障碍的知识。我们总结了帕金森病冲动控制障碍的患病率、临床特征、风险因素和潜在的内在机制。此外,我们还讨论了行为和影像特征以及管理策略方面的最新进展。有必要及早发现并采取有针对性的多学科方法,通常包括仔细调整多巴胺能疗法和治疗相关的神经精神症状。在某些情况下,可以考虑通过泵或多巴胺 D1 受体激动剂阿朴吗啡持续给药左旋多巴。在某些没有认知或语言障碍的患者中,对丘脑下核进行深部脑刺激也可以改善成瘾性。在减少多巴胺能剂量(通常是多巴胺受体激动剂)的同时不恶化运动症状,这两者之间找到适当的平衡点对于获得有益的长期疗效至关重要。
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引用次数: 0
Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial 口服δ-9-四氢大麻酚(THC)可提高慢性神经病理性疼痛男性患者的副交感神经活性和脊髓上条件性疼痛调节能力:一项交叉、双盲、安慰剂对照试验
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-10 DOI: 10.1007/s40263-024-01085-0
Libat Weizman, Haggai Sharon, Lior Dayan, Joumana Espaniol, Silviu Brill, Hadas Nahman-Averbuch, Talma Hendler, Giris Jacob

Background

Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain.

Methods

Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo.

Results

THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005].

Conclusions

THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation.

Clinical Trial Registry Number

NCT02560545.

背景慢性疼痛患者的自主神经系统调节紊乱和脊髓上疼痛抑制已被反复描述。我们旨在探索δ-9-四氢大麻酚(THC)这一新兴治疗方案对慢性疼痛患者自律神经系统和中枢疼痛调节措施的影响。方法12名男性慢性根性神经病理性疼痛患者参加了一项随机、双盲、交叉、安慰剂对照、单剂量试验。测量了低频/高频心率变异性(HRV)比率和条件性疼痛调制(CPM)反应,并在基线和舌下含服 0.结果与安慰剂相比,四氢大麻酚显著降低了 LF/HF 比值(交互效应 F(1,11) = 20.5; p < 0.005),并显著改善了 CPM 反应(交互效应 F(1,9) = 5.2; p = 0.048)。THC诱导的低频/高频比值降低与喙腹外侧延髓和背外侧前额叶皮层之间的功能连接增加有关[T(10) = 6.4,群集 p-FDR < 0.005]。迷走神经张力的增加与高阶调节脑区的连通性变化相关,表明四氢大麻酚具有自上而下的效应。这些变化可能反映了 THC 对脊髓上疼痛失调多个领域的正常化作用。
{"title":"Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial","authors":"Libat Weizman, Haggai Sharon, Lior Dayan, Joumana Espaniol, Silviu Brill, Hadas Nahman-Averbuch, Talma Hendler, Giris Jacob","doi":"10.1007/s40263-024-01085-0","DOIUrl":"https://doi.org/10.1007/s40263-024-01085-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>THC significantly reduced the LF/HF ratio compared with placebo (interaction effect <i>F</i>(1,11) = 20.5; <i>p</i> &lt; 0.005) and significantly improved CPM responses (interaction effect <i>F</i>(1,9) = 5.2; <i>p</i> = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster <i>p</i>-FDR &lt; 0.005].</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation.</p><h3 data-test=\"abstract-sub-heading\">Clinical Trial Registry Number</h3><p>NCT02560545.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"250 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561002","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
On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson’s Disease Psychosis 帕金森病精神病的最佳诊断和皮马万色林不断演变的作用
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-08 DOI: 10.1007/s40263-024-01084-1
Fernando L. Pagan, Paul E. Schulz, Yasar Torres-Yaghi, Gregory M. Pontone

Parkinson’s disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.

帕金森病(Parkinson's disease,PD)半数以上的患者会出现精神错乱(Psychosis,PDP),包括幻觉和妄想。因此,帕金森病的最佳治疗必须同时考虑运动症状和非运动症状。临床医生通常无法诊断出帕金森病患者是否患有精神病,即使发现了,治疗效果也不理想,尽管有多种干预措施可供选择。在本文中,我们总结了目前使用抗精神病药物治疗帕金森病的指南和临床证据。我们还提供了有关诊断和随访的建议。最后,我们利用专家的意见和经验,从有限的证据库中推断出一种最新的 PDP 治疗算法,其中包括使用匹马凡色林(美国 FDA 批准用于治疗 PDP 的唯一药物)。由于皮马凡色林只在美国获准用于治疗 PDP,因此在世界其他地区必须考虑其他建议和算法。
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引用次数: 0
Synergism of Anti-CGRP Monoclonal Antibodies and OnabotulinumtoxinA in the Treatment of Chronic Migraine: A Real-World Retrospective Chart Review 抗CGRP单克隆抗体与奥那巴妥妥毒素A在治疗慢性偏头痛中的协同作用:真实世界病历回顾
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-07 DOI: 10.1007/s40263-024-01086-z
Amira Salim, Elise Hennessy, Claire Sonneborn, Olivia Hogue, Sudipa Biswas, MaryAnn Mays, Aarushi Suneja, Zubair Ahmed, Ignacio F. Mata

Background

Many patients with chronic migraine do not achieve clinically meaningful improvement in their headache frequency with monotherapy. The burden associated with chronic migraine calls for a multifaceted treatment approach targeting multiple aspects of migraine pathophysiology.

Objective

The aim of this study was to evaluate the effect of concurrent anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) and onabotulinumtoxinA (onabot) treatment on median monthly migraine days (MMD) in patients with chronic migraine, through a retrospective study.

Methods

The electronic medical records of Cleveland Clinic patients either concurrently (dual therapy) or consecutively (monotherapy) treated with anti-CGRP mAbs and onabot between June 2018 and November 2021 were extracted. Only adult patients (≥ 18 years of age) were included in this study. MMDs for 194 concurrently treated (86.6% female and a median [interquartile range] age of 51 [41–61] years) and 229 consecutively treated (88.2% female and median age of 47 [IQR 39–57] years) patients were examined at baseline, after first therapy of either anti-CGRP mAb or onabot, and following dual therapy for 3 consecutive months. The reduction of MMDs for each treatment group were compared. The same approach was utilized to compare consecutive monotherapy at separate times (n = 229) and dual-therapy groups.

Results

The initial treatment of the dual-therapy group reduced the median (IQR) MMDs from 30 (30–30) to 15 (12–30) [p < 0.0001]. After initiation of dual therapy, the median MMDs was further decreased from 15 (12–30) to 8 (3–22) [p < 0.0001]. A majority [132/194 (68.0%)] of the dual-therapy patients reported a ≥ 50% reduction in MMD and 90/194 (46.4%) reported a ≥ 75% reduction. For the consecutive monotherapy group, median MMDs changed from a baseline of 30 (25–30) to 15 (8–25) from onabot monotherapy and decreased from 25 (15–30) to 12 (4–25) after anti-CGRP mAb monotherapy. Almost half (113/229 [49.3%] from onabot, and 104/229 [45.4%] from anti-CGRP mAb) of these patients achieved a ≥ 50% reduction in MMDs and a minority (38/229 [16.6%] from onabot, and 45/229 [19.7%] from anti-CGRP mAb) achieved a reduction of ≥ 75%. Additionally, dual therapy showed significant improvement in MMDs compared with monotherapy of either treatment (p < 0.0001).

Conclusion

Dual therapy of anti-CGRP mAbs and onabot may be more efficacious than monotherapy, possibly due to their synergistic mechanisms of action.

背景许多慢性偏头痛患者在接受单药治疗后,头痛频率并没有得到有临床意义的改善。本研究的目的是通过一项回顾性研究,评估同时使用抗降钙素基因相关肽(CGRP)单克隆抗体(mAb)和奥那博特(onabotulinumtoxinA,onabot)治疗对慢性偏头痛患者每月偏头痛中位天数(MMD)的影响。方法提取克利夫兰诊所患者在2018年6月至2021年11月期间同时(双重疗法)或连续(单一疗法)接受抗CGRP mAbs和onabot治疗的电子病历。本研究仅纳入成年患者(≥ 18 岁)。对194名同时接受治疗的患者(86.6%为女性,中位数[四分位间差]年龄为51[41-61]岁)和229名连续接受治疗的患者(88.2%为女性,中位数年龄为47[IQR 39-57]岁)在基线、首次接受抗CGRP mAb或onabot治疗后以及连续3个月接受双重治疗后的MMDs进行了检查。比较了各治疗组的 MMD 减少情况。结果双重疗法组的首次治疗将中位数(IQR)MMD 从 30(30-30)降至 15(12-30)[p <0.0001]。开始双重疗法后,MMDs 中位数进一步从 15 (12-30) 降至 8 (3-22) [p;0.0001]。大多数接受双重疗法的患者[132/194 (68.0%)]报告MMD减少了≥50%,90/194 (46.4%)报告减少了≥75%。在连续单药治疗组中,中位MMD从基线30(25-30)下降到onabot单药治疗后的15(8-25),从25(15-30)下降到抗CGRP mAb单药治疗后的12(4-25)。其中近一半患者(113/229 [49.3%] 来自onabot,104/229 [45.4%] 来自抗CGRP mAb)的MMDs减少了≥50%,少数患者(38/229 [16.6%] 来自onabot,45/229 [19.7%] 来自抗CGRP mAb)的MMDs减少了≥75%。此外,与单药治疗相比,双药治疗可显著改善 MMDs(p < 0.0001)。
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引用次数: 0
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