發(fā)布時(shí)間：2018-03-27 21:01

  本文選題：狼瘡性腎炎　切入點(diǎn)：兒童　出處：《天津醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:30例兒童LN患者接受環(huán)磷酰胺治療,首次用藥后在多個(gè)時(shí)間點(diǎn)采血,檢測(cè)血藥濃度,計(jì)算藥代動(dòng)力學(xué)參數(shù)。記錄臨床指標(biāo)和評(píng)價(jià)治療效果、藥物不良反應(yīng),分析影響藥代動(dòng)學(xué)和治療效果、不良反應(yīng)的因素,從而前期進(jìn)行干預(yù),提高治療效果和降低不良反應(yīng)。方法:本研究收集2014年1月至2016年12月在天津市兒童醫(yī)院免疫科住院接受治療的兒童LN患者30例,所有患者均為初發(fā)病例,詳細(xì)記錄患者信息,治療前采集臨床指標(biāo)。所有患者均接受激素和環(huán)磷酰胺治療,首次靜脈輸注環(huán)磷酰胺后采血,采血點(diǎn)為輸注結(jié)束后0.5h、1h、4h、12h、24h、36h。色譜柱為Hypersil ODS-2 C18柱,流動(dòng)相為乙腈-水(體積比為30:70),流速為1.0 ml/min,柱溫為30℃,檢測(cè)波長為195 nm,進(jìn)樣量為20μl。以異環(huán)磷酰胺為內(nèi)標(biāo),血漿樣品經(jīng)甲醇沉淀蛋白、離心取上清液進(jìn)樣檢測(cè)。建立高效液相色譜(HPLC)法來監(jiān)測(cè)環(huán)磷酰胺的各個(gè)時(shí)間點(diǎn)血藥濃度,計(jì)算藥代動(dòng)力學(xué)參數(shù)。所有患者隨訪24周,同時(shí)評(píng)價(jià)患者血漿白蛋白(ALB)、24小時(shí)尿蛋白定量、血肌酐(Scr)、補(bǔ)體3(C3)、臨床緩解情況和SLEDAI評(píng)分。應(yīng)用統(tǒng)計(jì)學(xué)方法,證實(shí)激素聯(lián)合環(huán)磷酰胺治療有效,分析影響藥代動(dòng)力學(xué)結(jié)果的臨床指標(biāo),并分析藥代動(dòng)力學(xué)結(jié)果和治療效果、不良反應(yīng)之間的關(guān)系。從而前期預(yù)測(cè)治療效果、采取臨床干預(yù)措施,從而獲得最佳治療效果,縮短治療時(shí)間及減少不良反應(yīng)的發(fā)生。結(jié)果:建立HPLC法測(cè)定血藥濃度,血漿中環(huán)磷酰胺在0.5~20.0 mg/L范圍內(nèi)時(shí),與內(nèi)標(biāo)的峰面積比呈良好的線性(r=0.999 4),最低檢出限為0.05 mg/L;相對(duì)標(biāo)準(zhǔn)偏差(RSD)在日內(nèi)、日間精密度和穩(wěn)定性實(shí)驗(yàn)中均8%;加樣回收率為100.60%~101.05%,結(jié)果滿意。所得血藥濃度數(shù)據(jù)計(jì)算藥代動(dòng)力學(xué)結(jié)果,藥代動(dòng)力學(xué)曲線成二室模型,AUC為(143.55±42.43)g L~(-1).h,Cmax為(20.02±3.55)g.L~(-1),T1/2為(4.21±0.96)h。年齡、體重對(duì)AUC、Cmax、T1/2均沒有影響,基線生化指標(biāo)中ALB和T1/2的相關(guān)性具有統(tǒng)計(jì)學(xué)意義,并且呈正相關(guān)(r=0.517,P=0.003)。尿蛋白定量、Scr、補(bǔ)體對(duì)藥代動(dòng)力學(xué)沒有影響。所有患者接受治療后隨訪16周達(dá)到部分緩解患者共7例(23.22%),完全緩解22例(73.33%),無效1例(3.33%);隨訪24周達(dá)部分緩解患者共6例(20%)),完全緩解24例(80%),無未緩解情況。本研究中,激素聯(lián)合環(huán)磷酰胺方案治療兒童LN的效果是理想的。治療16周后,完全緩解和部分緩解、未緩解患者組的AUC差異有統(tǒng)計(jì)學(xué)意義;而24周后完全緩解和部分緩解患者組的AUC差異無統(tǒng)計(jì)學(xué)意義。在治療16周后和24周后的臨床緩解情況分組之間比較患者的T1/2和Cmax差異,結(jié)果顯示沒有統(tǒng)計(jì)學(xué)意義。不良反應(yīng)包括白細(xì)胞減少(10.00%)、消化道癥狀(13.33%)和呼吸道感染(20.00%)。T1/2、AUC、Cmax和不良反應(yīng)的發(fā)生之間亦沒有統(tǒng)計(jì)學(xué)意義。T1/2和16周、24周治療效果的相關(guān)性無統(tǒng)計(jì)學(xué)意義(rs=-0.339,P=0.067)。單因素分析顯示ALB、尿蛋白和治療效果的回歸關(guān)系有統(tǒng)計(jì)學(xué)意義,而多因素分析顯示各因素與治療效果的回歸關(guān)系無統(tǒng)計(jì)學(xué)意義。結(jié)論:本研究中激素聯(lián)合小劑量環(huán)磷酰胺治療兒童LN效果理想,沒有嚴(yán)重不良反應(yīng)發(fā)生。HPLC法可用于檢測(cè)環(huán)磷酰胺血藥濃度,該方法簡便、快速、準(zhǔn)確,兒童使用環(huán)磷酰胺的藥代動(dòng)力學(xué)情況與成人近似。ALB和T1/2呈線性正相關(guān),ALB水平越高,則T1/2越長,藥物在體內(nèi)暴露時(shí)間越長,單因素分析顯示ALB和治療效果之間有相關(guān)性,因此治療開始之前提高血漿ALB水平可能有利于提高治療效果。環(huán)磷酰胺的藥代動(dòng)力學(xué)情況和藥物不良反應(yīng)的發(fā)生無關(guān)。
[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.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.9

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 王來成;關(guān)鳳軍;王暉;呂冬梅;高莉莉;韓強(qiáng);;HPLC-UV法測(cè)定環(huán)磷酰胺血藥濃度及其臨床應(yīng)用[J];兒科藥學(xué)雜志;2014年07期

2 宋紅梅;李冀;;狼瘡性腎炎診療建議介紹[J];中華實(shí)用兒科臨床雜志;2014年05期

3 黎遠(yuǎn)冬;張煒煒;梁寧生;;HPLC法測(cè)定人體血漿中異環(huán)磷酰胺及環(huán)磷酰胺的濃度[J];廣西醫(yī)科大學(xué)學(xué)報(bào);2014年01期

4 張志勇;趙曉東;;兒童免疫系統(tǒng)疾病研究進(jìn)展[J];中國實(shí)用兒科雜志;2013年05期

5 石永兵;馮勝;;狼瘡性腎炎的生物靶向治療[J];臨床藥物治療雜志;2012年04期

6 徐虹;孫利;;兒童狼瘡性腎炎診治進(jìn)展[J];實(shí)用兒科臨床雜志;2012年09期

7 費(fèi)允云;吳慶軍;張文;徐東;李夢(mèng)濤;張p，

本文編號(hào)：1673219