| Objective: The aim of this study was to establish a high performance liquid chromatography(HPLC)method to monitor the drug concentration of sodium valproate(VPA)in plasma of patients with epilepsy.(1)To investigate the effects of different derivative conditions for the determination of serum concentration of sodium valproate on the HPLC method,and the optimization of derivatization conditions.(2)Analyze the monitoring results of the blood concentration of sodium valproate,investigate the relationship between serum concentrationits and clinical effect,and influence factors of serum concentration,to provide the reference for clinical rational use of sodium valproate.(3)A systematic evaluation of the efficacy and safety of valproic acid combined with lamotrigine in the treatment of epilepsy.Method:(1)High performance liquid chromatography(HPLC)method was established in this experiment for the determination of drug concentration of valproic acid in human plasma.we studied on the effects of different condition combination on sodium valproate concentration of HPLC by orthogonal design method on the basis of single factor analysis,and selected the best combination.(2)The monitoring effect of blood concentration of sodium valproate,clinical efficacy and adverse reactions were analyzed at our hospital since January 2016,and the influence factors involved were also investigated.(3)Computer made full searched large medical dataase both here and abroad,such as Pub Med,the ocohrance library,EMbase,CNKI,VIP,Wang Fang and so on.We selected the published journals of clinical effects of valproate combined with lamotrigine in epilepsy,the type was all of randomized controlled trials(RCT),the retrieval time was from inception to November 2015.Data were extracted and assessed for heterogeneity after screening literatureaccording to inclusion and exclusion criteria,meta analysis was performed after the data were collected.Results:(1)the mobile phase of acetonitrile-water ratio was 75:25,flow rate was 1.0ml·min-1,detection wavelength was 265 nm,column temperature was 30℃,valproic acid derivatives and internal standard derivatives were separated completely and showed a symmetrical peak shape.A2B2C1D3 combination is the optimal derivation conditions.Different derivatization conditions have a significant effect on the determination results(P < 0.05).The primary and secondary factors for the derivatization reaction are derived reagent concentration > derived temperature >catalyst concentration > derivatization time.The linear range of sodium valproate was10~200 μg·ml-1(R2=0.9995).The recovery was 95.0%~100.5%,the RSD of intra-day and inter-day was less than 5%(n = 5).(2)For 142 patients treated with sodium valproate,the concentration of 84 cases(59.15%)were within the effective concentration(50~100 μg·ml-1),the concentration of 35 cases(24.65%)were less than the concentration of 50 μg·ml-1,and there were 23 cases(16.20%)were higher than 100 μg·ml-1.The clinical effect which is excellent were accounted for a larger proportion,when the serum concentration of sodium valproate in 50~100 μg·ml-1.In other words,the majority of patients who serum concentration of valproic acid in the treatment window had better control in epilepsy.However,the patients who serum concentration of sodium valproate less than 50 μg·ml-1 had poor clinical efficacy.The incidence of adverse reactions was significantly increased when the serum concentration of sodium valproate higher than 100 μg·ml-1.Different age and dosage forms had a certain influence on blood concentration.The dose increased with age.The average plasma concentration of sustained-release tablets was significantly higher than that of syrup and common tablets.(3)According to the inclusion criteria and discharge standards,a total of 16 RCTs was included,involving 1687 patients.Results of meta-analysis showed that the total efficiency of combination are significantly high than sodium valproate or lamotrigine alone [OR=4.12,95% CI(3.06,5.54),P < 0.00001];the incidence of adverse reactions of blood system and skin attachment system were less likely compared with sodium valproate or lamotrigine alone.There was no statistical significance in the nervous system and digestive system.Conclusion:(1)The concentration of 2-Bromo-4-nitroacetophenoe is 2.0 mg·ml-1,the concentration of triethylamine is 20%,the reaction temperature is 60℃ and time is 5min,the result was best.The optimized method is simple,reproducible and reliable.(2)The serum concentration of valproate sodium was affected by age,gender,dosage form and other factors.It was showed a greatly individual difference in serum concentration.In order to realize individualized medication and ensure medication safety,clinical treatment of drug monitoring should be used as a routine monitoring means,if necessary,adjust the dosage of drugs,to achieve the best therapeutic effect with the smallest dose.(3)The effect of sodium valproate combined with lamotrigine is better than single sodium valproate or lamotrigine in epilepsy,and good tolerance.Due to methodology limit of included studies,large-scale and high quality RCT are required for further validation of the conclusions. |
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