A real-world study of DL-3-n-butylphthalide in preventing early neurological deterioration after cerebral infarction_West China Medical Journal

Authors：

ZHANG Ping ¹ ,  LI Jie ¹ , Yi Xingyang ¹ , QING Ting ² , CHEN Hong ¹ , ZHU Yalan ³ , LIU Shan ⁴ , DUAN Yong ⁵ , XIE Juan ⁶

1. Department of Neurology, Deyang People’s Hospital, Deyang, Sichuan 618000, P. R. China;
2. Department of Neurology, the Second People’s Hospital of Deyang, Deyang, Sichuan 618000, P. R. China;
3. Department of Neurology, Guanghan People’s Hospital, Guanghan, Sichuan 618300, P. R. China;
4. Department of Neurology, Deyang Jingyang Hospital of T.C.M, Deyang, Sichuan 618000, P. R. China;
5. Department of Neurology, People’s Hospital of Zhongjiang County, Zhongjiang, Sichuan 618100, P. R. China;
6. Department of Neurology, Deyang Integrated Traditional Chinese and Western Medicine Hospital, Deyang, Sichuan 618000, P. R. China;

Corresponding author：

LI Jie, Email: lijie860114@163.com

Keywords：

DL-3-n-butylphthalide; cerebral infarction; early neurological deterioration

DOI：

10.7507/1002-0179.202303196

Video：

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Objective To explore the correlation between DL-3-n-butylphthalide (NBP) and early neurological deterioration (END) after cerebral infarction in real-world study. Methods A multicenter registry observational study was conducted, enrolling patients with acute cerebral infarction within 72 h of onset from five hospitals in Deyang from March 31st, 2019, to July 31st, 2021. The patients were divided into two groups based on the treatment regimen, whether they received NBP in addition to standard therapy or not. The primary endpoint was END after cerebral infarction, and the secondary endpoint was unfavorable outcome (defined as modified Rankin Scale score of 3 to 6) 90 d after onset. Results A total of 314 patients with cerebral infarction were included in the study, among whom, 126 received standard therapy without NBP treatment (standard treatment group) and 188 received NBP in addition to standard therapy (NBP treatment group). A total of 69 cases occurred END within 10 d after admission. In the NBP treatment group, 32 cases (17.0%) had END within 10 d after admission, while in the standard treatment group, 37 cases (29.4%) occurred END, and the difference between the two groups was statistically significant (P=0.010). Logistic regression analyses showed that the influencing factors related to END included the serum neurofilament light chain level on admission [odds ratio (OR)=1.020, 95% confidence interval (CI) (1.004, 1.035), P=0.013], NBP treatment [OR=0.449, 95%CI (0.253, 0.797), P=0.006], and dual antiplatelet therapy [OR=0.373, 95%CI (0.196, 0.710), P=0.003], and the influencing factors for poor neurological functional prognosis in patients with cerebral infarction included age [OR=1.063, 95%CI (1.024, 1.103), P=0.002], National Institute of Health Stroke Scale score on admission [OR=1.532, 95%CI (1.313, 1.787), P<0.001], NBP treatment [OR=0.375, 95%CI (0.177, 0.794), P=0.010], and END [OR=7.450, 95%CI (3.294, 16.852), P<0.001]. Conclusion The results of our study provide the initial evidence that NBP treatment reduces the occurrence of END, and improves the neurological functional prognosis 90 d after onset in the real world.

Citation： ZHANG Ping, LI Jie, Yi Xingyang, QING Ting, CHEN Hong, ZHU Yalan, LIU Shan, DUAN Yong, XIE Juan. A real-world study of DL-3-n-butylphthalide in preventing early neurological deterioration after cerebral infarction. West China Medical Journal, 2023, 38(5): 680-687. doi: 10.7507/1002-0179.202303196 Copy

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10.	崔丽英, 刘秀琴, 朱以诚, 等. dl-3-正丁基苯酞治疗中度急性缺血性脑卒中的多中心、随机、双盲和安慰剂对照研究. 中华神经科杂志, 2005, 38(4): 251-254.
11.	崔丽英, 李舜伟, 吕传真, 等. 恩必普软胶囊治疗中度急性缺血性卒中的多中心开放临床研究. 中国脑血管病杂志, 2005, 2(3): 112-115.
12.	朱以诚, 崔丽英, 高山, 等. 丁苯酞注射液治疗急性脑梗死的多中心、随机、双盲双模拟、对照Ⅲ期临床试验. 中华神经科杂志, 2014, 47(2): 113-118.
13.	中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组. 中国急性缺血性脑卒中指南 2018. 中华神经科杂志, 2018, 51(9): 666-682.
14.	Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol, 2007, 57(2): 96-102.
15.	Martí-Vilalta JL, Arboix A. The Barcelona Stroke Registry. Eur Neurol, 1999, 41(3): 135-142.
16.	Tei H, Uchiyama S, Ohara K, et al. Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project. Stroke, 2000, 31(9): 2049-2054.
17.	卿婷, 易兴阳, 朱亚兰, 等. 神经丝轻链蛋白水平与急性脑梗死后早期神经功能恶化的相关性. 华西医学, 2023, 38(3): 403-407.
18.	Julien JP, Mushynski WE. The distribution of phosphorylation sites among identified proteolytic fragments of mammalian neurofilaments. J Biol Chem, 1983, 258(6): 4019-4025.
19.	Gentil BJ, Tibshirani M, Durham HD. Neurofilament dynamics and involvement in neurological disorders. Cell Tissue Res, 2015, 360(3): 609-620.
20.	Tiedt S, Duering M, Barro C, et al. Serum neurofilament light: a biomarker of neuroaxonal injury after ischemic stroke. Neurology, 2018, 91(14): e1338-e1347.
21.	Nielsen HH, Soares CB, Høgedal SS, et al. Acute neurofilament light chain plasma levels correlate with stroke severity and clinical outcome in ischemic stroke patients. Front Neurol, 2020, 11: 448.
22.	DeGraba TJ, Hallenbeck JM, Pettigrew KD, et al. Progression in acute stroke: value of the initial NIH stroke scale score on patient stratification in future trials. Stroke, 1999, 30(6): 1208-1212.
23.	董高翔, 冯亦璞. 丁基苯酞对大鼠局部脑缺血再灌注损伤皮层钙凋磷酸酶和钙蛋白酶活性的影响. 药学学报, 2000, 35(10): 790-792.
24.	董高翔, 冯亦璞. 丁基苯酞对局部脑缺血再灌注大鼠脑线粒体 ATPase、抗氧化酶活性和脂质过氧化的影响. 中国医学科学院学报, 2002, 24(1): 93-97.
25.	王蕊, 步燕利, 刘超. 丁苯酞对缺氧诱导神经细胞凋亡的保护作用. 中国新药杂志, 2016, 25(20): 2382-2385.
26.	Liu CL, Liao SJ, Zeng JS, et al. dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP. J Neurol Sci, 2007, 260(1/2): 106-113.
27.	Liao SJ, Lin JW, Pei Z, et al. Enhanced angiogenesis with dl-3n-butylphthalide treatment after focal cerebral ischemia in RHRSP. Brain Res, 2009, 1289: 69-78.

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet, 2020, 396(10258): 1204-1222.
2. 中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2021 概要. 中国循环杂志, 2022, 37(6): 553-578.
3. 王拥军, 李子孝, 谷鸿秋, 等. 中国卒中报告 2020(中文版)(1). 中国卒中杂志, 2022, 17(5): 433-447.
4. Girot JB, Richard S, Gariel F, et al. Predictors of unexplained early neurological deterioration after endovascular treatment for acute ischemic stroke. Stroke, 2020, 51(10): 2943-2950.
5. Thanvi B, Treadwell S, Robinson T. Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management. Postgrad Med J, 2008, 84(994): 412-417.
6. 龚鹏宇, 周俊山, 龚亚驰, 等. 轻度急性缺血性卒中早期神经功能恶化的风险因素及列线图预测模型的构建. 南京医科大大学报(自然科学版), 2021, 41(7): 1039-1043, 1083.
7. 熊杰, 冯亦璞. 丁基苯酞对局灶性脑缺血过程中线粒体损伤的保护作用. 药学学报, 2000, 35(6): 408-412.
8. 尹春丽, 李永秋, 王耀伍. 丁苯酞软胶囊对急性脑梗死缺血半暗带的影响. 临床神经病学杂志, 2013, 26(3): 219-221.
9. 李姝雅, 王伊龙, 郑华光, 等. 丁苯酞氯化钠注射液治疗急性缺血性卒中安全性及有效性研究—多中心、前瞻性、开放标签Ⅳ期临床试验. 中国卒中杂志, 2019, 14(5): 450-455.
10. 崔丽英, 刘秀琴, 朱以诚, 等. dl-3-正丁基苯酞治疗中度急性缺血性脑卒中的多中心、随机、双盲和安慰剂对照研究. 中华神经科杂志, 2005, 38(4): 251-254.
11. 崔丽英, 李舜伟, 吕传真, 等. 恩必普软胶囊治疗中度急性缺血性卒中的多中心开放临床研究. 中国脑血管病杂志, 2005, 2(3): 112-115.
12. 朱以诚, 崔丽英, 高山, 等. 丁苯酞注射液治疗急性脑梗死的多中心、随机、双盲双模拟、对照Ⅲ期临床试验. 中华神经科杂志, 2014, 47(2): 113-118.
13. 中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组. 中国急性缺血性脑卒中指南 2018. 中华神经科杂志, 2018, 51(9): 666-682.
14. Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol, 2007, 57(2): 96-102.
15. Martí-Vilalta JL, Arboix A. The Barcelona Stroke Registry. Eur Neurol, 1999, 41(3): 135-142.
16. Tei H, Uchiyama S, Ohara K, et al. Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project. Stroke, 2000, 31(9): 2049-2054.
17. 卿婷, 易兴阳, 朱亚兰, 等. 神经丝轻链蛋白水平与急性脑梗死后早期神经功能恶化的相关性. 华西医学, 2023, 38(3): 403-407.
18. Julien JP, Mushynski WE. The distribution of phosphorylation sites among identified proteolytic fragments of mammalian neurofilaments. J Biol Chem, 1983, 258(6): 4019-4025.
19. Gentil BJ, Tibshirani M, Durham HD. Neurofilament dynamics and involvement in neurological disorders. Cell Tissue Res, 2015, 360(3): 609-620.
20. Tiedt S, Duering M, Barro C, et al. Serum neurofilament light: a biomarker of neuroaxonal injury after ischemic stroke. Neurology, 2018, 91(14): e1338-e1347.
21. Nielsen HH, Soares CB, Høgedal SS, et al. Acute neurofilament light chain plasma levels correlate with stroke severity and clinical outcome in ischemic stroke patients. Front Neurol, 2020, 11: 448.
22. DeGraba TJ, Hallenbeck JM, Pettigrew KD, et al. Progression in acute stroke: value of the initial NIH stroke scale score on patient stratification in future trials. Stroke, 1999, 30(6): 1208-1212.
23. 董高翔, 冯亦璞. 丁基苯酞对大鼠局部脑缺血再灌注损伤皮层钙凋磷酸酶和钙蛋白酶活性的影响. 药学学报, 2000, 35(10): 790-792.
24. 董高翔, 冯亦璞. 丁基苯酞对局部脑缺血再灌注大鼠脑线粒体 ATPase、抗氧化酶活性和脂质过氧化的影响. 中国医学科学院学报, 2002, 24(1): 93-97.
25. 王蕊, 步燕利, 刘超. 丁苯酞对缺氧诱导神经细胞凋亡的保护作用. 中国新药杂志, 2016, 25(20): 2382-2385.
26. Liu CL, Liao SJ, Zeng JS, et al. dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP. J Neurol Sci, 2007, 260(1/2): 106-113.
27. Liao SJ, Lin JW, Pei Z, et al. Enhanced angiogenesis with dl-3n-butylphthalide treatment after focal cerebral ischemia in RHRSP. Brain Res, 2009, 1289: 69-78.

West China Medical Journal

A real-world study of DL-3-n-butylphthalide in preventing early neurological deterioration after cerebral infarction

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