Background DI-3-n-butylphthalide （NBP）, first isolated from the seeds of celery, showed efficacy in animal models of stroke. This study was a clinical trial to assess the efficacy and safety of NBP with a continuous...Background DI-3-n-butylphthalide （NBP）, first isolated from the seeds of celery, showed efficacy in animal models of stroke. This study was a clinical trial to assess the efficacy and safety of NBP with a continuous dose regimen among patients with acute ischemic stroke. Methods A randomized, double-blind, double-dummy trial enrolled 573 patients within 48 hours of onset of ischemic stroke in China. Patients were randomly assigned to receive a 14-day infusion of NBP followed by an NBP capsule, a 14- day infusion of NBP followed by aspirin, or a 14-day infusion of ozagrel followed by aspirin. The efficacy measures were Barthel index score and the modified Rankin scale （mRS） at day 90. Differences among the three groups on mRS were compared using X2 test of proportions （with two-sided e=0.05） and Logistic regression analysis was conducted to take the baseline National Institutes of Health Stroke Scale （NIHSS） score into consideration. Results Among the 535 subjects included in the efficacy analysis, 90-day treatment with NBP was associated with a significantly favorable outcome than 14-day treatment with ozagrel as measured by mRS （P 〈0.001）. No significant difference was found among the three groups on Barthel index at day 90. The rate of adverse events was similar among the three groups. Conclusions The 90-day treatment with NBP could improve outcomes at the third month after stroke. The NBP treatment （both intravenous and oral） is safe （ChiCTR-TRC-09000483）.展开更多
The present study evaluated the effect of dl-3-n-butylphthalide(NBP) ,a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (M...The present study evaluated the effect of dl-3-n-butylphthalide(NBP) ,a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (MCAO).producing permanent focal ischemia in the right cerebral hemisphere,which developed ip-silateral brain edema reproducibly. Edema was assessed 24 h after MCA occlusion by determining the brain water content from wet and dry weight measurements,and the sodium,potassium concentrations with ion-selective electrodes. In this model,NBP at the dose of 80,160 and 240 mg/kg po 15 min after MCAO prevented from brain edema in a dose-dependent manner. A significant reduction of sodium content and an increase in potassium level were observed in all drug-treated groups. It showed that NBP strongly attenuated brain water entry,sodium accumulation and potassium loss. Nimodipine treatment(5mg/kg sc) also reduced brain edema (P<0. 05). The results suggest that a strong anti-edema activity of NBP may play an important role to contribute to the treatment of ischemic damage.展开更多
目的：评价丁苯酞（NBP）注射液对急性脑梗死的疗效及药物不良反应。方法选择2012年9月至2013年11月陕西省人民医院70例急性脑梗死住院患者，随机分为治疗组（n＝35）和对照组（n＝35），对照组仅予常规治疗，治疗组在常规治疗的基础上...目的：评价丁苯酞（NBP）注射液对急性脑梗死的疗效及药物不良反应。方法选择2012年9月至2013年11月陕西省人民医院70例急性脑梗死住院患者，随机分为治疗组（n＝35）和对照组（n＝35），对照组仅予常规治疗，治疗组在常规治疗的基础上给予NBP注射液治疗。于治疗前及治疗后14d进行神经功能缺损程度评定美国国立卫生研究院卒中量表（NIHSS）和日常生活自理能力评定[Barthel指数（BI）和改良Rankin量表（mRS）]并记录不良反应。90d随访时再次评定BI和mRS。结果与治疗前相比，治疗后14d两组NIHSS均下降，治疗组优于对照组[治疗组（13.60±4.26） vs （9.31±3.79），对照组（13.57±4.20） vs （11.23±4.06），P＝0.045]。与治疗前相比，治疗后14d两组BI差异无统计学意义（P＞0.05）；随访90d时两组BI均明显升高，且治疗组优于对照组[治疗组（54.57±24.17） vs （77.86±21.46），对照组（54.14±23.81） vs （67.0±23.30），P＝0.047]。与治疗前相比，治疗后14d两组mRS变化不明显（P＞0.05）；治疗后90d，治疗组mRS较治疗前明显减低，且治疗组优于对照组[治疗组（3.40±0.81）vs（2.80±0.96），对照组（3.49±0.82）vs（3.29±0.93），P＝0.035]。两组不良反应发生率相似。结论 NBP注射液可改善急性脑梗死所致的神经功能缺损，改善90d远期预后，安全性良好。展开更多
Background:The increased permeability of the blood-brain barrier (BBB) induced by ischemia/hypoxia is generally correlated with alteration of tight junctions (TJs). DL-3-n-butylphthalide (NBP) has been shown to exert ...Background:The increased permeability of the blood-brain barrier (BBB) induced by ischemia/hypoxia is generally correlated with alteration of tight junctions (TJs). DL-3-n-butylphthalide (NBP) has been shown to exert neuroprotective effects after ischemic injury. However, few studies have assessed the correlation between NBP and TJs. This study aimed to investigate the potential effect of NBP on the TJ proteins claudin-5, zonula occludens-1 (ZO-1), and occludin during brain ischemia. Methods: A chronic cerebral hypoperfusion (CCH) Sprague-Dawley rat model was established, and NBP (20, 40, or 80 mg/kg, gavage, once a day) treatment was performed for 14 days. NBP (0.1 or 1.0μmol/L) pre-treatment was applied to an in vitro hypoxia microvascular endothelial cell model (1%〇2, 24 h). BBB permeability was assessed by performing the Evans blue assay. The expressions and localization of claudin-5, ZO-1, occludin, phosphorylated/total protein kinase B (p-Akt/Akt), phosphorylated/total glycogen synthase kinase 3p (GSK-3(3)/GSK-3p, and (3-catenin/p-actin were evaluated by Western blotting or immunofluorescence. Reactive oxygen species (ROS) generation was measured by flow cytometry analysis. TJ ultrastructure was observed by transmission electron microscopy. Results: In CCH rats, treatment with 40 and 80 mg/kg NBP decreased the Evans blue content in brain tissue (9.0 ± 0.9 (μg/g vs. 12.3 ± 1.9 (μg/g, P = 0.005;6.7 ± 0.6 μg/g vs. 12.3 ± 1.9μg/g, P < 0.01), increased the expression of claudin-5 (0.79 ± 0.08 mvs. 0.41 ± 0.06, P < 0.01;0.07 ± 0 .0 7 vs. 0.41 ± 0 .0 6 , P < 0 .61 ), and elevated the ZO-1 protein level (P < 0.05) in brain microvascular segments in a dose-dependent manner in comparison with the corresponding values in the model group. There was no significant difference in occludin expression (P > 0.05). In the hypoxia cell model, NBP pre-treatment improved TJ ultrastructure, decreased intracellular ROS level, and increased the expression of claudin-5 (P < 0.01) and ZO-1 (P < 0.01) in comparison with展开更多
Background Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the huma...Background Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the human SOD1 gene develop an ALS-like phenotype. Currently, there is no effective treatment or drug for the fatal disease. Previous studies reported potent efficacy of dl-3-n-butylphthalide （DL-NBP） for several neurodegenerative disorders and cerebral ischemia. SOD1-G93A mice are a mouse model of ALS. In this study, we investigated the efficacy of DL-NBP on this ALS mouse model. Methods Sixty SOD1-G93A female mice were divided into four groups. The vehicle control group received 0 mg.kg-1.d-~ DL-NBP. The experimental groups received DL-NBP with doses of 30, 60 or 120 mg.kgl.d1, respectively. For measurement of motor activity, the hanging wire test and rotarod test were performed. Survival statistics were analyzed by Kaplan-Meier survival curves. The body weight of each mouse was recorded twice per week. The statistical motor unit number estimation （MUNE） technique was used to estimate the number of functioning motor units in gastrocnemius muscle. Muscle morphology was evaluated by hematoxylin and eosin staining. Motor neuron quantJtation was performed by Nissl staining and microglia activation was observed by immunohistochemistry. Results Oral administration of 60 mg.kg-l-d-1 DL-NBP significantly prolonged survival （（164.78±16.67） days） of SOD1-G93A mice compared with vehicle control （（140.00＋16.89） days）. Treating mice with DL-NBP （60 mg.kg-1.d-1） significantly decreased the progression rate of motor deficits and suppressed body weight reduction. Furthermore, we found that treating SOD1-G93A mice with DL-NBP （60 mg.kgl.d1） slowed the rate of MUNE reduction （P 〈0.01）. Motor neurons were remarkably preserved in the anterior horns in mice treated with DL-NBP （60 mg.kg-1d-1） at the stage of 19 weeks （P 〈0.01）. Treating mice with DL-NBP （60 mg.kg1.d1） si展开更多
文摘Background DI-3-n-butylphthalide （NBP）, first isolated from the seeds of celery, showed efficacy in animal models of stroke. This study was a clinical trial to assess the efficacy and safety of NBP with a continuous dose regimen among patients with acute ischemic stroke. Methods A randomized, double-blind, double-dummy trial enrolled 573 patients within 48 hours of onset of ischemic stroke in China. Patients were randomly assigned to receive a 14-day infusion of NBP followed by an NBP capsule, a 14- day infusion of NBP followed by aspirin, or a 14-day infusion of ozagrel followed by aspirin. The efficacy measures were Barthel index score and the modified Rankin scale （mRS） at day 90. Differences among the three groups on mRS were compared using X2 test of proportions （with two-sided e=0.05） and Logistic regression analysis was conducted to take the baseline National Institutes of Health Stroke Scale （NIHSS） score into consideration. Results Among the 535 subjects included in the efficacy analysis, 90-day treatment with NBP was associated with a significantly favorable outcome than 14-day treatment with ozagrel as measured by mRS （P 〈0.001）. No significant difference was found among the three groups on Barthel index at day 90. The rate of adverse events was similar among the three groups. Conclusions The 90-day treatment with NBP could improve outcomes at the third month after stroke. The NBP treatment （both intravenous and oral） is safe （ChiCTR-TRC-09000483）.
文摘The present study evaluated the effect of dl-3-n-butylphthalide(NBP) ,a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (MCAO).producing permanent focal ischemia in the right cerebral hemisphere,which developed ip-silateral brain edema reproducibly. Edema was assessed 24 h after MCA occlusion by determining the brain water content from wet and dry weight measurements,and the sodium,potassium concentrations with ion-selective electrodes. In this model,NBP at the dose of 80,160 and 240 mg/kg po 15 min after MCAO prevented from brain edema in a dose-dependent manner. A significant reduction of sodium content and an increase in potassium level were observed in all drug-treated groups. It showed that NBP strongly attenuated brain water entry,sodium accumulation and potassium loss. Nimodipine treatment(5mg/kg sc) also reduced brain edema (P<0. 05). The results suggest that a strong anti-edema activity of NBP may play an important role to contribute to the treatment of ischemic damage.
文摘目的：评价丁苯酞（NBP）注射液对急性脑梗死的疗效及药物不良反应。方法选择2012年9月至2013年11月陕西省人民医院70例急性脑梗死住院患者，随机分为治疗组（n＝35）和对照组（n＝35），对照组仅予常规治疗，治疗组在常规治疗的基础上给予NBP注射液治疗。于治疗前及治疗后14d进行神经功能缺损程度评定美国国立卫生研究院卒中量表（NIHSS）和日常生活自理能力评定[Barthel指数（BI）和改良Rankin量表（mRS）]并记录不良反应。90d随访时再次评定BI和mRS。结果与治疗前相比，治疗后14d两组NIHSS均下降，治疗组优于对照组[治疗组（13.60±4.26） vs （9.31±3.79），对照组（13.57±4.20） vs （11.23±4.06），P＝0.045]。与治疗前相比，治疗后14d两组BI差异无统计学意义（P＞0.05）；随访90d时两组BI均明显升高，且治疗组优于对照组[治疗组（54.57±24.17） vs （77.86±21.46），对照组（54.14±23.81） vs （67.0±23.30），P＝0.047]。与治疗前相比，治疗后14d两组mRS变化不明显（P＞0.05）；治疗后90d，治疗组mRS较治疗前明显减低，且治疗组优于对照组[治疗组（3.40±0.81）vs（2.80±0.96），对照组（3.49±0.82）vs（3.29±0.93），P＝0.035]。两组不良反应发生率相似。结论 NBP注射液可改善急性脑梗死所致的神经功能缺损，改善90d远期预后，安全性良好。
文摘Background:The increased permeability of the blood-brain barrier (BBB) induced by ischemia/hypoxia is generally correlated with alteration of tight junctions (TJs). DL-3-n-butylphthalide (NBP) has been shown to exert neuroprotective effects after ischemic injury. However, few studies have assessed the correlation between NBP and TJs. This study aimed to investigate the potential effect of NBP on the TJ proteins claudin-5, zonula occludens-1 (ZO-1), and occludin during brain ischemia. Methods: A chronic cerebral hypoperfusion (CCH) Sprague-Dawley rat model was established, and NBP (20, 40, or 80 mg/kg, gavage, once a day) treatment was performed for 14 days. NBP (0.1 or 1.0μmol/L) pre-treatment was applied to an in vitro hypoxia microvascular endothelial cell model (1%〇2, 24 h). BBB permeability was assessed by performing the Evans blue assay. The expressions and localization of claudin-5, ZO-1, occludin, phosphorylated/total protein kinase B (p-Akt/Akt), phosphorylated/total glycogen synthase kinase 3p (GSK-3(3)/GSK-3p, and (3-catenin/p-actin were evaluated by Western blotting or immunofluorescence. Reactive oxygen species (ROS) generation was measured by flow cytometry analysis. TJ ultrastructure was observed by transmission electron microscopy. Results: In CCH rats, treatment with 40 and 80 mg/kg NBP decreased the Evans blue content in brain tissue (9.0 ± 0.9 (μg/g vs. 12.3 ± 1.9 (μg/g, P = 0.005;6.7 ± 0.6 μg/g vs. 12.3 ± 1.9μg/g, P < 0.01), increased the expression of claudin-5 (0.79 ± 0.08 mvs. 0.41 ± 0.06, P < 0.01;0.07 ± 0 .0 7 vs. 0.41 ± 0 .0 6 , P < 0 .61 ), and elevated the ZO-1 protein level (P < 0.05) in brain microvascular segments in a dose-dependent manner in comparison with the corresponding values in the model group. There was no significant difference in occludin expression (P > 0.05). In the hypoxia cell model, NBP pre-treatment improved TJ ultrastructure, decreased intracellular ROS level, and increased the expression of claudin-5 (P < 0.01) and ZO-1 (P < 0.01) in comparison with
基金FENG Xin-hong and YUAN Wei contributed equally to the work. The study was supported by the grants from National Natural Science Foundation of China （No. 30971002 and No. 30911120496）.
文摘Background Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the human SOD1 gene develop an ALS-like phenotype. Currently, there is no effective treatment or drug for the fatal disease. Previous studies reported potent efficacy of dl-3-n-butylphthalide （DL-NBP） for several neurodegenerative disorders and cerebral ischemia. SOD1-G93A mice are a mouse model of ALS. In this study, we investigated the efficacy of DL-NBP on this ALS mouse model. Methods Sixty SOD1-G93A female mice were divided into four groups. The vehicle control group received 0 mg.kg-1.d-~ DL-NBP. The experimental groups received DL-NBP with doses of 30, 60 or 120 mg.kgl.d1, respectively. For measurement of motor activity, the hanging wire test and rotarod test were performed. Survival statistics were analyzed by Kaplan-Meier survival curves. The body weight of each mouse was recorded twice per week. The statistical motor unit number estimation （MUNE） technique was used to estimate the number of functioning motor units in gastrocnemius muscle. Muscle morphology was evaluated by hematoxylin and eosin staining. Motor neuron quantJtation was performed by Nissl staining and microglia activation was observed by immunohistochemistry. Results Oral administration of 60 mg.kg-l-d-1 DL-NBP significantly prolonged survival （（164.78±16.67） days） of SOD1-G93A mice compared with vehicle control （（140.00＋16.89） days）. Treating mice with DL-NBP （60 mg.kg-1.d-1） significantly decreased the progression rate of motor deficits and suppressed body weight reduction. Furthermore, we found that treating SOD1-G93A mice with DL-NBP （60 mg.kgl.d1） slowed the rate of MUNE reduction （P 〈0.01）. Motor neurons were remarkably preserved in the anterior horns in mice treated with DL-NBP （60 mg.kg-1d-1） at the stage of 19 weeks （P 〈0.01）. Treating mice with DL-NBP （60 mg.kg1.d1） si
