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

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.	中國心血管健康與疾病報告編寫組. 中國心血管健康與疾病報告 2021 概要. 中國循環雜志, 2022, 37(6): 553-578.
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8.	尹春麗, 李永秋, 王耀伍. 丁苯酞軟膠囊對急性腦梗死缺血半暗帶的影響. 臨床神經病學雜志, 2013, 26(3): 219-221.
9.	李姝雅, 王伊龍, 鄭華光, 等. 丁苯酞氯化鈉注射液治療急性缺血性卒中安全性及有效性研究—多中心、前瞻性、開放標簽Ⅳ期臨床試驗. 中國卒中雜志, 2019, 14(5): 450-455.
10.	崔麗英, 劉秀琴, 朱以誠, 等. dl-3-正丁基苯酞治療中度急性缺血性腦卒中的多中心、隨機、雙盲和安慰劑對照研究. 中華神經科雜志, 2005, 38(4): 251-254.
11.	崔麗英, 李舜偉, 呂傳真, 等. 恩必普軟膠囊治療中度急性缺血性卒中的多中心開放臨床研究. 中國腦血管病雜志, 2005, 2(3): 112-115.
12.	朱以誠, 崔麗英, 高山, 等. 丁苯酞注射液治療急性腦梗死的多中心、隨機、雙盲雙模擬、對照Ⅲ期臨床試驗. 中華神經科雜志, 2014, 47(2): 113-118.
13.	中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國急性缺血性腦卒中指南 2018. 中華神經科雜志, 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, 易興陽, 朱亞蘭, 等. 神經絲輕鏈蛋白水平與急性腦梗死后早期神經功能惡化的相關性. 華西醫學, 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, H?gedal 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, 馮亦璞. 丁基苯酞對大鼠局部腦缺血再灌注損傷皮層鈣凋磷酸酶和鈣蛋白酶活性的影響. 藥學學報, 2000, 35(10): 790-792.
24.	董高翔, 馮亦璞. 丁基苯酞對局部腦缺血再灌注大鼠腦線粒體 ATPase、抗氧化酶活性和脂質過氧化的影響. 中國醫學科學院學報, 2002, 24(1): 93-97.
25.	王蕊, 步燕利, 劉超. 丁苯酞對缺氧誘導神經細胞凋亡的保護作用. 中國新藥雜志, 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. 中國心血管健康與疾病報告編寫組. 中國心血管健康與疾病報告 2021 概要. 中國循環雜志, 2022, 37(6): 553-578.
3. 王擁軍, 李子孝, 谷鴻秋, 等. 中國卒中報告 2020(中文版)(1). 中國卒中雜志, 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. 龔鵬宇, 周俊山, 龔亞馳, 等. 輕度急性缺血性卒中早期神經功能惡化的風險因素及列線圖預測模型的構建. 南京醫科大大學報(自然科學版), 2021, 41(7): 1039-1043, 1083.
7. 熊杰, 馮亦璞. 丁基苯酞對局灶性腦缺血過程中線粒體損傷的保護作用. 藥學學報, 2000, 35(6): 408-412.
8. 尹春麗, 李永秋, 王耀伍. 丁苯酞軟膠囊對急性腦梗死缺血半暗帶的影響. 臨床神經病學雜志, 2013, 26(3): 219-221.
9. 李姝雅, 王伊龍, 鄭華光, 等. 丁苯酞氯化鈉注射液治療急性缺血性卒中安全性及有效性研究—多中心、前瞻性、開放標簽Ⅳ期臨床試驗. 中國卒中雜志, 2019, 14(5): 450-455.
10. 崔麗英, 劉秀琴, 朱以誠, 等. dl-3-正丁基苯酞治療中度急性缺血性腦卒中的多中心、隨機、雙盲和安慰劑對照研究. 中華神經科雜志, 2005, 38(4): 251-254.
11. 崔麗英, 李舜偉, 呂傳真, 等. 恩必普軟膠囊治療中度急性缺血性卒中的多中心開放臨床研究. 中國腦血管病雜志, 2005, 2(3): 112-115.
12. 朱以誠, 崔麗英, 高山, 等. 丁苯酞注射液治療急性腦梗死的多中心、隨機、雙盲雙模擬、對照Ⅲ期臨床試驗. 中華神經科雜志, 2014, 47(2): 113-118.
13. 中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國急性缺血性腦卒中指南 2018. 中華神經科雜志, 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, 易興陽, 朱亞蘭, 等. 神經絲輕鏈蛋白水平與急性腦梗死后早期神經功能惡化的相關性. 華西醫學, 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, H?gedal 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, 馮亦璞. 丁基苯酞對大鼠局部腦缺血再灌注損傷皮層鈣凋磷酸酶和鈣蛋白酶活性的影響. 藥學學報, 2000, 35(10): 790-792.
24. 董高翔, 馮亦璞. 丁基苯酞對局部腦缺血再灌注大鼠腦線粒體 ATPase、抗氧化酶活性和脂質過氧化的影響. 中國醫學科學院學報, 2002, 24(1): 93-97.
25. 王蕊, 步燕利, 劉超. 丁苯酞對缺氧誘導神經細胞凋亡的保護作用. 中國新藥雜志, 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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