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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
CNS Viral Infections—What to Consider for Improving Drug Treatment: A Plea for Using Mathematical Modeling Approaches 中枢神经系统病毒感染--改进药物治疗的考虑因素:呼吁使用数学建模方法
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-05 DOI: 10.1007/s40263-024-01082-3
Ming Sun, Martijn L. Manson, Tingjie Guo, Elizabeth C. M. de Lange

Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood–brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.

神经性病毒可引起脑膜炎、脊髓炎、脑炎或脑膜脑炎。如果治疗不当,这些中枢神经系统(CNS)炎症可能会造成严重的破坏性后果。在这篇综述中,我们首先总结了神经性病毒如何通过以下途径进入中枢神经系统:(1)穿过血脑屏障或血-脑脊液屏障;(2)通过嗅觉途径侵入鼻腔;或(3)侵入周围神经系统。然后,神经病毒可能通过内吞和/或膜融合进入脑细胞的细胞内空间。目前,抗病毒药物被用于治疗不同的中枢神经系统病毒感染,但除了阿昔洛韦外,其他抗病毒药物在中枢神经系统内的使用和给药方案几乎没有临床证据支持。因此,我们提供了优化这些神经毒性病毒药物治疗的注意事项。抗病毒药物应穿过血脑屏障/血脑脊液屏障并通过脑细胞膜,以抑制脑细胞内的这些病毒。有些抗病毒药物可能还需要在细胞内转化为其活性代谢物。这说明有必要更好地了解这些机制,因为这些过程决定了中枢神经系统内的药物暴露,最终决定了治疗中枢神经系统感染的抗病毒药物的成功与否。最后,我们讨论了基于数学模型的优化抗病毒治疗方法。由于在活人体内直接测量脑细胞内暴露量面临伦理限制,因此我们强调基于中枢神经系统生理的药代动力学模型的潜力。现有的基于生理学的药代动力学模型与体外药代动力学/药效学信息相结合,可用于预测中枢神经系统内的药物暴露和评估抗病毒药物的疗效,最终优化中枢神经系统病毒感染的治疗。
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引用次数: 0
Observation on the Analgesic Effect of Different Doses of a Combination of Esketamine and Dexmedetomidine Administered for Percutaneous Endoscopic Transforaminal Discectomy: A Randomized, Double-Blind Controlled Trial 观察经皮内窥镜经椎间孔椎间盘切除术中使用不同剂量的艾司他敏和右美托咪定组合的镇痛效果:随机双盲对照试验
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-04 DOI: 10.1007/s40263-024-01083-2
Jian-Shun Zhou, Zhen Chen, Ying-Ying Liu, Mao-Lin Zhong, Qiong Zhong, Jun Wei, Qian Hu, Jia-Sheng Wang, Li-Feng Wang
<h3 data-test="abstract-sub-heading">Background</h3><p>Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems.</p><h3 data-test="abstract-sub-heading">Objectives</h3><p>The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg<sup>−1</sup> esketamine + dexmedetomidine), and an E2 group (0.2 mg kg<sup>−1</sup> esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO<sub>2</sub>) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at <i>T</i><sub>6</sub>, <i>T</i><sub>7</sub>, and <i>T</i><sub>9</sub> (<i>P</i> < 0.05). From <i>T</i><sub>4</sub> to <i>T</i><sub>10</sub>, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (<i>P</i> < 0.05), and at the <i>T</i><sub>4</sub>–<i>T</i><sub>6</sub> time points, the OAA/S score of the E2 group was lower than that of group E1 (<i>P</i> < 0.05). At <i>T</i><sub>4</sub> and <i>T</i><sub>5</sub>, the HR and BP of patients in groups E1 and E2 were greater than those in group C (<i>P</i> < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (<i>P</i> < 0.01). There was no significant difference in patient RR, SpO<sub>2</sub>, or postoperative satisfaction with anesthesia among the three groups (<i>P</i> > 0.05).</p><h3 data-test="abstract-sub-heading">Conclusion</h3><p>The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients’ compliance with surgical instructions from medical staff. Patient sati
背景经皮内窥镜经椎间孔椎间盘切除术(PETD)是治疗腰椎间盘突出症的有效方法,通常在局部麻醉下进行。本研究旨在观察不同剂量的艾司卡胺联合右美托咪定对降低手术干预期间视觉模拟量表(VAS)评分的影响。方法 将 120 名接受 PETD 的患者随机分为对照组(C 组:生理盐水 + 右美托咪定)、E1 组(0.1 mg kg-1 esketamine + 右美托咪定)和 E2 组(0.2 mg kg-1 esketamine + 右美托咪定)。主要结果是六个时间点的最大视觉模拟量表(VAS)(评分:0 = 无痛,10 = 疼痛最严重)。次要结果包括警觉性评估/镇静量表(OAA/S)评分和 11 个时间点的平均动脉压(BP)、心率(HR)、呼吸频率(RR)和血氧饱和度(SpO2)。结果与 C 组相比,E1 和 E2 组患者在 T6、T7 和 T9 的 VAS 评分较低(P <0.05)。从 T4 到 T10,E1 组和 E2 组的 OAA/S 评分均低于 C 组(P <;0.05),在 T4-T6 时间点,E2 组的 OAA/S 评分低于 E1 组(P <;0.05)。在 T4 和 T5,E1 组和 E2 组患者的心率和血压均高于 C 组(P < 0.05)。与 C 组相比,E1 组和 E2 组患者术中错觉、漂浮感、术后头晕和痛觉过敏的发生率明显更高(P < 0.01)。三组患者的 RR、SpO2 或术后麻醉满意度无明显差异(P >0.05)。结论埃斯氯胺酮和右美托咪定联合使用可降低此类手术某些阶段的 VAS 评分;对呼吸和循环的影响最小。然而,这种方法会增加术后头晕和精神副作用的发生率,也可能影响患者对医务人员手术指令的依从性。右美托咪定联合艾司氯胺酮的患者满意度并不比单独使用右美托咪定高。试验注册http://www.chictr.org.cn。标识符:ChiCTR2300068206。注册日期:2023年2月10日。
{"title":"Observation on the Analgesic Effect of Different Doses of a Combination of Esketamine and Dexmedetomidine Administered for Percutaneous Endoscopic Transforaminal Discectomy: A Randomized, Double-Blind Controlled Trial","authors":"Jian-Shun Zhou, Zhen Chen, Ying-Ying Liu, Mao-Lin Zhong, Qiong Zhong, Jun Wei, Qian Hu, Jia-Sheng Wang, Li-Feng Wang","doi":"10.1007/s40263-024-01083-2","DOIUrl":"https://doi.org/10.1007/s40263-024-01083-2","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objectives&lt;/h3&gt;&lt;p&gt;The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg&lt;sup&gt;−1&lt;/sup&gt; esketamine + dexmedetomidine), and an E2 group (0.2 mg kg&lt;sup&gt;−1&lt;/sup&gt; esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO&lt;sub&gt;2&lt;/sub&gt;) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;6&lt;/sub&gt;, &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;7&lt;/sub&gt;, and &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;9&lt;/sub&gt; (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). From &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;4&lt;/sub&gt; to &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;10&lt;/sub&gt;, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), and at the &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;4&lt;/sub&gt;–&lt;i&gt;T&lt;/i&gt;&lt;sub&gt;6&lt;/sub&gt; time points, the OAA/S score of the E2 group was lower than that of group E1 (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). At &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;4&lt;/sub&gt; and &lt;i&gt;T&lt;/i&gt;&lt;sub&gt;5&lt;/sub&gt;, the HR and BP of patients in groups E1 and E2 were greater than those in group C (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (&lt;i&gt;P&lt;/i&gt; &lt; 0.01). There was no significant difference in patient RR, SpO&lt;sub&gt;2&lt;/sub&gt;, or postoperative satisfaction with anesthesia among the three groups (&lt;i&gt;P&lt;/i&gt; &gt; 0.05).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusion&lt;/h3&gt;&lt;p&gt;The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients’ compliance with surgical instructions from medical staff. Patient sati","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"48 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561211","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
The Gut Microbiota in Parkinson Disease: Interactions with Drugs and Potential for Therapeutic Applications 帕金森病中的肠道微生物群:与药物的相互作用及治疗应用潜力
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-03 DOI: 10.1007/s40263-024-01073-4

Abstract

The concept of a ‘microbiota-gut-brain axis’ has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.

This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.

摘要 "微生物群-肠道-大脑轴 "的概念最近已成为帕金森病(PD)病理生理学中的一个重要角色,这主要是因为肠道细菌与药物之间存在相互影响。肠道微生物群会影响左旋多巴的动力学,反之,治疗帕金森病的药物也会影响肠道微生物群的组成。通过两步酶解途径,肠道微生物可在小肠中将左旋多巴脱羧为多巴胺,然后脱羟基为间苯二胺,从而降低左旋多巴的可用性。因此,抑制细菌脱羧途径可能是增加左旋多巴吸收的一种策略。其他常见于帕金森病的细菌紊乱,如小肠细菌过度生长和幽门螺旋杆菌感染,也会调节左旋多巴的代谢,根除细菌的疗法可能会改善左旋多巴的吸收。针对肠道微生物群的干预措施为控制致残性运动并发症和多巴无反应症状提供了一个新的机会。由地中海饮食引起的肠道微生物群组成的变化可能会改善一系列非运动症状。益生元能提高短链脂肪酸细菌的水平,减少促炎菌,从而对临床症状和左旋多巴动力学产生积极影响。不同配方的益生菌对便秘都有益处,其中一些还能改善多巴胺水平;然而,这些治疗方法的最有效剂量、持续时间和长期效果仍不得而知。粪便微生物群移植研究的数据尚属初步,但显示出运动和非运动结果均有令人鼓舞的改善趋势。本文总结了帕金森病药理微生物组学的最新知识,并讨论了操纵肠道微生物群如何成为治疗帕金森病的潜在新途径。
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引用次数: 0
The Dose-Response Relationship between Opioid Agonist Therapy and Alterations in Pain Pathways in Patients with Opioid Use Disorders: A Cross-Sectional Study. 阿片类药物使用障碍患者中阿片类药物激动剂治疗与疼痛途径改变之间的剂量-反应关系:一项横断面研究
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-01 Epub Date: 2024-02-29 DOI: 10.1007/s40263-024-01069-0
Kordula Lang-Illievich, Johanna Lang, Gudrun Rumpold-Seitlinger, Christian Dorn, Connor T A Brenna, Christoph Klivinyi, Helmar Bornemann-Cimenti

Introduction: The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances.

Objective: The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship.

Methods: This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed.

Results: A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization.

Conclusion: The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.

简介服用阿片类药物后,外周和中枢神经系统会发生持久的神经重塑变化。这种重塑可导致阿片类药物诱发的痛觉减退,从而增加对疼痛刺激的敏感性。在治疗阿片类药物使用障碍的阿片激动剂疗法中,很少有关于阿片类药物诱发的躯体感觉系统变化的描述,现有的少数报告也没有就不同剂量或物质的影响提供指导:本研究旨在评估接受阿片类受体激动剂治疗的患者疼痛通路的改变,并阐明剂量-反应关系:本研究计划在奥地利格拉茨的一家门诊诊所进行横断面研究。接受阿片类药物激动剂(包括美沙酮、左美沙酮、丁丙诺啡和缓释吗啡)治疗的阿片类药物使用障碍患者被要求填写一份调查问卷,其中包括中枢敏感性清单。然后进行了一系列体感系统评估:共有 120 名患者(85 名男性/35 名女性)参与了此次研究。平均口服吗啡毫克当量(MME)为 694 ± 249 毫克/天。我们的研究发现,疼痛感知、条件性疼痛调节和上风均发生了明显改变。我们证明了高剂量阿片类药物与中枢敏化标记物之间存在适度的剂量反应关系:本试验表明,阿片类激动剂疗法对躯体感觉系统有明显的影响。高剂量阿片类药物会对中枢敏化和下行疼痛调节产生负面影响,我们的数据阐明了这些现象之间的中度剂量反应关系。
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引用次数: 0
Magnetic Resonance Imaging Evidence Supporting the Efficacy of Cladribine Tablets in the Treatment of Relapsing-Remitting Multiple Sclerosis. 支持克拉利宾片治疗复发性多发性硬化症疗效的磁共振成像证据
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-01 Epub Date: 2024-03-15 DOI: 10.1007/s40263-024-01074-3
Rosa Cortese, Giovanna Testa, Francesco Assogna, Nicola De Stefano

Numerous therapies are currently available to modify the disease course of multiple sclerosis (MS). Magnetic resonance imaging (MRI) plays a pivotal role in assessing treatment response by providing insights into disease activity and clinical progression. Integrating MRI findings with clinical and laboratory data enables a comprehensive assessment of the disease course. Among available MS treatments, cladribine is emerging as a promising option due to its role as a selective immune reconstitution therapy, with a notable impact on B cells and a lesser effect on T cells. This work emphasizes the assessment of MRI's contribution to MS treatment, particularly focusing on the influence of cladribine tablets on imaging outcomes, encompassing data from pivotal and real-world studies. The evidence highlights that cladribine, compared with placebo, not only exhibits a reduction in inflammatory imaging markers, such as T1-Gd+, T2 and combined unique active (CUA) lesions, but also mitigates the effect on brain volume loss, particularly within grey matter. Importantly, cladribine reveals early action by reducing CUA lesions within the first months of treatment, regardless of a patient's initial conditions. The selective mechanism of action, and sustained efficacy beyond year 2, combined with its early onset of action, collectively position cladribine tablets as a pivotal component in the therapeutic paradigm for MS. Overall, MRI, along with clinical measures, has played a substantial role in showcasing the effectiveness of cladribine in addressing both the inflammatory and neurodegenerative aspects of MS.

目前有多种疗法可用于改变多发性硬化症(MS)的病程。核磁共振成像(MRI)通过深入了解疾病活动和临床进展情况,在评估治疗反应方面发挥着关键作用。将磁共振成像结果与临床和实验室数据相结合,可对疾病进程进行全面评估。在现有的多发性硬化症治疗方法中,克拉利宾作为一种选择性免疫重建疗法,对B细胞的影响显著,而对T细胞的影响较小,因此正在成为一种很有前景的选择。这项工作强调评估核磁共振成像对多发性硬化症治疗的贡献,尤其关注克拉利宾片对成像结果的影响,包括关键研究和实际研究的数据。这些证据强调,与安慰剂相比,克拉利宾不仅能减少炎症成像标志物,如 T1-Gd+、T2 和联合独特活性(CUA)病变,还能减轻对脑容量损失的影响,尤其是在灰质中。重要的是,无论患者的初始病情如何,克拉利宾都能在治疗的头几个月内减少CUA病变,从而显示出早期作用。克雷利宾片的选择性作用机制、第二年后的持续疗效以及它的早期起效,共同将克雷利宾片定位为多发性硬化症治疗范例中的关键组成部分。总体而言,核磁共振成像和临床测量在展示克拉利宾治疗多发性硬化症的炎症和神经退行性方面的有效性方面发挥了重要作用。
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引用次数: 0
SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. SAFE-ROCK:口服 ROCK 抑制剂 Fasudil 的 I 期试验,评估健康参与者的生物利用度、安全性和耐受性。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-01 Epub Date: 2024-02-28 DOI: 10.1007/s40263-024-01070-7
Andreas W Wolff, Jörg Peine, Josef Höfler, Gabriela Zurek, Claus Hemker, Paul Lingor
<p><strong>Background: </strong>The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.</p><p><strong>Objective: </strong>The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.</p><p><strong>Methods: </strong>This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).</p><p><strong>Results: </strong>Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC<sub>0-tz</sub>) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.</p><p><strong>Conclusions: </strong>Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to
背景:自 1995 年以来,Rho-激酶(ROCK)抑制剂法舒地尔的静脉注射制剂已被批准用于治疗蛛网膜下腔出血。此外,法舒地尔在治疗各种慢性疾病(包括神经退行性疾病,如肌萎缩性脊髓侧索硬化症、帕金森病和痴呆症)的临床前研究中也显示出良好的效果,因为在这些疾病中可能不适合长期静脉注射:本研究旨在评估口服法舒地尔(ERIL®)批准制剂的绝对生物利用度(与静脉注射相比),并评估口服法舒地尔的安全性和耐受性:这是一项在健康女性和男性中进行的一期、单中心、开放标签、随机、两期交叉临床试验。通过采用交叉设计,每个受试者都作为自己的对照组。试验采用两种治疗方法,中间有至少 3 天的冲淡期。第1天口服法舒地尔一次,以评估药代动力学;第2天口服三次,每次间隔8±1小时,以评估安全性和胃肠道耐受性。静脉注射法舒地尔的药代动力学评估在第1天进行一次。通过液相色谱电喷雾串联质谱法测定口服或静脉注射后法舒地尔及其活性代谢物羟基法舒地尔的血浆概况。耐受性以无明显药物不耐受的受试者比例进行评估,安全性以无临床或实验室治疗相关严重不良事件的受试者比例进行评估。胃肠道安全性通过胃肠道症状评分量表(GSRS)进行评估:14名年龄在30-70岁之间的受试者参加了此次试验。口服后,法舒地尔在血液中的浓度大多很低[1.4克/升;变异系数(CV)41.0%]。静脉注射后,峰值浓度为 100.6 µg/L(变异系数为 74.2%);然而,两种治疗方法的峰值浓度差异都很大。口服和静脉注射后,血液中羟基法舒地尔的最大浓度相似[分别为 111.6 µg/L (CV 24.1%) 和 108.4 µg/L (CV 19.7%)]。两种治疗方法的羟基法舒地暴露量(以AUC0-tz评估)不同,静脉注射治疗后为449微克×小时/升,口服治疗后为309微克×小时/升。因此,口服治疗后羟氟地尔的绝对生物利用度约为静脉注射治疗的 69%。试验期间未发生严重不良事件(SAE),口服法舒地尔(90 毫克/天)的耐受性良好:结论:研究对象对口服法舒地尔的耐受性普遍良好,未发现任何安全问题。然而,口服羟基法舒地尔的全身生物利用度为69%,因此需要考虑调整剂量。本文介绍的结果为今后法舒地尔在需要长期口服的慢性疾病中的试验奠定了基础。该试验已在EudraCT注册(编号:2019-001805-26)。
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引用次数: 0
Current Understanding of Compulsive Sexual Behavior Disorder and Co-occurring Conditions: What Clinicians Should Know about Pharmacological Options. 目前对强迫性性行为障碍和并发症的认识:临床医生应了解的药理选择。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-01 Epub Date: 2024-03-14 DOI: 10.1007/s40263-024-01075-2
Gemma Mestre-Bach, Marc N Potenza

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.

强迫性性行为障碍(CSBD)最近被认定为一种精神疾病。针对 CSBD 的药物治疗研究很少,因此得到的经验支持有限。本研究的主要目的是回顾现有文献中不同药物对 CSBD 症状的疗效,包括对问题性色情使用(PPU)亚型的疗效。治疗 CSBD 的主要药物疗法包括阿片类拮抗剂(纳曲酮和纳美芬)、选择性血清素再摄取抑制剂(帕罗西汀、西酞普兰、氟西汀和舍曲林)、情绪稳定剂(托吡酯)、三环类抗抑郁剂(氯米帕明)、血清素拮抗剂和再摄取抑制剂(奈法唑酮)以及 N-乙酰半胱氨酸。由于 CSBD 患者可能同时患有不同的并发症,因此在选择最佳药物治疗时应考虑到这些并发症。有人建议将 CSBD/PPU 的药物疗法作为心理疗法的辅助疗法,目前,心理疗法拥有最多的实证证据。然而,要评估本综述中介绍的大多数药物的疗效,迄今为止只能从病例研究中获得数据。因此,实证支持很少,结果的推广性也很有限,这凸显了在这一领域开展更多研究的必要性。
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引用次数: 0
Attention-Deficit Hyperactivity Disorder (ADHD) Medication Use Trajectories Among Women in the Perinatal Period. 围产期妇女使用注意力缺陷多动障碍 (ADHD) 药物的轨迹。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-01 Epub Date: 2024-03-15 DOI: 10.1007/s40263-024-01076-1
Kathrine Bang Madsen, Mette Bliddal, Charlotte Borg Skoglund, Henrik Larsson, Trine Munk-Olsen, Malene Galle Madsen, Per Hove Thomsen, Veerle Bergink, Chaitra Srinivas, Jacqueline M Cohen, Isabell Brikell, Xiaoqin Liu

Background: An increasing number of women of reproductive age are treated with attention-deficit hyperactivity disorder (ADHD) medication; however, patterns of ADHD medication use for women in the perinatal period have not been well described.

Objective: This study aimed to describe ADHD medication use patterns from 1 year before pregnancy to 1 year after delivery, and to describe sociodemographic characteristics and clinical features by medication trajectories.

Methods: The population-based cohort study included pregnancies in Denmark between 1997 and 2020, from the Medical Birth Register, by women who filled at least one prescription for ADHD medication from 12 months before pregnancy until 12 months after delivery. We applied group-based trajectory modeling to classify women into subgroups based on the identification of heterogeneous ADHD medication treatment patterns, and described the characteristics associated with these groups.

Results: Overall, we included 4717 pregnancies leading to liveborn singletons by 4052 mothers with a mean (standard deviation) age of 27.5 (5.6) years. We identified four treatment trajectories across pregnancy and the postpartum period: continuers (23.3%), discontinuers (41.8%), interrupters who ceased filling prescriptions during pregnancy but resumed postpartum (17.2%), and postpartum initiators (17.7%). Continuers were older at the time of conception, gave birth in more recent years, were more likely to smoke during pregnancy, and used other psychotropic medications during pregnancy. A large proportion of continuers used methylphenidate (89.1%) compared with the other groups (75.9-84.1%) and had switched ADHD medication type during the whole period (16.4% vs. 7.4-14.8%).

Conclusion: We found that approximately 60% of women discontinued or interrupted their ADHD medication around pregnancy, and those who continued differed in sociodemographic and clinical factors that may reflect more severe ADHD.

背景:越来越多的育龄妇女接受注意力缺陷多动障碍(ADHD)药物治疗;然而,围产期妇女使用ADHD药物的模式尚未得到很好的描述:本研究旨在描述从怀孕前 1 年到分娩后 1 年的多动症用药模式,并根据用药轨迹描述社会人口学特征和临床特征:这项基于人群的队列研究纳入了 1997 年至 2020 年期间在丹麦怀孕的妇女,她们在怀孕前 12 个月至分娩后 12 个月期间至少开过一次 ADHD 药物处方。我们采用基于群体的轨迹模型,在确定不同ADHD药物治疗模式的基础上,将妇女划分为不同的亚组,并描述了这些亚组的相关特征:总体而言,我们共纳入了 4717 例妊娠,这些妊娠导致 4052 名平均(标准差)年龄为 27.5 (5.6) 岁的母亲活产了单胎。我们确定了孕期和产后的四种治疗轨迹:持续治疗者(23.3%)、中断治疗者(41.8%)、孕期停止处方但产后恢复治疗的中断治疗者(17.2%)和产后开始治疗者(17.7%)。继续用药者受孕时年龄较大,分娩时间较近,更有可能在怀孕期间吸烟,并在怀孕期间使用其他精神药物。与其他组别(75.9%-84.1%)相比,大部分持续用药者使用哌醋甲酯(89.1%),并且在整个孕期更换了多动症药物类型(16.4% 对 7.4%-14.8%):我们发现,约有 60% 的妇女在怀孕前后停止或中断了多动症药物治疗,而那些继续服药的妇女在社会人口学和临床因素方面存在差异,这可能反映出多动症更为严重。
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