Effects of DL-3-n-butylphthalide on Chemotherapy-Induced Cognitive Impairment (NBP CICI)：a Prospective, Randomized, Double Blinded, Multicenter, Placebo Controlled Study

Chemotherapy-related cognitive Impairment (CICI) is a series of neurocognitive deficits experienced during and after cancer chemotherapy. Studies have reported that CICI affects 25% to 75% of survivors and can persist for years after chemotherapy is discontinued, causing more severe progressive manifestations and placing a heavy burden on families and society. Numerous studies have proposed several potential mechanisms and etiologies for CICI, including direct neurotoxicity, disruption of the blood-brain barrier, reduced hippocampal neurogenesis, white matter abnormalities, secondary neuroinflammatory responses, and increased oxidative stress. At present, there is no clear and effective diagnosis and therapy for CICI, and how to diagnose and treat cognitive impairment caused by chemotherapy effectively is still the focus and difficulty.
Based on the previous consensus on the application of dl-3-n-butylphthalide, butylphthalein can play a neuroprotective role by reducing oxidative stress and inflammatory response, inhibiting neuronal apoptosis, improving mitochondrial function and other mechanisms, and significantly improve the performance of the central nervous system caused by cerebral ischemia and vascular dementia. However, the increase of neuroinflammatory response and oxidative stress is precisely one of the potential mechanisms of CICI pathogenesis. Therefore, based on the above findings, this study hypothesized that dl-3-n-butylphthalide would also have considerable efficacy in the treatment of CICI.

开始日期2024-07-01

申办/合作机构

中国医科大学附属第一医院

NCT05976152

/ Recruiting临床3期IIT

Effect of Butyphthalide on Cognitive Level Change After Cerebral Vascular Event-a Randomized Control Trial (Be-CLEVER)

Post-stroke cognitive impairment (PSCI) refers to a clinical syndrome characterized by cognitive impairment that occurs after a stroke event and persists for at least 24 weeks. Due to the early recovery of conditions such as delirium and transient cognitive impairment after stroke, the diagnosis of PSCI often requires cognitive assessment at 12 to 24 weeks post-stroke to determine the severity of cognitive impairment. It can be classified according to the severity of cognitive impairment as post-stroke cognitive impairment no dementia (PSCIND) and post-stroke dementia (PSD). Recent large international cohort studies have reported an incidence rate of PSCI ranging from 24% to 53.4%, and patients with PSCI have a significantly higher mortality rate compared to those without cognitive impairment. Guidelines such as American Heart Association/American Society of Anesthesiologists (AHA/ASA) and the Chinese "Expert Consensus on the Management of Post-Stroke Cognitive Impairment" propose integrating cognitive impairment and stroke intervention strategies. Early comprehensive intervention and treatment for high-risk individuals after stroke, aiming to delay or prevent the progression from PSCIND to PSD, are the primary goals in the current treatment of PSCI. However, there is currently a lack of large randomized controlled trials (RCTs) for PSCI, and research is still needed to determine whether cognitive-enhancing drugs can reduce the risk of PSCI occurrence and improve outcomes and prognosis for PSCI patients. A randomized, double-blind, multicenter clinical study involving 281 non-dementia vascular cognitive impairment (VCI) patients showed that the overall cognitive scores of patients treated with donepezil for 24 weeks significantly improved compared to the placebo group.
The aim of this study is to evaluate the effectiveness of donepezil in the treatment of post-stroke cognitive impairment. It will be a multicenter, randomized, double-blind, placebo-controlled trial with a 48-week treatment duration. The study will observe the difference in PSCI incidence rate between the donepezil treatment group and the conventional stroke treatment group at 24 weeks and evaluate the improvement in post-stroke cognitive impairment after 6 months of donepezil treatment compared to conventional treatment.
This study will be conducted in two stages: the first stage (0-24 weeks) aims to assess whether donepezil can reduce the risk of PSCI occurrence and will be a multicenter, randomized, double-blind, placebo-controlled study. The second stage (24-48 weeks) aims to evaluate whether donepezil can improve the prognosis of PSCI patients and will also be a multicenter, randomized, double-blind, placebo-controlled study.

开始日期2024-04-01

申办/合作机构

复旦大学

NCT04675450

/ Withdrawn临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of n-Butylphthalide (NBP) Softgel Capsules Administered to Patients With Metastatic Breast Cancer to Prevent Nab-paclitaxel Induced Toxic Neuropathy

Phase 2, randomized, double-blind, Placebo-Controlled, Multiple Dose Study for the treatment of Patients with Metastatic Breast Cancer.

开始日期2023-06-30

申办/合作机构

Conjupro Biotherapeutics, Inc.

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100 项与左旋丁苯酞相关的临床结果

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100 项与左旋丁苯酞相关的转化医学

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100 项与左旋丁苯酞相关的专利（医药）

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项与左旋丁苯酞相关的文献（医药）

2025-06-01·Brain Research Bulletin

DL-3-n-butylphthalide inhibits astrocyte activation in the cortical penumbra of ischemia-reperfusion model rats via AKT signaling

Article

作者: Ji, Yifei ; Li, Biao ; Li, Qiuling ; Xiao, Yu ; Yu, Yiwen ; Wang, Shan ; Dong, Fei ; Wang, Tinghong ; Zhao, Hao ; Lei, Dong

Ischemic stroke triggers rapid activation of astrocytes, which contributes to tissue damage. Dl-3-n-butylphthalide (NBP), an independently developed compound in China for the treatment of ischemic stroke, has unclear molecular mechanisms. In this study, we established a Sprague-Dawley rat model of middle cerebral artery occlusion (MCAO) by occluding the middle cerebral artery for 1.5 h followed by reperfusion for 72 h. We assessed neurological scores, infarct volume, neuronal injury, and the expression levels of GFAP, C3, S100A10, GLT-1, p-AKT/AKT, and p-mTOR/mTOR, as well as immunofluorescence double staining of C3/S100A10 with GFAP and GLT-1 respectively. NBP significantly improved neurological function in MCAO rats, reduced infarct area, alleviated neuronal injury, inhibited A1 astrocyte polarization, promoted A2 astrocyte polarization, and upregulated GLT-1 expression. However, the AKT inhibitor (TCN) weakened NBP's regulatory effects on astrocytes and GLT-1. Finally, immunofluorescence experiments showed that GLT-1 colocalized more effectively with A2 astrocytes than with A1 astrocytes. We demonstrated that NBP reduces astrocyte activation and upregulates GLT-1 expression via the AKT/mTOR pathway, providing new insights into therapeutic strategies for ischemic stroke and valuable clues for drug design.

2025-06-01·European Journal of Medicinal Chemistry

A brain-targeting dl-3-n-butylphthalide prodrug to treat ischemic stroke

Article

作者: Huang, Shiqi ; Han, Yikun ; Lin, Qing ; Zhang, Ling ; Zhang, Qiang ; Zhang, Zhirong ; Zhou, Shuhao ; Zhang, Yicong ; Zhang, Hanming ; Xiang, Honglin

Stroke is an acute cerebrovascular disease worldwide, featured by stubbornly high mortality and morbidity. 3-n-butylphthalide (NBP) is a first-line agent to treat ischemic stroke, but its unsatisfactorily intracephalic bioavailability is detrimental to the therapeutic efficacy. We have previously developed a series of prodrugs analogous to NBP, however, their conversion rate in the targeted sites cannot meet the clinical demand. Hence, it is imperative to ameliorate the bioavailability and cellular uptake efficiency of the prodrugs, which may be driven by potential energy consuming cationic transporters. Accordingly, we fabricated a novel prodrug named DB-10, which were used tertiary amine to possess active targeting capacity and connected through amide bonds. Moreover, it is noteworthy that DB-10 could rapidly convert into active original drug in the brain to treat acute injury caused by ischemia-reperfusion (I/R). The cytotoxicity of DB-10 was equivalent to that of NBP and would not cause obviously undesired damage in vivo. These encouraging results demonstrate that DB-10 could easily increase the accumulation in the brain site, and significantly improve the treatment effect for ischemic stroke, indicating this biosafety prodrug holds tremendous potential for clinical application prospects.

2025-05-01·International Journal of Biological Macromolecules

Effects of Ganoderma lucidum fermentation on the structure of Tartary buckwheat polysaccharide and its impact on gut microbiota composition

Article

作者: Chen, Hongyan ; Zeng, Xuefeng ; Hu, Wenkang ; Tan, Fuyao ; Hui, Fuyi ; Zou, Shiping ; Da, Ziru ; Cen, Qin ; Zhang, Rui

Fermentation modifies plant polysaccharides and enhances their bioactivity. In this study, polysaccharides were extracted from Ganoderma lucidum-fermented (FBP) and non-fermented (NBP) Tartary buckwheat. The structure of the polysaccharides and their effects on gut microbial composition were explored. According to the results, the molecular weight of FBP lowered from 8.86 × 10⁵ Da to 3.83 × 10⁴ Da, the fermentation process produced fucose (7.72 %) and mannose (6.68 %), and the content of glucose and galactose increased. Compared with NBP, FBP showed a significant increase in solubility, crystallinity and thermal stability, while there was a decrease in apparent viscosity. The in vitro fecal fermentation results suggested that FBP promoted the production of short-chain fatty acids, with acetic acid, propionic acid and butyric acid being the main metabolites. FBP and NBP dramatically decreased the relative abundance of Escherichia-Shigella. FBP increased the relative abundances of Bacteroides, Parabacteroides, and Megamonas, while NBP increased those of Bifidobacterium and Phascolarctobacterium. Finally, further analysis of functional prediction indicated that carbohydrate metabolism, lipid metabolism and cardiovascular disease were the most vital pathways for FBP to promote health. This study offers some theoretical foundation for the chemical structure and regulation of gut microbiota by Ganoderma lucidum fermented buckwheat modified polysaccharides.

项与左旋丁苯酞相关的新闻（医药）

2024-12-11

·石药集团

一项丁苯酞可改善卒中后失语的研究结果发布

导读 2024年11月22日，河北医科大学第一医院刘晓云教授团队的最新研究结果“Efficacy and safety of DL-3-N-butylphthalide in the treatment of ischemic poststroke aphasia: A randomized clinical trial”在《Annals Of Clinical And Translational Neurology》（IF=4.4）杂志上发表。研究结果表明：丁苯酞软胶囊序贯治疗6个月能够显著提高卒中后失语（PSA）患者的失语商（AQ），回归分析显示丁苯酞软胶囊序贯治疗与AQ的改善独立相关，且安全性良好。这一改善可能与丁苯酞软胶囊提高单胺类神经递质水平相关。研究背景卒中后失语症（PSA）每年影响全球约450万卒中患者，并且导致卒中后抑郁和痴呆患病率升高。目前，PSA的治疗方法是行为干预（以言语语言疗法为主），其有效性已被大量随机对照试验和荟萃分析证实。然而在高卒中患病率的农村地区和低收入人群中康复资源匮乏，因此很难大规模实施行为干预。许多研究表明，药物治疗已经成为治疗PSA的替代或补充疗法。药物治疗PSA主要是利用神经递质活性促进适应性神经可塑性和神经网络。丁苯酞（NBP）是国内目前治疗脑梗死的常用药物。NBP改善了未接受再灌注治疗的脑卒中患者、接受静脉溶栓治疗，以及接受血管内治疗的脑卒中患者90天预后，且不增加不良事件的发生率。NBP还可以通过改善线粒体动力学、抑制神经炎症和氧化应激改善脑血管病患者的认知功能和自理能力。本研究旨在探究NBP序贯治疗是否能够改善急性缺血性卒中后失语患者的语言能力及其潜在机制。研究方法该研究是一项单中心、随机、双盲研究，纳入标准为：年龄≥18岁；因急性脑梗死入院，并伴有任何类型的急性失语，WAB-AQ评分<93.7；病情稳定，保持清醒警觉状态至少30分钟，听力和视力正常或矫正。排除标准如下：既往痴呆；并发进行性神经障碍；头部损伤；神经外科手术；入院时临床诊断为抑郁症；不能用中文（普通话）交流；同时参与其他干预试验。所有患者住院期间均给予NBP注射液（100 mL/瓶，每日2次），疗程为10 ~ 14 d，并记录患者的既往病史、肝肾功能、血脂水平、合并用药和并发症。出院时随机分为NBP组和安慰剂组。NBP组服用NBP软胶囊（0.2g/次，3次/天），安慰剂组服用NBP模拟软胶囊（0.2g/次，3次/天），连续服药6个月。研究结果该研究于2021年7月至2022年8月在河北医科大学第二医院进行，最终118名患者纳入分析，NBP组和安慰剂组分别有61例和57例患者。出院后随访数据（图1）显示，两组之间出院6个月时的AQ改善率差异具有统计学意义（NBP组0.450±0.231 vs.对照组0.310 ±0.271, p=0.003）。并且各组在6个月随访时的mRS评分差异有统计学意义(NBP组[2 (1-3)] vs.安慰剂组[2 (1.5-3)], p=0.037）。图1. NBP组与安慰剂组预后比较对于出院6个月随访时的AQ值，NBP组较安慰剂组表现出升高趋势（图2），mRS评分的变化趋势图如图3所示。NBP组患者的语言评估各项得分的改善程度也高于安慰剂组（图4）。图2. NBP组和安慰剂组AQ随时间变化的折线图图3. NBP组与安慰剂组mRS随时间变化的折线图图4. NBP组和安慰剂组语言评估各项得分的改善以(AQ4-AQ1)/(100-AQ1)为因变量，纳入分组、年龄、教育程度、高血压、糖尿病、既往卒中、mRS1进行回归分析，结果显示NBP治疗与6个月AQ改善独立相关（MD=0.117, 95% CI: 0.031-0.203, p=0.008）（图5）。此外，NBP治疗与6个月时无法独立行走（mRS≥3）呈负相关（OR = 0.279, 95% CI: 0.099-0.786, p=0.016）（图6）。图5. 与6个月AQ恢复程度相关变量的线性回归分析图6. 急性脑梗死后6个月时mRS≥3的相关变量通过收集56例受试者的血浆样本：NBP组27例，安慰剂组29例，比较两组出院时和随访1个月时血浆中神经递质的变化。酪氨酸（Tyr, p=0.043）和5-羟色氨酸（5-HT, p=0.041）的差异有统计学意义（图7）。其中治疗后NBP组3-羟酪胺（DA, p=0.014）和去甲肾上腺素（NE, p=0.042）水平显著升高，安慰剂组在治疗前后无显著变化(DA, p=0.850；NE, p=0.838)。图7. PSA患者外周血神经递质变化的比较研究结论 NBP软胶囊序贯治疗可以改善AIS后失语患者6个月时的AQ和mRS评分，且安全性良好。潜在作用机制可能是NBP胶囊增加了单胺类神经递质水平，促进了神经功能的可塑性。【声明】本新闻旨在旨在为医疗卫生专业人士传递更多医学信息。发布的内容，不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议。

临床结果临床研究

100 项与左旋丁苯酞相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
转移性乳腺癌	临床2期	-	石药集团恩必普药业有限公司	2023-06-30
转移性乳腺癌	临床2期	-	Conjupro Biotherapeutics, Inc.	2023-06-30
周围神经系统疾病	临床2期	-	Conjupro Biotherapeutics, Inc.	2023-06-30
周围神经系统疾病	临床2期	-	石药集团恩必普药业有限公司	2023-06-30
阿尔茨海默症	临床前	中国	首都医科大学宣武医院	2023-06-16
急性缺血性卒中	临床前	美国	石药集团恩必普药业有限公司	2018-02-28
脑卒中	临床前	中国	石药集团中奇制药技术（石家庄）有限公司	2005-02-17

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


Pubmed 人工标引	N/A	失语	118	DL-3-N-butylphthalide (NBP) soft capsules	築艱築糧鏇願築鑰築鹽(網積憲鹽顧鏇夢憲膚選): Difference (Mean) = 0.106 (95% CI, 0.018 ~ 0.195), P-Value = 0.003 更多	积极	2024-11-22
				Placebo