Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL

AIM: The vehicle Cremophor EL (CrEL) has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal tract. The goal of this study was to develop a semimechanistic population pharmacokinetic model to study the influence of CrEL on the oral absorption of paclitaxel. METHOD: Paclitaxel plasma-concentration time profiles were available from 55 patients (M:F, 17 : 38; total 67 courses; 797 samples), receiving paclitaxel orally once or twice daily (dose range 60-360 mg m(-2)) together with 12-15 mg kg(-1) cyclosporin A. A population pharmacokinetic model was developed using the nonlinear mixed effect modelling program NONMEM. RESULTS: After absorption, paclitaxel pharmacokinetics were best described using a two-compartment model with linear distribution from the central compartment into a peripheral compartment and first-order elimination. Paclitaxel in the gastrointestinal tract was modelled as free fraction or bound to CrEL, with only the free fraction available for absorption into the central compartment. The equilibrium between free and bound paclitaxel was influenced by the concentration of CrEL present in the gastrointestinal tract. The concentration of CrEL in the gastrointestinal tract decreased with time with a first order rate constant of 1.73 h(-1). The bioavailability of paclitaxel was independent of the dose and of CrEL. Estimated apparent paclitaxel clearance and volume of distribution were 127 l h(-1) and 409 l, respectively. Large interpatient variability was observed. Covariate analysis did not reveal significant relationships with any of the pharmacokinetic parameters. CONCLUSION: A pharmacokinetic model was developed that described the pharmacokinetics of orally administered paclitaxel. CrEL strongly influenced paclitaxel absorption from the gastrointestinal tract resulting in time-dependent but no significant dose-dependent absorption over the examined dose range studied.     

转化生长因子β1在白细胞介素1β诱导大鼠肾小管上皮细胞转分化及大黄素干预中的作用

目的:大黄素对白细胞介素1β诱导NRK52E细胞转分化有显著抑制作用。实验拟进一步观察转化生长因子β1在白细胞介素1β诱导大鼠肾小管上皮细胞-肌成纤维细胞转分化及大黄素抑制作用中的意义。方法:实验于2006-10/2007-05在泸州医学院附属医院免疫实验室完成。⑴实验材料及分组:以培养的大鼠肾小管上皮细胞株(NRK52E)为观察对象,按如下分组分别添加不同处理因素:①对照组:仅加入体积分数为0.05小牛血清的高糖DMEM培养基。②白细胞介素1β诱导组:加含白细胞介素1β终浓度为10μg/L的高糖DMEM培养基。③SB431542阻断组:加含白细胞介素1β终浓度为10μg/L及SB431542终浓度为10μmol/L的高糖DMEM培养基。④白细胞介素1β 大黄素组:同时加分别含白细胞介素1β终浓度为10μg/L及大黄素终浓度为25mg/L的高糖DMEM培养基。⑵实验评估:培养48h后用倒置相差显微镜观察细胞形态,细胞免疫化学染色法检测肌酸激酶、α-平滑肌肌动蛋白及转化生长因子β1的表达。结果:①白细胞介素1β可诱导部分细胞由卵圆形转变为梭形,且肌酸激酶表达减弱(P<0.01),α-平滑肌肌动蛋白及转化生长因子β1表达显著增强(P<0.01)。②SB431542特异性抑制转化生长因子β1作用后,白细胞介素1β诱导的细胞形态改变受抑,同时肌酸激酶表达增强(P<0.01),α-平滑肌肌动蛋白表达减弱(P<0.01),但转化生长因子β1的表达却无明显变化。③大黄素对白细胞介素1β诱导的细胞形态改变及肌酸激酶、α-平滑肌肌动蛋白的表达有明显抑制作用,其抑制作用与SB431542的作用相比无显著差异;同时,大黄素对白细胞介素1β诱导的转化生长因子β1的表达也有明显抑制作用(P<0.01)。结论:转化生长因子β1可能介导了白细胞介素1β诱导大鼠肾小管上皮细胞-肌成纤维细胞转分化,并参与了大黄素抑制白细胞介素1β诱导大鼠肾小管上皮细胞转分化的作用。     

白藜芦醇对一次性力竭游泳大鼠肝脏组织保护作用的量效关系

目的:观察白藜芦醇对一次性力竭游泳大鼠肝脏组织的作用及发挥作用的最佳口服剂量。方法:实验于2006-05/07在成都体育学院运动医学系动物实验室完成。①实验分组:选取雄性SD大鼠70只,随机分为7组,每组10只,分别为安静对照组,运动对照组,运动 15mg/kg白藜芦醇组,运动 50mg/kg白藜芦醇组,运动 100mg/kg白藜芦醇组,运动 200mg/kg白藜芦醇组,运动 300mg/kg白藜芦醇组。②实验干预:不同剂量白藜芦醇组每天灌胃15,50,100,200,300mg/kg白藜芦醇,安静对照组和运动对照组分别灌胃相同体积的溶媒(二甲亚砜 生理盐水),连续5周。末次给予实验用样品1h后,各运动组每只鼠尾跟部负荷3%体质量铅皮,置于水深50cm、水温(31±1)℃游泳槽中游泳。游泳力竭后即刻,股动脉取血并迅速取出肝组织。③指标检测:赖氏比色法测定血清中谷丙转氨酶活性;邻苯三酚自氧化法测定肝组织超氧化物歧化酶活性;硫代巴比妥酸法测定肝组织丙二醛含量。结果:纳入动物70只,均进入结果分析。①血清谷丙转氨酶活性和肝组织中丙二醛含量:运动对照组显著高于安静对照组,不同剂量白藜芦醇组低于运动对照组(P<0.05或P<0.01)。运动 100,200,300mg/kg白藜芦醇组低于运动 15,50mg/kg白藜芦醇组[谷丙转氨酶活性:(972.36±121.86),(944.36±105.35),(888.34±88.68),(1773.52±89.35),(1377.78±27.01)nkat/L,P<0.01;丙二醛含量:(7.90±2.56),(7.69±3.69),(7.13±2.62),(19.90±2.21),(12.16±1.78)μmol/g,P<0.05]。100,200,300mg/kg白藜芦醇组间差异无显著性。②肝脏组织中超氧化物歧化酶活性:运动对照组显著低于安静对照组,不同剂量白藜芦醇组高于运动对照组(P<0.05或P<0.01)。运动 100,200,300mg/kg白藜芦醇组高于15,50mg/kg白藜芦醇组[(2325.80±163.37),(2379.14±121.86),(2447.16±89.18),(1096.05±120.19),(1514.64±28.17)μkat/g,P<0.01]。结论:①白藜芦醇对力竭性运动大鼠肝脏组织具有保护作用。②100,200,300mg/kg白藜芦醇对肝脏组织发挥保护作用效果优于15,50mg/kg,建议使用100mg/kg白藜芦醇就能达到理想效果。     

Molecular genetic rearrangements distinguish pre- and post-bone marrow transplantation lymphoproliferative processes

Chronic myelocytic leukemia (CML) may display a lymphoproliferative phase (lymphoid blast crisis) that is generally of B cell phenotype. Since lymphoproliferative disorders may occur following bone marrow transplantation (BMT), it may be difficult to distinguish posttransplant relapse of CML lymphoid blast crisis from de novo lymphoproliferation. Lymphoid blast crisis cells from a patient with CML displayed immunoglobulin heavy chain gene (C mu) rearrangement before BMT. Following BMT the patient developed a lymphoproliferative disorder involving multiple organs. Clonal rearrangement of C mu was demonstrated in several involved tissues. The rearranged C mu restriction fragment was distinct from that displayed before BMT. Additionally, rearrangement of the breakpoint cluster region (bcr) was demonstrated in the pretransplant blast crisis sample, but not in the posttransplant lymphoproliferation samples, thus confirming that these lymphoproliferative disorders were distinct. Molecular genetic techniques offer powerful diagnostic tools for monitoring the course of patients with CML undergoing BMT.     

Critical illness polyneuromyopathy after artificial respiration.

Up to now, 71 critically ill patients have been reported with neuromuscular complications after artificial respiration. The authors review the literature and present data of a personal series of 22 patients all suffering from severe flaccid tetraparesis and muscle atrophy, which developed after an average of two weeks artificial respiration. The prognosis was relatively good in those surviving the primary disease. The multiconditional causes are discussed with emphasis on the combination of polyneuropathy and myopathy. Tumor necrosis factor (TNF), a key mediator of sepsis, which also has an influence on muscle and nerves, is mentioned as a possible cause of this illness.     

L-精氨酸对糖尿病大鼠心肌缺血再灌注损伤的影响

目的:观察糖尿病大鼠心肌缺血再灌注时血管紧张素Ⅱ、胰岛素样生长因子1、醛固酮、细胞间黏附分子1和自由基代谢的变化及L-精氨酸对其的影响。方法:实验于2005-02/2006-06在江苏大学医学院机能学实验室完成。①实验分组:腹腔注射链脲佐菌素制作糖尿病大鼠模型,30只大鼠造模成功。按随机数字表法分为3组(n=10):心肌缺血再灌注组:开胸结扎冠脉,造成心肌缺血,60min后放松再灌注60min;L-精氨酸治疗组:于手术前4周灌胃L-精氨酸250mg/(kg·d),然后重复心肌缺血再灌注组操作;假手术组:完成操作后只穿线不结扎,观察2h作为对照。实验结束时心室取血6mL,摘取心脏,留取左心室心肌组织。②实验评估:检测大鼠血浆血管紧张素Ⅱ、醛固酮和血清胰岛素样生长因子1含量及心肌细胞间黏附分子1蛋白表达。检测大鼠血清、心肌组织超氧化物歧化酶、谷胱甘肽-过氧化物酶活性、丙二醛含量及心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性。结果:30只大鼠全部进入结果分析。①与假手术组相比,心肌缺血再灌注组血浆血管紧张素Ⅱ、醛固酮含量明显升高(P<0.05～0.01),血清胰岛素样生长因子1含量降低(P<0.05);L-精氨酸治疗4周后血浆血管紧张素Ⅱ、醛固酮含量低于心肌缺血再灌注组(P<0.05～0.01),血清胰岛素样生长因子1含量高于心肌缺血再灌注组(P<0.05)。②与假手术组相比,心肌缺血再灌注组血清、心肌丙二醛含量明显升高(P<0.05),血清、心肌超氧化物歧化酶和谷胱甘肽-过氧化物酶活性明显降低(P<0.05￣0.01);用L-精氨酸治疗4周后血清、心肌丙二醛含量低于心肌缺血再灌注组(P<0.05￣0.01),血清、心肌超氧化物歧化酶和谷胱甘肽-过氧化物酶活性高于心肌缺血再灌注组(P<0.05～0.01)。③与假手术组相比,心肌缺血再灌注组心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性明显降低(P<0.05),心肌细胞间黏附分子1蛋白表达明显升高(P<0.01);用L-精氨酸治疗4周后心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性明显高于心肌缺血再灌注组(P<0.05),心肌细胞间黏附分子1蛋白表达低于心肌缺血再灌注组(P<0.05)。结论:血管紧张素Ⅱ、醛固酮和胰岛素样生长因子1可能共同参与了糖尿病心肌缺血再灌注的发生,细胞间黏附分子1蛋白表达与糖尿病心肌损伤关系密切。L-精氨酸通过减少细胞间黏附分子1蛋白表达,起心肌保护作用。糖尿病心肌缺血再灌注时存在自由基代谢异常,补充L-精氨酸后,可通过提高超氧化物歧化酶、谷胱甘肽-过氧化物酶和ATP酶活性,降低丙二醛水平,减轻自由基损伤,改善心肌组织功能。     

广东地区散发克罗恩病患者β防御素2启动子区基因突变检测

目的:对广东地区散发克罗恩病患者β防御素2启动子区基因突变进行筛查,探讨该基因在克罗恩病发病中的作用。方法:克罗恩病组为2002-01/2006-10于南方医院消化科确诊的克罗恩病患者45例,对照组为门诊健康志愿者50例。签定知情同意书后分别取静脉血5mL,提取基因组DNA,并根据设计好的引物序列及PCR反应条件进行目的片段的扩增,阴性对照使用蒸馏水代替DNA。扩增成功的目的基因片段用DNA纯化试剂盒进行纯化,并由上海英俊公司完成测序工作。利用DNAMAN软件将患者测序结果与正常对照结果进行比对,并与基因库数据对照(http://www.ncbi.nlm.nih.gov/BLAST/),SPSS13.0进行统计学分析。并根据结果分析其与克罗恩病患者病变特点的相关性。结果:①纳入的45例克罗恩病患者与50例健康志愿者在性别和年龄上无统计学意义,并全部进入实验分析。②45例克罗恩病患者中有4例在β防御素2启动子区第-233(G→C)位发现基因突变,密码子由AGG变成AGC,编码氨基酸由精氨酸变成丝氨酸,而50例对照组未发现此改变,二者比较具有统计学意义(χ2=4.34,P<0.05)。③4例突变的患者病变均位于小肠(χ2=10.81,P<0.01)且病情较重。结论:在克罗恩患者中存在着β防御素2启动子区基因突变携带者,与患者发病年龄、病变部位、病变程度明显相关,有必要对其功能进行进一步探讨。     

A phase I safety and pharmacologic study of a twice weekly dosing regimen of the oral taxane BMS-275183.

PURPOSE: BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied. EXPERIMENTAL DESIGN: A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m(2) and the dose was increased by 20 mg/m(2) increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15. RESULTS: A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m(2) twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non-small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease. CONCLUSIONS: BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non-small cell lung cancer using the twice weekly schedule has been initiated.