儿童狼疮性肾炎治疗中环磷酰胺药物代谢的临床研究

发布时间：2018-03-27 21:01

本文选题：狼疮性肾炎　切入点：儿童　出处：《天津医科大学》2017年硕士论文

【摘要】：目的:30例儿童LN患者接受环磷酰胺治疗,首次用药后在多个时间点采血,检测血药浓度,计算药代动力学参数。记录临床指标和评价治疗效果、药物不良反应,分析影响药代动学和治疗效果、不良反应的因素,从而前期进行干预,提高治疗效果和降低不良反应。方法:本研究收集2014年1月至2016年12月在天津市儿童医院免疫科住院接受治疗的儿童LN患者30例,所有患者均为初发病例,详细记录患者信息,治疗前采集临床指标。所有患者均接受激素和环磷酰胺治疗,首次静脉输注环磷酰胺后采血,采血点为输注结束后0.5h、1h、4h、12h、24h、36h。色谱柱为Hypersil ODS-2 C18柱,流动相为乙腈-水(体积比为30:70),流速为1.0 ml/min,柱温为30℃,检测波长为195 nm,进样量为20μl。以异环磷酰胺为内标,血浆样品经甲醇沉淀蛋白、离心取上清液进样检测。建立高效液相色谱(HPLC)法来监测环磷酰胺的各个时间点血药浓度,计算药代动力学参数。所有患者随访24周,同时评价患者血浆白蛋白(ALB)、24小时尿蛋白定量、血肌酐(Scr)、补体3(C3)、临床缓解情况和SLEDAI评分。应用统计学方法,证实激素联合环磷酰胺治疗有效,分析影响药代动力学结果的临床指标,并分析药代动力学结果和治疗效果、不良反应之间的关系。从而前期预测治疗效果、采取临床干预措施,从而获得最佳治疗效果,缩短治疗时间及减少不良反应的发生。结果:建立HPLC法测定血药浓度,血浆中环磷酰胺在0.5~20.0 mg/L范围内时,与内标的峰面积比呈良好的线性(r=0.999 4),最低检出限为0.05 mg/L;相对标准偏差(RSD)在日内、日间精密度和稳定性实验中均8%;加样回收率为100.60%~101.05%,结果满意。所得血药浓度数据计算药代动力学结果,药代动力学曲线成二室模型,AUC为(143.55±42.43)g L~(-1).h,Cmax为(20.02±3.55)g.L~(-1),T1/2为(4.21±0.96)h。年龄、体重对AUC、Cmax、T1/2均没有影响,基线生化指标中ALB和T1/2的相关性具有统计学意义,并且呈正相关(r=0.517,P=0.003)。尿蛋白定量、Scr、补体对药代动力学没有影响。所有患者接受治疗后随访16周达到部分缓解患者共7例(23.22%),完全缓解22例(73.33%),无效1例(3.33%);随访24周达部分缓解患者共6例(20%)),完全缓解24例(80%),无未缓解情况。本研究中,激素联合环磷酰胺方案治疗儿童LN的效果是理想的。治疗16周后,完全缓解和部分缓解、未缓解患者组的AUC差异有统计学意义;而24周后完全缓解和部分缓解患者组的AUC差异无统计学意义。在治疗16周后和24周后的临床缓解情况分组之间比较患者的T1/2和Cmax差异,结果显示没有统计学意义。不良反应包括白细胞减少(10.00%)、消化道症状(13.33%)和呼吸道感染(20.00%)。T1/2、AUC、Cmax和不良反应的发生之间亦没有统计学意义。T1/2和16周、24周治疗效果的相关性无统计学意义(rs=-0.339,P=0.067)。单因素分析显示ALB、尿蛋白和治疗效果的回归关系有统计学意义,而多因素分析显示各因素与治疗效果的回归关系无统计学意义。结论:本研究中激素联合小剂量环磷酰胺治疗儿童LN效果理想,没有严重不良反应发生。HPLC法可用于检测环磷酰胺血药浓度,该方法简便、快速、准确,儿童使用环磷酰胺的药代动力学情况与成人近似。ALB和T1/2呈线性正相关,ALB水平越高,则T1/2越长,药物在体内暴露时间越长,单因素分析显示ALB和治疗效果之间有相关性,因此治疗开始之前提高血浆ALB水平可能有利于提高治疗效果。环磷酰胺的药代动力学情况和药物不良反应的发生无关。
[Abstract]:Objective: 30 cases of LN patients received cyclophosphamide treatment after the first medication, blood sampling at multiple time points, serum concentration, pharmacokinetic parameters were calculated. The effect of clinical treatment of record indicators and evaluation, adverse drug reactions, analysis of the impact of the pharmacokinetic factors and treatment effect, adverse reactions, and early intervention and improve the therapeutic effect and reduce the adverse reaction. Methods: 30 cases of children being treated LN patients in this study were collected from January 2014 to December 2016 in Tianjin Children's Hospital Department of immunology, all patients were first diagnosed, the patients were recorded before treatment, the collection of the clinical indicators. All patients received treatment with glucocorticoid and cyclophosphamide intravenous cyclophosphamide for the first time. After blood collection, blood collection point for infusion after the end of 0.5h, 1H, 4h, 12h, 24h, Hypersil ODS-2 36h. column C18 column, the mobile phase of acetonitrile - water (volume ratio 30:70), flow The speed is 1 ml/min, the column temperature was 30 degrees Celsius, the detection wavelength was 195 nm, the injection volume was 20 L. with ifosfamide as internal standard, plasma proteins were precipitated with methanol, centrifugation supernatant sample detection. To establish a high performance liquid chromatography (HPLC) method to monitor the cyclophosphamide each time point blood concentration. The pharmacokinetic parameters were calculated. All patients were followed up for 24 weeks, and the evaluation of patients with plasma albumin (ALB), 24 hour urinary protein, serum creatinine (Scr), complement 3 (C3), clinical remission and SLEDAI score. The application of statistical methods, effective hormone combined with cyclophosphamide treatment, clinical medicine effect index analysis the pharmacokinetic results, and pharmacokinetic analysis and treatment effect, the relationship between adverse reactions. In order to forecast the treatment effect, the clinical treatment, so as to get the best treatment effect, shorten treatment time and reduce the occurrence of adverse reactions. Results: to establish a HPLC method for determination of plasma concentration, plasma cyclophosphamide in 0.5~20.0 mg/L range, the linear peak area and internal standard was good (r=0.999 4), the lowest detection limit was 0.05 mg/L; the relative standard deviation (RSD) in the days of day, precision and stability experiments are 8%; the recovery rate was 100.60%~101.05%, with satisfactory results. The blood drug concentration data calculate the pharmacokinetic results of pharmacokinetic curves into two compartment model, AUC (143.55 + 42.43) g L~ (-1).H, Cmax (20.02 + 3.55) g.L~ (-1), T1/2 (4.21 + 0.96 h. age, weight) of AUC, Cmax, T1/2 had no effect, statistically significant correlation between ALB and T1/2 baseline biochemical indexes, and positive correlation (r=0.517, P=0.003). Urine protein, complement Scr, had no effect on the pharmacokinetics. All patients received partial remission in patients with a total of 7 cases achieved after treatment 16 weeks of follow-up (23.22%), end Complete remission in 22 cases (73.33%), invalid in 1 cases (3.33%); 24 weeks follow-up of partial remission in patients with a total of 6 cases (20%)), 24 cases of complete remission (80%), no relief. In this study, steroid and cyclophosphamide regimen in the treatment of children LN effect is ideal after 16 weeks of treatment., complete and partial remission and no remission AUC patients group difference was statistically significant; after 24 weeks of complete remission and partial remission group AUC difference was not statistically significant. To ease the comparison of patients with T1/2 and Cmax differences between groups and clinical after 24 weeks at 16 weeks after treatment, the results showed no statistical significance. Adverse reactions included neutropenia (10%), digestive tract symptoms of respiratory tract infection (13.33%) and (20%).T1/2, AUC, Cmax and adverse reactions occurred between the.T1/2 and no statistical significance in 16 weeks, 24 weeks of treatment was not statistically significant (rs=-0.339, P=0.067). Factor analysis showed that ALB had significant regression relationship between the urinary protein and the effect of treatment, and multi factor regression analysis showed that the relationship between the factors and the treatment effect was not statistically significant. Conclusion: the ideal effect of hormone in this study combined with low dose cyclophosphamide in the treatment of children with LN, no serious adverse reactions occurred in the.HPLC method can be used to detect the blood concentration of cyclophosphamide the method is simple, rapid, accurate, and pharmacokinetics of cyclophosphamide in children and adult use approximate.ALB and T1/2 showed a linear positive correlation, the higher the ALB level, T1/2 is more long, the drug in vivo exposure time is longer, the single factor analysis results show that there is a correlation between ALB and treatment, so before the start of treatment increased plasma the level of ALB may improve the therapeutic effect. There are not pharmacokinetics and adverse drug reaction of cyclophosphamide.

【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.9

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