發(fā)布時間：2018-03-27 21:01

  本文選題：狼瘡性腎炎　切入點：兒童　出處：《天津醫(yī)科大學》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,首次用藥后在多個時間點采血,檢測血藥濃度,計算藥代動力學參數(shù)。記錄臨床指標和評價治療效果、藥物不良反應,分析影響藥代動學和治療效果、不良反應的因素,從而前期進行干預,提高治療效果和降低不良反應。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,詳細記錄患者信息,治療前采集臨床指標。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,采血點為輸注結束后0.5h、1h、4h、12h、24h、36h。色譜柱為Hypersil ODS-2 C18柱,流動相為乙腈-水(體積比為30:70),流速為1.0 ml/min,柱溫為30℃,檢測波長為195 nm,進樣量為20μl。以異環(huán)磷酰胺為內標,血漿樣品經甲醇沉淀蛋白、離心取上清液進樣檢測。建立高效液相色譜(HPLC)法來監(jiān)測環(huán)磷酰胺的各個時間點血藥濃度,計算藥代動力學參數(shù)。所有患者隨訪24周,同時評價患者血漿白蛋白(ALB)、24小時尿蛋白定量、血肌酐(Scr)、補體3(C3)、臨床緩解情況和SLEDAI評分。應用統(tǒng)計學方法,證實激素聯(lián)合環(huán)磷酰胺治療有效,分析影響藥代動力學結果的臨床指標,并分析藥代動力學結果和治療效果、不良反應之間的關系。從而前期預測治療效果、采取臨床干預措施,從而獲得最佳治療效果,縮短治療時間及減少不良反應的發(fā)生。結果:建立HPLC法測定血藥濃度,血漿中環(huán)磷酰胺在0.5~20.0 mg/L范圍內時,與內標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;相對標準偏差(RSD)在日內、日間精密度和穩(wěn)定性實驗中均8%;加樣回收率為100.60%~101.05%,結果滿意。所得血藥濃度數(shù)據(jù)計算藥代動力學結果,藥代動力學曲線成二室模型,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AUC、Cmax、T1/2均沒有影響,基線生化指標中ALB和T1/2的相關性具有統(tǒng)計學意義,并且呈正相關(r=0.517,P=0.003)。尿蛋白定量、Scr、補體對藥代動力學沒有影響。所有患者接受治療后隨訪16周達到部分緩解患者共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)計學意義;而24周后完全緩解和部分緩解患者組的AUC差異無統(tǒng)計學意義。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,結果顯示沒有統(tǒng)計學意義。不良反應包括白細胞減少(10.00%)、消化道癥狀(13.33%)和呼吸道感染(20.00%)。T1/2、AUC、Cmax和不良反應的發(fā)生之間亦沒有統(tǒng)計學意義。T1/2和16周、24周治療效果的相關性無統(tǒng)計學意義(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系有統(tǒng)計學意義,而多因素分析顯示各因素與治療效果的回歸關系無統(tǒng)計學意義。結論: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,沒有嚴重不良反應發(fā)生。HPLC法可用于檢測環(huán)磷酰胺血藥濃度,該方法簡便、快速、準確,兒童使用環(huán)磷酰胺的藥代動力學情況與成人近似。ALB和T1/2呈線性正相關,ALB水平越高,則T1/2越長,藥物在體內暴露時間越長,單因素分析顯示ALB和治療效果之間有相關性,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)磷酰胺的藥代動力學情況和藥物不良反應的發(fā)生無關。
[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.

【學位授予單位】：天津醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R725.9

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