MAO-B

点击上方“蓝字”关注我们吧！ 疼痛是帕金森病（PD）患者最常见的非运动症状，同时也是PD最早的症状之一，其患病率约为40-85%，尽管它严重影响着患者的生活质量，但仍经常被低估甚至漏诊，并且患者通常只能得到非系统性的治疗，据报道，大约有50%的PD疼痛患者从未接受过任何镇痛治疗。疼痛的病因和病理生理学特征复杂多样，关于治疗的建议也十分有限。目前的研究表明，除了多巴胺能系统外，5-羟色胺能、去甲肾上腺素能、谷氨酸能和GABA能途径可能也参与其中。此外，除PD本身及其他相关继发疾病（如骨关节炎）导致的疼痛外，PD的运动或非运动症状（如运动迟缓或抑郁）本身就会放大疼痛。因此，我们试图总结概述PD患者中疼痛的分类和治疗，为临床更好的疼痛管理提供建议1-2。 1.疼痛的分类 Wasner和Deuschl提出的分类方法在临床实践中使用较为广泛，他们将PD中的疼痛分为四个层次，结合了之前分类的特点和慢性疼痛分类的原则（图1）。 图1：PD疼痛的分类 另一种常用的分类方法是Ford的方法，它将疼痛分为五类：肌肉骨骼疼痛、肌张力障碍性疼痛、神经病理性/根性疼痛、中枢性/原发性疼痛以及静坐不能性疼痛。 2.疼痛的治疗 肌肉骨骼疼痛是PD患者最常提及的类型，通常源于肌肉或关节的痉挛和疼痛，沙非胺已被证明可改善PD患者的肌肉骨骼疼痛3。此外，深部脑刺激（DBS）、非甾体抗炎药（NSAID）或其他镇痛药、关节内注射皮质类固醇或手术也可根据临床情况进行选择。 肌张力障碍是一种不受控制且剧烈的肌肉收缩，导致畸形和姿势异常。肌张力障碍是多巴胺能治疗的并发症。因此推荐优化治疗以稳定多巴胺血浆水平，比如使用单胺氧化酶B（MAO-B）或儿茶酚胺-O-甲基转移酶（COMT）抑制剂，可减少白天和夜间的疼痛性运动波动以及早晨运动迟缓。在基于两项大型随机对照试验（RCT）汇总数据的事后分析中4-5，沙非胺作为左旋多巴治疗的附加疗法，与安慰剂相比，减少了疼痛药物的使用（约24%），并在PDQ-39量表的三个子项中有两项（肌肉骨骼和神经病理性疼痛）得分显著降低。 神经病理性/根性疼痛可能伴有感觉异常（刺痛）和麻木，沿着外周神经或神经根的支配区域分布，一线药物包括三环类抗抑郁药（TCAs）、抗癫痫药（如普瑞巴林和加巴喷丁）以及血清素和去甲肾上腺素再摄取抑制剂（如度洛西汀）。沙非胺也可能对根性疼痛有效3。弱阿片类药物（曲马多）被视为二线药物，而利多卡因或辣椒素贴片仅推荐用于外周神经病变。 中枢性疼痛是最难描述的感觉之一，热感、灼烧感、针刺感，甚至刺痛都较为常见，多巴胺能药物在缓解这种疼痛方面并不特别有效。因此，通常使用传统的镇痛药，如阿片类药物、三环类抗抑郁药（TCAs）和氯氮平。大麻素和双侧亚核团深部脑刺激（subthalamic DBS）也可能有效。 静坐不能是一种以内心不安和持续的冲动去移动或改变位置为特征的疾病，在病理上与中皮质通路的多巴胺缺乏有关，氯氮平可能在治疗上有所帮助。 3.临床研究现状 2024年1月发表在《Lancet》中的《Medical, surgical, and physical treatments for Parkinson’s disease》对目前帕金森病的治疗进行了系统综述6，其中疼痛部分见表1。 表1：PD非运动症状中疼痛的治疗 2021年在日本PD患者中的 2/3 期临床研究的事后分析提示4，沙非胺50mg和100mg降低了PD患者的UPDRS第17项评分，尤其是在关期。中度至重度运动迟缓和早期肌张力障碍患者可能受益于沙非胺的治疗（图2、3）。 图2：在关期和开期UPDRS第17项评分从基线到第24周的平均变化*P值与安慰剂相比 图3：关期（A）和开期（B）UPDRS第17项评分相对于基线的平均变化 2018年一项研究沙非胺对PD患者慢性疼痛长期（2年）疗效的研究表明5，与安慰剂相比，沙非胺显著改善了PDQ-39中第37项（“痛苦的痉挛或痉挛”，p = 0.0074）和第39项（“令人不快的热或冷”，p = 0.0209）（图4），并显著减少了26.2%伴随疼痛治疗的数量（p = 0.005），且沙非胺组中治疗 2 年后未使用止痛药的患者比例更高（p = 0.0478）（图5）。 图4：PDQ-39中第37-39项从基线到第 102 周（2年）的变化 图5：第102周（2年）同时使用疼痛治疗的情况 4.总结 疼痛对PD患者的生活质量有重大影响，并且常常被临床医生忽视。但导致PD疼痛表现出如此广泛谱系的原因至今未明。其中，运动症状（如肌肉僵硬、姿势障碍、运动波动等）与肌肉骨骼疼痛、肌张力障碍性疼痛和神经性疼痛相关，非运动症状，如自主神经功能障碍、睡眠障碍和情绪障碍，也发挥着重要作用。因此，对疼痛进行分类有助于选择适当的管理策略。疼痛的治疗方案较为复杂，建议进行多学科综合管理，目前在中国上市的甲磺酸沙非胺片无疑为PD患者的疼痛治疗提供新选择，多篇临床研究及系统综述均阐述了其对PD患者疼痛的积极影响，且经过2年研究观察长期有效。希望在日后诊疗中，“帕”痛不再被忽视，早期识别和处理可大大减轻患者残疾，从而改善远期生活质量。 参考文献 [1] Cattaneo C, Jost WH. Pain in Parkinson's Disease: Pathophysiology, Classification and Treatment. J Integr Neurosci. 2023 Sep 8;22(5):132. [2] Buhmann C, Kassubek J, Jost WH. Management of Pain in Parkinson's Disease. J Parkinsons Dis. 2020;10(s1):S37-S48. [3]Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of Safinamide on Pain in Fluctuating Parkinson’s Disease Patients: A Post-Hoc Analysis. Journal of Parkinson’s Disease. 2017; 7: 95–101. [4] Tsuboi Y, Koebis M, Kogo Y, et al. Effects of safinamide adjunct therapy on pain in patients with Parkinson’s disease: post hoc analysis of a Japanese phase 2/3 study. J Neurol Sci 2021; 429: 118070. [5]Cattaneo C, Kulisevsky J, Tubazio V, Castellani P. Long-term efficacy of safinamide on Parkinson’s disease chronic pain. Adv Ther 2018; 35: 515–22. [6] Foltynie T, Bruno V, Fox S, Kühn AA, Lindop F, Lees AJ. Medical, surgical, and physical treatments for Parkinson's disease. Lancet. 2024 Jan 20;403(10423):305-324. [7]Bruno V, Freitas ME, Mancini D, Lui JP, Miyasaki J, Fox SH. Botulinum toxin type A for pain in advanced Parkinson’s disease. Can J Neurol Sci 2018; 45: 23–29. [8]Rieu I, Degos B, Castelnovo G, et al. Incobotulinum toxin A in Parkinson’s disease with foot dystonia: a double blind randomized trial. Parkinsonism Relat Disord 2018; 46: 9–15. [9]Iwaki H, Ando R, Tada S, et al. A double-blind, randomized controlled trial of duloxetine for pain in Parkinson’s disease. J Neurol Sci 2020; 414: 116833 提示：本材料仅供医疗卫生专业人士进行医学科学交流，不用于推广目的。

文献分享 2024年12月19日，北京师范大学教授，博士生导师，放射性药物教育部重点实验室主任崔孟超教授、解放军总医院第一医学中心核医学科研究员，解放军医学院博士研究生导师张锦明教授和崔教授课题组李钰莹博士为通讯作者于《Journal of Medicinal Chemistry》发表题为“Fluorinated Coumarin Derivatives as Selective PET Tracer for MAO-B Imaging”的论文，研究开发了适用于神经炎症脑内星形胶质细胞的PET成像的新MAO-B PET示踪剂。 DOI: 10.1021/acs.jmedchem.4c01952 111 研究简介 星形胶质细胞是中枢神经系统（central nervous system，CNS）中一种重要的胶质细胞，在维持内环境稳态和损伤修复方面发挥着至关重要的作用。它们还是血脑屏障（blood-brain barrier，BBB）的关键组成部分，能够保护脑组织免受病原体和毒素的侵害，同时维持神经元的正常功能。当中枢神经系统受到感染、损伤和疾病的影响时，星形胶质细胞会从静息状态转变为激活状态，这一过程称为“星形胶质细胞活化”。研究表明，活化的星形胶质细胞会经历一系列结构和功能的变化，其中之一就是线粒体外膜单胺氧化酶B（monoamine oxidase B，MAO-B）的过度表达，该变化过程已被证实与神经炎症密切相关。因此，MAO-B被认为是星形胶质细胞活化的重要生物标志物。 正电子发射断层显像（Positron emission tomography，PET）是一种高灵敏度、无创的影像学技术，可以为神经炎症过程中脑内MAO-B的表达提供准确的影像和定量信息。在过去的几十年中，选择性MAO-B PET显像剂得到了广泛的研究和报道，总体可分为三类：（a）不可逆结合显像剂，（b）可逆结合显像剂和（c）代谢捕获显像剂。 （A）表示神经炎症状态下MAO-B在反应性星形胶质细胞中表达上调。（B）展示了已报道的MAO-B PET显像剂的化学结构。 基于MAO-B表达上调与星形胶质细胞活化及神经炎症的显著相关性，北京师范大学崔孟超教授等开发了具有高亲和力、优异药代动力学性质和临床应用潜力的新型选择性MAO-B显像剂，扩展了MAO-B PET显像剂的分子库。该研究以已知MAO-B抑制剂的化学结构为基础，通过策略性的结构修饰和构效关系分析，结合小动物PET显像及体内放射自显影等临床前生物评价手段，最终筛选出性质优异的示踪剂[18F]8。[18F]8对MAO-B具有高亲和力（IC50 = 0.59 nM），在大鼠中表现出良好的脑动力学性质（SUVmax = 2.15，brain2 min/60 min = 7.67）。此外，[18F]8在大鼠脑内MAO-B高表达区域的特异性信号能够被MAO-B选择性抑制剂Selegiline有效抑制。总之，初步研究结果表明，[18F]8满足MAO-B PET显像剂的基本要求，值得进一步的临床评估。 2202 Figure解析 探针的设计策略 [18F]1和[18F]8的合成 化合物1-23，抑制剂Clorgyline、Selegiline及示踪剂SMBT-1的MAO-A/B亲和力测定结果。 [18F]1在SD大鼠脑内的micro-PET/CT显像结果（A-C）以及体内放射自显影结果（D, E）。 [18F]8在SD大鼠脑内的micro-PET/CT显像结果。 [18F]8在SD大鼠脑内的体内放射自显影结果。 33 结论 本研究成功设计并合成了一系列选择性MAO-B抑制剂。通过策略性的结构优化（包括对芳香环类型、取代基位置和类型、苄醚中氧的位置及醚键的位置进行修饰）和构效关系分析，筛选出了具有优于探针SMBT-1的高亲和力和优异亚型选择性的候选化合物1（MAO-B, IC50 = 6.59 nM）和8（MAO-B, IC50 = 0.59 nM）。进一步的临床前生物学评价表明，与[18F]1相比，[18F]8的体内放射自显影结果能够更加准确地反映MAO-B在大鼠脑内的区域特异性分布。PET显像结果表明，提前注射抑制剂Selegiline可以显著降低[18F]8在大鼠脑内的放射性信号，而对[18F]1的显像未产生明显的抑制作用。此外，[18F]8在啮齿类动物中表现出良好的脑动力学性质和生物稳定性。综上所述，初步研究结果表明[18F]8满足MAO-B PET显像剂的基本要求，具有较好的临床应用前景，有望在神经炎症相关的神经退行性疾病患者中进行进一步的临床评估。 ●重磅：PSMA新核药的首次人体PET研究！ ●Tau的新核药[18F]FPND-4！ ●全球1类创新药氟[18F]贝他嗪注射液！ ●4.0版本：Lutetium-177激活铂(IV)前药系统！ 声明：本文观点仅代表小核本人，视角局限，欢迎批评指正；如需转载，请务必注明文章作者和来源。如有其它问题，请在本平台留言或联系xiaoheshuoheyao777@163.com，小核将在第一时间处理。 内容 | 崔孟超教授课题组 图文排版 | 小核 媒体合作 | 科研宣传 | 转载开白 xiaoheshuoheyao777（小核微信）

DUBLIN, Ireland I December 19, 2024 I Prothena Corporation plc (NASDAQ:PRTA), today announced results from the Phase IIb PADOVA study conducted by partner Roche investigating prasinezumab in 586 people with early-stage Parkinson’s disease, treated for a minimum of 18 months while on stable symptomatic treatment. Prasinezumab showed potential clinical effect in the primary endpoint of time to confirmed motor progression with a HR=0.84 [0.69-1.01] and p=0.0657. The effect of prasinezumab was more pronounced in a pre-specified analysis in the population treated with levodopa (75% of participants), HR=0.79 [0.63-0.99] and nominal p=0.0431. Pre-specified supplementary covariate-adjusted* analyses of these endpoints demonstrated nominally significant effects on the primary endpoint (HR=0.81 [0.67-0.98]; nominal p=0.0334) and in the levodopa subgroup (HR=0.76 [0.61-0.95]; nominal p=0.0175). Consistent positive trends across multiple secondary and exploratory endpoints were also observed. Prasinezumab continues to be well tolerated and no new safety signals were observed in the study. The Phase IIb PADOVA results along with prior clinical study results will inform future clinical development, including study design, statistical analysis, and appropriate evaluation of patient sub-groups, of prasinezumab as a potential first-in-class disease-modifying treatment for patients with Parkinson’s disease. “The results from the Phase 2b PADOVA study are a significant step forward to potentially bring the first disease-modifying treatment option to the millions of individuals living with Parkinson’s disease and their families,” stated Gene Kinney, Ph.D., President and Chief Executive Officer, Prothena. “As pioneers in developing the first anti-alpha synuclein targeting antibody, we look forward to Roche presenting the results from the PADOVA study at an upcoming medical conference and sharing with health authorities to determine the most appropriate path forward.” The Phase II PASADENA and Phase IIb PADOVA open-label extension studies will continue in order to explore the observed effects in both studies. Roche will continue to evaluate the data and work together with health authorities to determine next steps. Full results from the PADOVA study will be presented at an upcoming medical meeting. About prasinezumab Prasinezumab is an investigational monoclonal antibody designed to selectively bind aggregated α-syn and reduce neuronal toxicity. By targeting the build-up of α-syn protein in the brain, prasinezumab can potentially prevent further accumulation and spreading between cells, thereby slowing down the progression of the disease. The evidence supporting targeting α-syn aggregates as a mechanism of action in Parkinson’s disease is based on a wide range of scientific evidence in the field. Prasinezumab is currently being assessed in ongoing open-label extensions of the Phase II PASADENA and Phase IIb PADOVA studies. Four-year data from the PASADENA study showed potential evidence of sustained slowing of motor progression compared to a matched PPMI natural history study cohort, published in the October 2024 edition of Nature Medicine. The PASADENA delayed-start (n = 94) and early-start (n = 177) groups showed a slower decline (a smaller increase in score) in MDS–UPDRS Part III scores in the OFF state (delayed start, −51%; early start, −65%) than did the PPMI external comparator (n = 303). The safety database for prasinezumab consists of data from more than 900 Parkinson’s disease study participants that have been treated with the investigational medicine, including more than 500 who were treated over 1.5-5 years. Roche entered into a Licensing, Development, and Commercialization agreement with Prothena in December 2013 to develop and commercialize monoclonal antibodies targeting α-syn, such as prasinezumab, for the potential treatment of Parkinson’s disease. About the PADOVA study PADOVA is a Phase IIb multicenter, randomized, double-blind trial evaluating the efficacy and safety of prasinezumab compared with placebo in 586 randomized patients with early-stage Parkinson’s disease who were on stable symptomatic treatment (stable doses of levodopa or monoamine oxidase-B inhibitor as monotherapy for more than three months at baseline). Patients receive monthly intravenous doses of prasinezumab 1500 mg or placebo every four weeks for at least 76 weeks. This is followed by a two-year open-label extension phase in which all participants receive active treatment, which is currently ongoing. The primary endpoint of PADOVA is the time to confirmed motor progression of Parkinson’s disease (≥5-point increase in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] Part III score assessed in OFF medication state). A 5-point increase in MDS-UPDRS Part III represents a clinically meaningful motor progression event (Trundell et al., in press). About Parkinson’s disease Parkinson’s disease is a chronic, progressive and debilitating neurodegenerative disease that has a devastating impact on patients and families. Parkinson’s disease is characterized by the gradual loss of neurons that make dopamine and other nerve cells, and the development of motor and non-motor symptoms that may appear years before diagnosis. Symptoms can vary widely between individuals and disease progression is not predictable, in which symptoms can develop gradually over time or suddenly. Clinical diagnosis of Parkinson’s disease is late in the disease course and currently based only on motor symptoms, with non-motor symptoms often preceding diagnosis by up to 20 years. About Prothena Prothena Corporation plc is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases. Fueled by its deep scientific expertise built over decades of research, Prothena is advancing a pipeline of therapeutic candidates for a number of indications and novel targets for which its ability to integrate scientific insights around neurological dysfunction and the biology of misfolded proteins can be leveraged. Prothena’s pipeline includes both wholly-owned and partnered programs being developed for the potential treatment of diseases including AL amyloidosis, ATTR amyloidosis with cardiomyopathy, Alzheimer’s disease, Parkinson’s disease and a number of other neurodegenerative diseases. For more information, please visit the Company’s website at www.prothena.com and follow the Company on Twitter @ProthenaCorp. SOURCE: Prothena