丁苯酞对不同CYP2C19基因型急性脑梗死患者神经与内皮功能及血液流变学的影响

Effects of dl-3-n-butylphthalide on neurological and endothelial functions and hemorheology in patients with acute cerebral infarction of different CYP2C19 genotypes

目的探讨丁苯酞对不同CYP2C19基因型急性脑梗死患者神经与内皮功能以及血液流变学的影响。方法选择2023年1月—2023年6月天水市第一人民医院神经内科收治的363例急性脑梗死患者作为研究对象。丁苯酞连续给药5 d后采集患者的血液样本,采用液相色谱-串联质谱(LC-MS)检测丁苯酞水平;采用二代高通量基因分型(Hi-SNP)对CYP2C19基因型进行测序,根据测序结果将急性脑梗死患者分为丁苯酞快代谢型(CYP2C19*1/*1)、中代谢型(CYP2C19*1/*2、CYP2C19*1/*3、CYP2C19*2/*17、CYP2C19*3/*17)、慢代谢型(CYP2C19*2/*2、CYP2C19*3/*3、CYP2C19*2/*3)三组。参考《中国急性缺血性脑卒中诊治指南2018》检测患者神经功能、内皮功能指标[内皮血管肽(EN-1)、一氧化氮(NO)]和血液流变学指标(全血黏度和血浆黏度);比较各组患者上述指标的水平差异。结果慢代谢型患者的丁苯酞血药浓度明显高于快代谢型和中代谢型(mg/L:0.57±0.09比0.28±0.04、0.12±0.00,均P<0.05),且中代谢型患者的丁苯酞血药浓度明显高于快代谢型(P<0.05)。快代谢型、中代谢型和慢代谢型患者的治疗总有效率分别为52.63%、63.09%、81.39%,差异有统计学意义(P<0.05)。慢代谢型患者的ET-1水平明显低于快代谢型和中间代谢型(ng/L:38.56±6.59比65.26±6.36、54.01±5.36,均P<0.05),NO水平明显高于快代谢型和中间代谢型(μmol/L:60.54±5.99比38.71±3.96、49.22±4.51,均P<0.05),而中间代谢型患者的ET-1水平明显低于快代谢型,NO水平明显高于快代谢型(均P<0.05)。慢代谢型患者的高切全血黏度、低切全血黏度、血浆黏度、红细胞沉降率(ESR)均明显低于快代谢型和中间代谢型[高切全血黏度(mPa·s):5.44±0.51比6.76±0.63、6.07±0.59,低切全血黏度(mPa·s):8.41±0.82比9.64±0.96、9.02±0.90,血浆黏度(mPa·s):1.36±0.13比2.46±0.22、1.89±0.19,ESR(mm/h):27.33±2.64比33.56±3.41、30.24±3.22,均P<0.05],而中间代谢型上述指标均明显低于快代谢型(均P<0.05)。结论CYP2C19基因多态性对接受丁苯酞治疗的急性脑梗死患者患者神经与内皮功能以及血液流变学指标均有明显影响,检测CYP2C19基因分型以指导丁苯酞的个体化应用具有重要价值。

Objective To investigate the effects of dl-3-n-butylphthalide on neuralogical and endothelial functions and hemorheology in patients with acute cerebral infarction of different CYP2C19 genotypes.Methods Totally 363 patients with acute cerebral infarction admitted in the neurology department of Tianshui First People's Hospital from January to June 2023 were selected as research objects,and blood samples were collected after continuous administration of dl-3-n-butylphthalide for 5 days.The concentration of dl-3-nbutylphthalide was determined by liquid chromatograph mass spectrometer(LC-MS),and the CYP2C19 genotype was sequenced by second-generation single nucleotide polymorphism(Hi-SNP).The participants were divided into three dl-3-n-butylphthalide metabolism groups based the results of CYP2C19 genotypes:fast group for CYP2C19*1/*1 genotype,intermediate group for CYP2C19*1/*2,CYP2C19*1/*3,CYP2C19*2/*17 and CYP2C19*3/*17 genotypes,and slow group for CYP2C19*2/*2,CYP2C19*3/*3 and CYP2C19*2/*3 genotypes.According to Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018,neural function and endothelial function indexes[including endothelin-1(EN-1)and nitric oxide(NO)],and hemorheological indexes(including whole blood viscosity and plasma viscosity)were detected.The indexes above-mentioned were compared among three groups.Results The dl-3-n-butylphthalide concentration in slow group was significantly higher than those in fast group and intermediate group(mg/L:0.57±0.09 vs.0.28±0.04,0.12±0.00,both P<0.05),and the dl-3-n-butylphthalide concentration in intermediate group was significantly higher than that in fast group(P<0.05).The total effective rates of fast group,intermediate group and slow group were 52.63%,63.09%and 81.39%,respectively,with statistically difference(P<0.05).The ET-1 concentration in slow group was significantly lower than those in fast group and intermediate group(ng/L:38.56±6.59 vs.65.26±6.36,54.01±5.36,both P<0.05),and the NO concentration in slow group was markedly higher than those in fast group and intermediate group(μmol/L:60.54±5.99 vs.38.71±3.96,49.22±4.51,both P<0.05).In intermediate group,the ET-1 concentration was significantly lower than that in fast group,but the NO concentration was obviously higher than that in fast group(both P<0.05).The levels of high-shear viscosity,low-shear viscosity,plasma viscosity and erythrocyte sedimentation rate(ESR)were significantly lower than those in fast group and intermediate group[high-shear viscosity(mPa·s):5.44±0.51 vs.6.76±0.63,6.07±0.59,low-shear viscosity(mPa·s):8.41±0.82 vs.9.64±0.96,9.02±0.90,plasma viscosity(mPa·s):1.36±0.13 vs.2.46±0.22,1.89±0.19,ESR(mm/h):27.33±2.64 vs.33.56±3.41,30.24±3.22,all P<0.05].However,the indexes in intermediate group were obviously lower than those in fast group(all P<0.05)Conclusions CYP2C19 gene polymorphism has significant effects on nerve function,endothelial function and hemorheology in patients with acute cerebral infarction treated with dl-3-n-butylphthalide.It is of great value to detect CYP2C19 genotype to guide the individualized application of dl-3-n-butylphthalide.