新疆某三甲医院急性髓系白血病患者阿糖胞苷不良反应影响因素的初步研究

发布时间：2018-01-19 04:24

  本文关键词： 急性髓性白血病 阿糖胞苷 阿糖尿苷 ADR(药物不良反应) 高效液相色谱法 血药浓度 群体药动学　出处：《新疆医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:初步阐明急性髓系白血病(acute myelogenous leukemia,AML)患者接受阿糖胞苷化疗后可能与其不良反应相关的影响因素,为后续研究并制定该药个体化给药方案奠定研究基础。方法:1)以52例初治AML患者血常规中四项(白细胞、血红蛋白、血小板、中性粒细胞)指标为分析指标,采用重复测量方差分析法考察患者血常规影响因素。2)以52例初治AML患者血常规中四项指标为分析指标,采用spearman-相关法、二分类-logistic回归以及有序-logistic回归综合考察患者基本资料与各化疗周期下各类不良反应风险及程度之间的关系。3)建立测定AML患者全血中阿糖胞苷及其代谢物阿糖尿苷血药浓度高效液相色谱法,完成方法学考察,进行不同采血点下12例患者全血中阿糖胞苷与阿糖尿苷浓度的检测。4)以12例接受阿糖胞苷化疗患者全血中阿糖胞苷及其代谢物阿糖尿苷浓度为分析指标,采用重复测量方差分析、spearman-相关分析、pearson相关分析讨论患者基本资料、血药浓度与不良反应之间的关系。5)以12例患者血药浓度建立群体药动学模型,验证模型,通过模型拟合出群体以及个体药动学参数。结果:1)重复测量方差分析结果表明:化疗第15-28天内,疾病分型组间的患者Hb计数之间的差异有统计学意义(P0.05),化疗第8-14天内,表面积组间患者PLT计数之间的差异有统计学意义(P0.05),化疗第8-14天内,性别组间患者中性粒细胞之间差异有统计学意义(P0.05),不同化疗第15-28天内,年龄组间患者中性粒细胞之间差异有统计学意义(P0.05)。2)spearman-相关法、二分类-logistic回归模型以及有序-logistic回归模型结果表明:性别、体表面积、化疗方案与患者不同化疗周期出现出血反应以及出血程度有关(P0.05),患者不同化疗周期内发生胃肠道ADR及严重程度与患者性别、体表面积有关(P0.05),患者不同化疗周期内发生发热及严重程度与化疗方案、体表面积有关(P0.05),患者不同化疗周期内发生乏力及严重程度与民族、体表面积有关(P0.05),患者不同化疗周期内发生感染及严重程度与性别、体表面积有关(P0.05),患者不同化疗周期内发生血液系统ADR及严重程度与性别、体表面积、民族、化疗方案、疾病类型有关(P0.05)。3)采用蛋白沉淀法处理全血样品。在1.55~198.0μg·mL-1范围内阿糖胞苷浓度与其峰面积有良好的线性关系(r=0.993),在1.34~171.00μg·mL-1范围内阿糖尿苷浓度与其峰面积有良好的线性关系(r=0.9978);阿糖胞苷的最低检测浓度为0.47μg·m L-1,提取回收率74.84%~87.74%;阿糖尿苷最低检测限为0.402μg·mL-1,回收率77.76%~88.92%,二者日内精密度RSD均≤15%,高、中浓度点日间精密度RSD均≤15%,低浓度日间精密度RSD小于20%。12例患者接受阿糖胞苷化疗后第40min、60min、90min、120min、150min全血中阿糖胞苷的浓度分别1.63±0.43μg/μl、3.14±1.66μg/μl、3.94±1.85μg/μl、4.10±2.38μg/μl、2.79±1.53μg/μl,全血中阿糖尿苷浓度分别为1.69±1.02μg/μl、2.26±1.17μg/μl、2.8±1.73μg/μl、5.11±3.18μg/μl、4.22±2.04μg/μl、2.47±0.96μg/μl。4)重复测量方差分析结果表明:患者静脉滴注阿糖胞苷120min、150min时间下,性别组间患者阿糖胞苷浓度间的差异有统计学意义(P0.05),静脉滴注阿糖胞苷第180min时,性别组间患者阿糖尿苷浓度间的差异有统计学意义(P0.05)。静脉滴注阿糖胞苷40min时,化疗方案组间患者阿糖尿苷浓度间的差异有统计学意义(P0.05),静脉滴注阿糖胞苷90min时,民族组间患者,阿糖尿苷浓度间的差异有统计学意义(P0.05),静脉滴注阿糖胞苷120min时,体表面积组间患者阿糖尿苷浓度间的差异有统计学意义(P0.05)。患者性别、90min阿糖胞苷浓度、150min阿糖胞苷浓度、150min阿糖胞苷浓度、60min阿糖尿苷浓度、150min阿糖尿苷浓度与患者接受化疗后出现血液系统ADR以及程度有关(P0.05)。5)建立阿糖胞苷群体药动学模型,并通过验证,模型拟合出的12例患者药动学参数的群体典型值分别为:θ3=3.47L/h,θ4=21.1L,θ5=29 L/h,θ6=129L。在拟合个体间变异度中,固定三个变量,最终得到药动学参数Q的个体间变异度?5=0.915。阿糖胞苷血药浓度比例型模型得到的误差?1=8.39。结论:1)患者的基本资料与患者治疗后的ADR有相关性。确定了具体化疗时间段内的各类不良反应与资料之间的相关性,为后续个体化给药提供充分的资料支撑。2)建立了可行的、用于检测急性髓性白血病患者全血中阿糖胞苷及阿糖尿苷浓度的高效液相色谱法。3)患者接受化疗后的临床结果与患者全血中阿糖胞苷及其阿糖尿苷的浓度有关,二者的血药浓度受到患者化疗方案、性别等因素的影响,患者血常规指标与患者血药浓度存在关联性。故有可能以血药浓度作为预测阿糖胞苷不良反应、监测阿糖胞苷预后结果的指标。4)初步建立了阿糖胞苷在AML患者中的群体药动学模型,模型验证证明该模型合理、可行,为阿糖胞苷个体化用药进行了有益的探索。
[Abstract]:Objective: To study acute myeloid leukemia (acute myelogenous, leukemia, AML) patients received cytarabine chemotherapy and the factors that may affect the adverse reactions, for further study and develop the individualized medicine lay on the basis of dosing regimen. Methods: 1) in four patients with AML treated blood in 52 cases of early (white cell, hemoglobin, platelet, neutrophil) index analyzing index analysis method to analyze the influence factors of.2 in blood by repeated measurement of variance) in 52 cases of untreated AML four indicators for blood routine analysis index, using spearman- correlation method, the relationship between the.3 two classification -logistic regression and ordered -logistic regression comprehensive survey of patients the basic data and the chemotherapy cycle under various types of adverse reactions and risk degree) determination in patients with AML blood cytarabine and its metabolite uridine blood concentration of arabinose and high performance liquid chromatography Spectrum method, method study, detection of.4 of different sampling points in the next 12 patients blood and cytarabine spongouridine concentration) in 12 patients receiving cytarabine chemotherapy in patients with blood of cytarabine and its metabolite uracil arabinoside as analysis indicators, using repeated measure variance analysis, spearman- correlation analysis, Pearson correlation analysis on basic data of patients with.5, the relationship between adverse reactions and blood drug concentration) a population pharmacokinetic model, 12 cases of blood concentration were verified by model fitting model, a dynamic parameter group and individual medicine. Results: 1) repeated measures ANOVA results showed that chemotherapy in 15-28 days. There were statistically significant differences between groups of disease type with Hb count (P0.05), chemotherapy in 8-14 days, there are statistically significant differences between groups table area PLT count (P0.05), the first 8-14 days of chemotherapy. There were statistically significant differences between the groups were not neutrophils (P0.05), different chemotherapy in 15-28 days, there were statistically significant differences between the age groups of neutrophils in patients with (P0.05).2) spearman- correlation method, two classification -logistic regression model and ordinal -logistic regression model results show that the surface area, sex, chemotherapy patients with different chemotherapy cycle bleeding and bleeding related to the extent of reaction (P0.05), gastrointestinal ADR and severity and gender in patients with different chemotherapy period, surface area (P0.05), and the severity of fever and chemotherapy in patients with different chemotherapy period, surface area (P0.05), and the severity of fatigue and national patients with different chemotherapy period, surface area (P0.05), and the severity of infection and gender in patients with different chemotherapy period, surface area (P0.05) ADR, the blood system and severity and gender, patients with different chemotherapy cycles in the body surface area, nationality, chemotherapy, disease related to the type of (P0.05).3) by protein precipitation method in whole blood samples. 1.55~198.0 ~ g ~ mL-1 range of cytarabine concentration and a good linear relationship between peak area (r=0.993), in 1.34~171.00 G - mL-1 range of NEA sugar concentration and uridine peak area has a good linear relationship (r=0.9978); the lowest detectable concentration of cytarabine is 0.47 G - M L-1, the recovery rate of 74.84%~87.74%; spongouridine minimum detection limit was 0.402 g / mL-1, the recovery rate of 77.76%~88.92%, two days precision the degree of RSD were less than 15% and high concentration point day precision were less than 15% RSD, low concentration day precision less than 20%.12 RSD patients received cytarabine chemotherapy after 40min, 60min, 90min, 120min, 150min blood concentration of cytarabine were 1.63 卤0.43渭g/渭l,3.14卤1.66渭g/渭l,3.94卤1.85渭g/渭l,4.10卤2.38渭g/渭l,2.79卤1.53渭g/渭l,鍏ㄨ��涓�闃跨硸灏胯嫹娴撳害鍒嗗埆涓�1.69卤1.02渭g/渭l,2.26卤1.17渭g/渭l,2.8卤1.73渭g/渭l,5.11卤3.18渭g/渭l,4.22卤2.04渭g/渭l,2.47卤0.96渭g/渭l.4)閲嶅�嶆祴閲忔柟宸�鍒嗘瀽缁撴灉琛ㄦ槑:鎮ｈ，

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