發(fā)布時(shí)間：2018-01-19 04:24

  本文關(guān)鍵詞： 急性髓性白血病 阿糖胞苷 阿糖尿苷 ADR(藥物不良反應(yīng)) 高效液相色譜法 血藥濃度 群體藥動(dòng)學(xué)　出處：《新疆醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:初步闡明急性髓系白血病(acute myelogenous leukemia,AML)患者接受阿糖胞苷化療后可能與其不良反應(yīng)相關(guān)的影響因素,為后續(xù)研究并制定該藥個(gè)體化給藥方案奠定研究基礎(chǔ)。方法:1)以52例初治AML患者血常規(guī)中四項(xiàng)(白細(xì)胞、血紅蛋白、血小板、中性粒細(xì)胞)指標(biāo)為分析指標(biāo),采用重復(fù)測(cè)量方差分析法考察患者血常規(guī)影響因素。2)以52例初治AML患者血常規(guī)中四項(xiàng)指標(biāo)為分析指標(biāo),采用spearman-相關(guān)法、二分類-logistic回歸以及有序-logistic回歸綜合考察患者基本資料與各化療周期下各類不良反應(yīng)風(fēng)險(xiǎn)及程度之間的關(guān)系。3)建立測(cè)定AML患者全血中阿糖胞苷及其代謝物阿糖尿苷血藥濃度高效液相色譜法,完成方法學(xué)考察,進(jìn)行不同采血點(diǎn)下12例患者全血中阿糖胞苷與阿糖尿苷濃度的檢測(cè)。4)以12例接受阿糖胞苷化療患者全血中阿糖胞苷及其代謝物阿糖尿苷濃度為分析指標(biāo),采用重復(fù)測(cè)量方差分析、spearman-相關(guān)分析、pearson相關(guān)分析討論患者基本資料、血藥濃度與不良反應(yīng)之間的關(guān)系。5)以12例患者血藥濃度建立群體藥動(dòng)學(xué)模型,驗(yàn)證模型,通過(guò)模型擬合出群體以及個(gè)體藥動(dòng)學(xué)參數(shù)。結(jié)果:1)重復(fù)測(cè)量方差分析結(jié)果表明:化療第15-28天內(nèi),疾病分型組間的患者Hb計(jì)數(shù)之間的差異有統(tǒng)計(jì)學(xué)意義(P0.05),化療第8-14天內(nèi),表面積組間患者PLT計(jì)數(shù)之間的差異有統(tǒng)計(jì)學(xué)意義(P0.05),化療第8-14天內(nèi),性別組間患者中性粒細(xì)胞之間差異有統(tǒng)計(jì)學(xué)意義(P0.05),不同化療第15-28天內(nèi),年齡組間患者中性粒細(xì)胞之間差異有統(tǒng)計(jì)學(xué)意義(P0.05)。2)spearman-相關(guān)法、二分類-logistic回歸模型以及有序-logistic回歸模型結(jié)果表明:性別、體表面積、化療方案與患者不同化療周期出現(xiàn)出血反應(yīng)以及出血程度有關(guān)(P0.05),患者不同化療周期內(nèi)發(fā)生胃腸道ADR及嚴(yán)重程度與患者性別、體表面積有關(guān)(P0.05),患者不同化療周期內(nèi)發(fā)生發(fā)熱及嚴(yán)重程度與化療方案、體表面積有關(guān)(P0.05),患者不同化療周期內(nèi)發(fā)生乏力及嚴(yán)重程度與民族、體表面積有關(guān)(P0.05),患者不同化療周期內(nèi)發(fā)生感染及嚴(yán)重程度與性別、體表面積有關(guān)(P0.05),患者不同化療周期內(nèi)發(fā)生血液系統(tǒng)ADR及嚴(yán)重程度與性別、體表面積、民族、化療方案、疾病類型有關(guān)(P0.05)。3)采用蛋白沉淀法處理全血樣品。在1.55~198.0μg·mL-1范圍內(nèi)阿糖胞苷濃度與其峰面積有良好的線性關(guān)系(r=0.993),在1.34~171.00μg·mL-1范圍內(nèi)阿糖尿苷濃度與其峰面積有良好的線性關(guān)系(r=0.9978);阿糖胞苷的最低檢測(cè)濃度為0.47μg·m L-1,提取回收率74.84%~87.74%;阿糖尿苷最低檢測(cè)限為0.402μg·mL-1,回收率77.76%~88.92%,二者日內(nèi)精密度RSD均≤15%,高、中濃度點(diǎn)日間精密度RSD均≤15%,低濃度日間精密度RSD小于20%。12例患者接受阿糖胞苷化療后第40min、60min、90min、120min、150min全血中阿糖胞苷的濃度分別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,全血中阿糖尿苷濃度分別為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)重復(fù)測(cè)量方差分析結(jié)果表明:患者靜脈滴注阿糖胞苷120min、150min時(shí)間下,性別組間患者阿糖胞苷濃度間的差異有統(tǒng)計(jì)學(xué)意義(P0.05),靜脈滴注阿糖胞苷第180min時(shí),性別組間患者阿糖尿苷濃度間的差異有統(tǒng)計(jì)學(xué)意義(P0.05)。靜脈滴注阿糖胞苷40min時(shí),化療方案組間患者阿糖尿苷濃度間的差異有統(tǒng)計(jì)學(xué)意義(P0.05),靜脈滴注阿糖胞苷90min時(shí),民族組間患者,阿糖尿苷濃度間的差異有統(tǒng)計(jì)學(xué)意義(P0.05),靜脈滴注阿糖胞苷120min時(shí),體表面積組間患者阿糖尿苷濃度間的差異有統(tǒng)計(jì)學(xué)意義(P0.05)�；颊咝詣e、90min阿糖胞苷濃度、150min阿糖胞苷濃度、150min阿糖胞苷濃度、60min阿糖尿苷濃度、150min阿糖尿苷濃度與患者接受化療后出現(xiàn)血液系統(tǒng)ADR以及程度有關(guān)(P0.05)。5)建立阿糖胞苷群體藥動(dòng)學(xué)模型,并通過(guò)驗(yàn)證,模型擬合出的12例患者藥動(dòng)學(xué)參數(shù)的群體典型值分別為:θ3=3.47L/h,θ4=21.1L,θ5=29 L/h,θ6=129L。在擬合個(gè)體間變異度中,固定三個(gè)變量,最終得到藥動(dòng)學(xué)參數(shù)Q的個(gè)體間變異度?5=0.915。阿糖胞苷血藥濃度比例型模型得到的誤差?1=8.39。結(jié)論:1)患者的基本資料與患者治療后的ADR有相關(guān)性。確定了具體化療時(shí)間段內(nèi)的各類不良反應(yīng)與資料之間的相關(guān)性,為后續(xù)個(gè)體化給藥提供充分的資料支撐。2)建立了可行的、用于檢測(cè)急性髓性白血病患者全血中阿糖胞苷及阿糖尿苷濃度的高效液相色譜法。3)患者接受化療后的臨床結(jié)果與患者全血中阿糖胞苷及其阿糖尿苷的濃度有關(guān),二者的血藥濃度受到患者化療方案、性別等因素的影響,患者血常規(guī)指標(biāo)與患者血藥濃度存在關(guān)聯(lián)性。故有可能以血藥濃度作為預(yù)測(cè)阿糖胞苷不良反應(yīng)、監(jiān)測(cè)阿糖胞苷預(yù)后結(jié)果的指標(biāo)。4)初步建立了阿糖胞苷在AML患者中的群體藥動(dòng)學(xué)模型,模型驗(yàn)證證明該模型合理、可行,為阿糖胞苷個(gè)體化用藥進(jìn)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 鹵0.43渭g/渭l,3.14鹵1.66渭g/渭l,3.94鹵1.85渭g/渭l,4.10鹵2.38渭g/渭l,2.79鹵1.53渭g/渭l,鍏ㄨ��涓�闃烤p栧翱鑻鋒祿搴﹀垎鍒�湄�(fù)1.69鹵1.02渭g/渭l,2.26鹵1.17渭g/渭l,2.8鹵1.73渭g/渭l,5.11鹵3.18渭g/渭l,4.22鹵2.04渭g/渭l,2.47鹵0.96渭g/渭l.4)閲嶅�崑箣閲忔柟宸�鍒嗘瀽緇撴灉琛ㄦ槑:鎮(zhèn)ｈ，

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