254例中国癫痫患者丙戊酸和2-丙基-4-戊烯酸浓度与不良反应的相关性（英文）

Association of valproic acid and 2-propyl-4-pentenoic acid concentrations with adverse reaction in 254 Chinese patients with epilepsy

目的:分析丙戊酸(valproic acid,VPA)及其毒性代谢物2-丙基-4-戊烯酸(2-propyl-4-pentenoic acid,4-ene-VPA)的血药浓度与二者所致不良反应的相关性,为临床安全合理使用VPA提供依据。方法:收集中南大学湘雅医院门诊确诊为癫痫,且长期服用丙戊酸钠口服溶液单药或者合并用药的254例患者,采用气相层析-质谱联用法测定血中VPA和4-ene-VPA浓度,采用双变量相关分析对血中VPA和4-ene-VPA浓度与所致不良反应的关系进行分析。结果:血小板(PLT)数量与VPA给药剂量呈显著负相关(P<0.01和P<0.05),红细胞(RBC)数量与VPA浓度呈显著负相关(P<0.01);合并用药组中4-ene-VPA,VPA,谷丙转氨酶(ALT)和谷草转氨酶(AST)均显著高于单药组(P<0.05);在单药组中≤2岁患者组ALT和AST显著高于>2岁患者组(P<0.001);在合并用药组中,≤2岁患者组AST,WBC和PLT水平同样显著高于>2岁患者组(P<0.05)。AST与4-ene-VPA和VPA浓度之间不相关(分别为r=0.031,r=0.035,P>0.05),ALT水平与4-ene-VPA和VPA浓度之间亦不相关(分别为r=–0.064,r=–0.089,P>0.05)。结论:VPA可能影响血常规指标,年龄、合并其他非肝药酶诱导抗癫痫药是VPA相关肝肾功能异常的危险因素,血中VPA及4-ene-VPA浓度监测不适合预警丙戊酸所致的肝毒性。

Objective:To investigate the correlation of the concentrations of valproic acid(VPA)and 2-propyl-4-pentenoic acid(4-ene-VPA)with their adverse reactions,and to guide the clinical safety and rational use of VPA.Methods:We collected 254 epilepsy outpatients who took long-term use of sodium valproate oral solution single or combined with other antiepileptic drugs from Xiangya Hospital.The plasma concentrations of VPA and 4-ene-VPA in patients were determined by gas chromatography-mass spectrometry(GC-MS).The double variable correlation analysis was performed to analyze the effect of plasma 4-ene-VPA and VPA concentrations on adverse reactions.Results:The correlations between the PLT level and the dosage of VPA(P<0.01 and P<0.05,respectively),and the RBC level and the concentration of VPA(All P<0.01)were significant negatively.The concentrations of 4-ene-VPA,VPA,ALT,and AST in the polytherapy group were much higher than those in the monotherapy group(All P<0.05).In the monotherapy group,the ALT and AST levels in patients younger than or equal to 2 years old were significantly higher than those over 2 years old(P<0.001).In the polytherapy group,the levels of AST,WBC,and PLT in patients younger than or equal to 2 years old were higher than those over 2 years old(P<0.05).The levels of AST did not show positive correlation with the concentrations of 4-ene-VPA and VPA(r=0.031,r=0.035,all P>0.05),and the levels of ALT also did not show positive correlation with the concentrations of 4-ene-VPA and VPA(r=–0.064,r=–0.089,all P>0.05).Conclusion:VPA may affect blood routine indexes.Age and combination therapy with the nonenzyme-induced anti-epileptic drugs are risk factors for VPA-related liver dysfunctions and renal impairment.The determination of VPA and 4-ene VPA is not a suitable tool for early warning of the VPA-induced liver dysfunction.