【作者】 陈妍；

【导师】 蒋萌；

【作者基本信息】 南京中医药大学 ， 中西医结合临床， 2009， 博士

【摘要】 根据前期药理学实验资料数据,首先进行鸦胆子油乳滴注液人体耐受性研究,确定人体的安全剂量范围,在此基础上选择鸦胆子油乳滴注液的指标成分油酸进行人体药代动力学试验,观察鸦胆子油乳滴注液在人体的代谢情况,推荐临床用药剂量,并进行鸦胆子油乳滴注液的有效性研究,科学规范地完成鸦胆子油乳滴注液的临床药理研究。选择肿瘤患者为受试者,单次给药耐受性试验:初试剂量为3g/日/人,最大剂量为20g/日/人。按费氏递增法（改良Fibonacci法）递增。连续给药耐受性试验:根据单次给药耐受性试验中的可耐受剂量选定10g、20g两个剂量。建立测定人血浆油酸含量的LC-ESI-MS方法,并研究了鸦胆子油脂肪乳中油酸在人体内的药动学。在Symmetry C8（5μm,2.1mm×50mm）色谱柱上,以甲醇:水:醋酸（90:10:0.1）为流动相,流速为0.15ml/min,柱温为30℃,进样量为10μl;质谱采用电喷雾源（ESI-）,选择性监测质荷比（m/z）为281。线性范围为:0.0308-2.00mg·L-1,最低检测限为0.2ng（S/N=10）,回收率大于65%,日内、日间变异系数小于15%。临床研究采用随机、对照设计,将245例非小细胞肺癌患者分为NP方案化疗组125例,NP方案+鸦胆子油乳滴注液联合组120例。通过评价治疗前后瘤体大小、体力状态、症状体征、生活质量等变化情况,全面评价鸦胆子油乳滴注液治疗非小细胞肺癌热毒蕴结证的临床疗效。人体耐受性试验共入组30例,其中单次给药组5个剂量组,共入组22人,连续给药2个剂量组,共入组8人;因不良反应中止病例1例,脱落率3.33%。无剔除例数。确定人体安全剂量范围为单次给药:20g:连续给药:10g,静脉滴注,每天1次,连续7天。受试者给药后,以体内血浆中油酸浓度估算的末端相半衰期为(t_1/2)12.14±6.42h,峰时间（Tmax）为1.08±0.19h,峰浓度（Cmax）95.20±29.10 mg·L-1,AUC_0-12为370.89±70.71mg·h·L-1。推荐临床用药剂量为每次100ml,1次/日。临床研究结果显示:两组首诊咳嗽、气促、胸痛、痰中带血的组间差别无统计学意义。两组首诊生活状态评分、病人生活质量评分、首诊CT/MRI瘤体大械淖榧洳畋鹞尥臣蒲б庖濉Ａ阶榫哂锌杀刃浴Ａ阶橹瘟坪蟾魇钡慵欠旨凹欠钟牖弑冉系牟畋鹁懈叨韧臣蒲б庖濉Ｈ治黾阶橹琢隽菩蓝ā⒘阶榻故奔涞淖榧洳畋鹞尥臣蒲б庖濉?本研究通过对鸦胆子油乳滴注液进行临床耐受性试验及药代动力学试验,为其临床安全使用提供了充分的依据,推荐临床研究合适剂量为:每次100ml,1次/日;在提高患者生活质量上,联合化疗组优于单纯化疗组,表明鸦胆子油乳滴注液对患者生活质量的改善可能有一定的作用。更多还原

【Abstract】 According to preliminary experimental data of Pharmacology,first infusion of Brucea javanica oil emulsion liquid human tolerance studies,selection on the basis of Brucea javanica oil emulsion infusion of oleic acid liquid ingredients to the target human pharmacokinetic testing,observation of Brucea javanica oil emulsion infusion fluid at the body’s metabolism,Clinical recommend dosage,Brucea javanica oil emulsion and the effectiveness of fluid infusion study,scientific norms to achieve Brucea javanica oil emulsion infusion fluid of clinical pharmacology research.Cancer patients were selected to have single dose tolerance test:Initial dose of 3g/day/person,maximum dose of 20g/day/person by incremental approach by Fernandez(modified Fibonacci method) increments.Continuous delivery tolerance test:Tolerance test can be tolerated dose selected 10g,20g dose of both according to single-dose.Establish a method to determine the content of oleic acid in human plasma by LC-ESI-MS method,and studied the fat emulsion of Brucea javanica oil oleic acid in the human body pharmacokinetics.We did the research at Symmetry C8(5μm, 2.1mm×50mm) column,methanol:water:acetic acid(90:10:0.1) as mobile phase, with flow rate at 0.15ml/min,column temperature at 30℃,Injection volume of 10μl;Source mass spectrometry using electrospray ionization(ESI-),Selective monitoring of quality of the Netherlands,Belgium,(m/z) to 281,Linear range of:0.0308-2.00 mg·L-1,The limit of detection of 0.2ng(S/N=10),Recovery more than 65%,Days,day coefficient of variation less than 15%.Clinical research using randomized,controlled design,245 cases of non-small cell lung cancer patients were divided into NP programs chemotherapy group 125 eases,NP programs+Brucea javanica oil emulsion infusion liquid 121 cases of United Group.Before and after treatment by evaluating tumor size,physical status, symptoms,quality of life,such as Change,a comprehensive evaluation of Brucea javanica oil emulsion infusion in treating non-small cell lung cancer permit clinical efficacy with the accumulated hotness-toxicity.Tolerance test body which was selected into the group at a total of 30 cases, one of single-dose group 5 dose group,a total of 22 people into the group,continuous administration of two dose group,a total of 8 people into the group.1 was suspended due to adverse reactions,the off rate of 3.33%,Without discounting the number of cases,emerging positive signs and symptoms mainly expressed in seven cases of low-grade fever,2 cases of diarrhea,1 case of laboratory indicators varying significantly decreased WBC,1 case of ALT increasing slightly.We studied with the way of Oleic acid in vivo plasma concentration of the estimated half-life of terminal phase(t1/2) 12.14±6.42h,Peak time(Tmax) at 1.08±0.19h,Peak concentration(Cmax) 95.20±29.10 mg·L-1,AUC0-12 was 370.89±70.71mg·h·L-1,After subjects are administrated.Clinical study results showed that:Attending the first two sets,the difference of the Symptoms,namely cough,shortness of breath,chest pain,bloody sputum was not statistically significant.Living status groups attending the first score,the patients quality of life score,the first patient CT/MRI tumor the size of the group difference was not statistically significant,either.Two groups are comparable.Two points after treatment and the de facto points compared with baseline were highly statistically significant difference.Cancer-wide analysis of efficacy evaluation of two sets,two sets of time to progression of the group difference was not statistically significant.This study of Brucea javanica oil emulsion fluid infusion test clinical tolerance and pharmacokinetics testing,Clinical safety of its use provides a sufficient basis for, recommend the appropriate dose for clinical studies:Per 100ml,1 times/day; Improve the quality of life in patients,the combination chemotherapy was superior to chemotherapy alone group,showed that infusion of Brucea javanica oil emulsion on the improvement of the quality of life of patients may have a role.更多还原