冰片修饰的姜黄素阳离子脂质体的制备及其脑靶向作用研究

目的 制备冰片修饰的姜黄素阳离子脂质体（curcumin-loaded modifying borneol cationic liposomes，Cur-BCLPs），鼻腔给药后考察其在大鼠体内的药动学行为并对其脑组织分布进行研究。方法 采用乙醇注入法制备Cur-BCLPs；透射电镜观察阳离子脂质体的形态；激光粒度仪考察粒径；超速离心法测定其包封率及载药量；以姜黄素混悬液（curcumin suspension，Cur-Sol）和冰片-姜黄素混悬液（borneol curcumin suspension，BO-Cur-Sol）为对照组，考察大鼠鼻腔给药Cur-BCLPs的体内药动学过程，并测定其在大鼠脑组织的浓度，运用DAS 2.0软件拟合药动学参数。结果 阳离子脂质体外观呈圆形或类圆形，平均粒径为（105.99±2.40）nm，包封率和载药量分别为（81.95±1.03）%和（4.28±0.46）%；体内药动学结果显示，Cur-Sol、BO-Cur-Sol和Cur-BCLPs的半衰期（T_1/2）分别为（4.27±1.53）h，（3.98±0.24）h和（6.01±0.63）h，AUC_0→t分别为（224.38±21.95）μg·h·L^-1，（243.40±12.26）μg·h·L^-1和（562.28±24.30）μg·h·L^-1，清除率分别为（1.82±0.36）L·h^-1·kg^-1，（1.72±0.11）L·h^-1·kg^-1和（0.78±0.03）L·h^-1·kg^-1，滞留时间分别为（4.28±0.23）h，（4.41±0.15）h和（8.09±0.17）h。脑组织分布结果显示，Cur-Sol、BO-Cur-Sol和Cur-BCLPs的AUC_0→t分别为（29.82±1.10）μg·h·g^-1，（35.47±1.75）μg·h·g^-1和（54.06±3.90）μg·h·g^-1，清除率分别为（15.73±0.84）L·h^-1·kg^-1，（13.23±0.52）L·h^-1·kg^-1和（8.52±0.92）L·h^-1·kg^-1。结论 Cur-BCLPs经鼻腔给药后显著提高姜黄素体内和脑组织蓄积量并且延缓消除。     

中国成年感染患者万古霉素群体药动学研究

目的 利用来自恩泽医疗中心3家医院的成年万古霉素治疗患者的治疗药物监测数据研究其群体药动学（population pharmacokinetics,PPK）模型,并利用所建药动学参数模型和该类群体患者治疗过程中的单点谷浓度经贝叶斯反馈参数估算法计算个体化药动学参数,建立个体化给药方案。方法 收集128例患者,共监测235个血清浓度,采用Kinetica软件的PPK模块中的一室静脉给药模型通过期望最大法（EM）和贝叶斯反馈拟合数据得到基础模型。利用逐步正向回归法研究消除速率常数（Kel和Vd）与患者个体协变量肌酐（Scr）、年龄（Age）、体质量（Wt）、性别（Sex）以及合并用药之间的关系,并拟合最终模型。利用内部自举法和外部验证法对模型进行评价。结果 本研究中最终模型公式为Kel=θ₁×（Scr）^θ₂×（Sex）^θ₃,V=θ₄×（Scr）^θ₅×（Age）^θ₆×（Wt）^θ₇（θ₁=0.18;θ₂=-0.19;θ₃=-0.31;θ₄=20.85;θ₅=-0.52;θ₆=-0.23;θ₇=0.98）。最终模型对应的CL和Vd群体典型值分别为5.0 L·h^-1和66.9 L,外部验证中贝叶斯预测平均误差分别为0.8 L·h^-1和9 L。结论 本研究通过所建立的万古霉素PPK模型,较好的反应出中国成年患者的万古霉素PPK特征,贝叶斯单点反馈误差较低,为提高治疗效果、减少不良反应以及实现个体化给药提供了重要的理论实验参考依据。     

NONMEM法探索CYP1A2对儿童卡马西平群体药动学的影响

目的 用非线性混合效应模型法探索CYP1A2对儿童卡马西平群体药动学的影响。方法 回顾性收集180名癫痫患儿的临床资料及720个卡马西平血药浓度监测数据,采用非线性混合效应模型法估算群体药动学参数并建立模型,采用图形法和可视化预测检验的方法对最终模型进行验证。结果 建立了该药物的一级吸收一室模型,最终模型参数如下：CL=3.25×（WT/29.8）^0.22×e^{0.05（AA=1）}×e^ηCL（L·h^-1）,V_d=34.78×e^ηVd（L）,K_a=1.2·h^-1。当CYP1A2-163为AA时,AA=1;当CYP1A2-163为CA或CC时,AA=0。患儿体质量的增长可以导致药物清除率的非线性增加,CYP1A2-163C>A突变可加快卡马西平的清除。结论 患儿的体质量与CYP1A2基因突变（-163C>A）对CL有显著影响,在用药前建议考虑患者体质量与CYP1A2基因型。     

老年感染患者替加环素群体药动学模型的建立及评价

目的 基于群体药动学（PPK）理论建立老年感染患者替加环素PPK模型并进行评价。方法 收集2019年1月1日—2022年8月30日在南京大学医学院附属鼓楼医院住院且静脉使用替加环素的老年患者为研究对象，回顾性收集符合纳入及排除标准患者的性别、年龄、体质量、药物剂量、给药时间、治疗药物监测采样时间、血药浓度、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（γ-GT）、白蛋白（ALB）、直接胆红素（DBIL）、总胆红素（TBIL）、尿素氮（BUN）、肌酐（Cr）以及采用Cockcroft-Gault公式计算的肌酐清除率（CrCL）等资料。患者临床给药方案为静脉滴注替加环素50 mg或100 mg，首剂加倍，每12小时给药1次。利用非线性混合效应模型法建立PPK模型，并计算药动学参数。最终模型采用拟合优度诊断、自举法（BS）、可视化预测检验法（VPC）进行内部评价，采用拟合优度诊断、VPC和预测检验误差进行外部验证，考察最终模型的预测性能。结果 纳入108例老年患者数据，其中建模组79例患者数据，血药浓度监测点309个；外部验证组29例患者数据，血药浓度监测点87个。患者感染类型主要包括肺部感染、腹腔感染、皮肤和软组织感染。最终PPK模型为二室模型，模型参数清除率（CL）、中央室分布体积（V₁）、房室间清除率（Q）、周边室分布体积（V₂）的典型值分别为8.85 L·h^-1、50.4 L、19.1 L·h^-1、202.0 L，BUN对替加环素的CL存在显著影响，模型的内部验证和外部验证均表现良好，说明最终模型的预测性能稳定可靠。结论 建立的PPK模型为首个针对老年患者的替加环素PPK模型，可为老年患者个性化使用替加环素提供参考。     

老年重症耐甲氧西林金黄色葡萄球菌感染患者替考拉宁的药动学研究和药效学评价

目的 探讨耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）肺部感染老年患者替考拉宁的药动学差异与药效学评价。方法 研究纳入2018年9月—2019年8月诊断为MRSA肺部感染患者50例，治疗前下呼吸道痰液标本培养提示为MRSA感染并对替考拉宁敏感。所有患者予静脉输注替考拉宁，前3剂400 mg，每12 h给药1次，维持剂量400 mg每24 h给药1次。将达到稳态后第5次给药前测得C_min≤10 μg·mL^-1的患者维持剂量方案更改为600 mg qd。注射用替考拉宁400 mg或600 mg溶于100 mL 0.9%氯化钠注射液，给药时间为30 min，疗程为14~21 d。按规定时间采集静脉血2 mL，采用HPLC检测血药浓度，使用DAS 3.0软件处理，求出各例患者的药动学参数。将达稳态后第5次给药前测得C_min>10 μg·mL^-1的药动学参数设为A；对于C_min≤10 μg·mL^-1的患者，将维持剂量调整为600 mg qd，并将调整剂量后第5次给药前测得C_min>10 μg·mL^-1的药动学参数设为B。按照APACHE II评分和SOFA评分将患者分为重症和非重症2组。结合PK/PD原理，比较2组患者在C_min处于10~20 μg·mL^-1和20~30 μg·mL^-1以及AUC/MIC≥345和<345的临床治疗有效率、细菌清除率及不良反应发生情况。结果 替考拉宁药动学以二室模型描述最佳。负荷剂量相同时，维持剂量为400 mg的A组与维持剂量为600 mg的B组药动学参数比较如下：C_max[（32.28±15.16） mg·L^-1vs（65.73±28.96） mg·L^-1]，t_1/2[（86.24±10.61） h vs（70.51±11.78） h]，V_d[（2.73±1.32） L·kg^-1vs（2.58±1.02） L·kg^-1]，CL[（0.11±0.05） L·h^-1·kg^-1vs（0.13±0.06） L·h^-1·kg^-1]，AUC_（0~t）[（2 698.16±1 603.25） mg·h·L^-1vs（4 076.85±1 873.09） mg·h·L^-1]，AUC_（0~∞）[（4 509.33±2 786.54） mg·h·L^-1vs（7 193.58±4 109.81） mg·h·L^-1]，差异有统计学意义（P<0.05）。患者SOFA评分≤5和>5的临床有效率为65.71%和53.33%，细菌清除率分别为65.79%和47.37%。APACHEII评分≤15和>15的临床有效率分别为63.64%和58.82%，细菌清除率分别为63.16%和52.63%。结论 MRSA肺部感染老年患者替考拉宁的药动学存在较大差异，结合PK/PD原理，能够为个体化治疗提供科学的给药方案。     

UPLC-MS/MS测定大鼠血浆中柴胡皂苷B2、B4的含量及药动学研究

目的 建立UPLC-MS/MS测定大鼠血浆中柴胡皂苷B2、B4,并对柴胡皂苷B2、B4静脉给药后的药动学进行研究。方法 以柴胡皂苷F为内标,采用UPLC BEH C₁₈（2.1 mm×50 mm,1.7 μm）柱,柱温为40℃。流动相为乙腈-0.1%甲酸水溶液,梯度洗脱,流速为0.4 mL·min^-1,洗脱时间为4 min,使用氮气作为去溶剂化气体（800 L·h^-1）和锥形气体（50 L·h^-1）。MRM模式对柴胡皂苷B2 m/z 825.4→617.5、柴胡皂苷B4 m/z 957.6→649.6和柴胡皂苷F（内标）m/z 973.7→119.0进行定量分析。大鼠血浆用乙腈沉淀法去除蛋白。结果 在5~5 000 ng·mL^-1内,大鼠血浆中柴胡皂苷B2、B4线性良好（r>0.995）,定量下限为5 ng·mL^-1。柴胡皂苷B2日内精密度RSD<12%,日间精密度RSD<15%。柴胡皂苷B4日内精密度RSD<14%,日间精密度RSD<15%。柴胡皂苷B2、B4的准确度范围为89.3%~110.2%。结论 该分析方法灵敏、快速、选择性良好,并成功应用于柴胡皂苷B2、B4静脉给药后的大鼠药动学研究。     

丙戊酸钠和丙戊酸镁在大鼠体内的药动学研究

目的 研究丙戊酸钠和丙戊酸镁在大鼠体内的药动学特征,评价其优势丙戊酸盐,为临床合理用药提供参考。方法 SD大鼠随机分为2组,分别灌胃给予丙戊酸钠片和丙戊酸镁片。于不同时间点眼眶取血。采用HPLC测定血清中丙戊酸的血药浓度,计算2种丙戊酸盐在大鼠体内的药动学参数,并比较2种丙戊酸盐之间的差异。结果 HPLC测定丙戊酸血药浓度方法专属性好,血清丙戊酸浓度在10.00~110.00 μg·mL^-1内线性关系良好。精密度、稳定性和回收率均符合要求。丙戊酸钠和丙戊酸镁在大鼠体内的主要药动学参数：T_1/2分别为（14.02±3.86） h和（12.11±1.95） h;T_max分别为（3.67±0.58） h和（2.67±0.26） h;C_max分别为（67.10±10.87）μg·mL^-1和（75.67±12.94）μg·mL^-1;AUC_（0-t）分别为（969.86±72.08）μg·mL^-1·h和（1 093.56±48.69）μg·mL^-1·h;AUC_（0-∞）分别为（1 178.10±185.29）μg·mL^-1·h和（1 279.35±109.18）μg·mL^-1·h;MRT_0-t分别为（10.73±2.05） h和（13.06±3.24） h。V_d分别为（16.31±2.18） L和（23.47±2.19） L;CL分别为（0.056 3±0.009） L·h^-1和（0.051 1±0.004） L·h^-1。结论 与丙戊酸钠相比,丙戊酸镁在大鼠体内的药动学参数具有一定的优势,可能是一种更具有治疗优势的丙戊酸盐。     

中国健康人群口服米格列奈钙片的群体药动学研究

摘 要 目的：通过建立米格列奈在健康人群体内群体药动学模型（PPK）,探究米格列奈在中国健康人体内的药动学特点,评价米格列奈的临床药动学影响因素。方法: 收集22名健康受试者的临床资料,进行单剂量给药试验,受试者口服米格列奈钙片10 mg后,利用LC MS/MS法测定米格列奈血药浓度,用非线性混合效应模型 ( NONMEM) 程序中的条件一级评估算法(FOCE) 对数据进行分析,定量评价人口统计学指标、生化指标等固定效应因素对药动学参数的影响,建立米格列奈群体药动学模型,并用Bootstrap和VPC法验证。结果:米格列奈在健康人体内药动学可用一室模型描述,个体间变异符合指数模型。米格列奈最终的群体药动学参数 CL/F、表观分布容积( V/F ) 和吸收常数(Ka )的群体典型值分别为2.4 L·h^-1( 24% )、9.82 L( 4% ) 和6.46h^-1 (14% )。肌酐清除率（Ccr）因素对 CL/F 有显著影响,丙氨酸氨基转移酶（ALT）因素对 Ka 有显著影响。结论:肌酐清除率CCr和丙氨酸氨基转移酶ALT对米格列奈的群体药动学参数有显著影响。所建立的PPK模型可以较好地估算服用米格列奈的个体及群体药动学参数,为指导临床合理用药提供药动学参考。     

UPLC-MS/MS测定大鼠血浆中胡蔓藤碱乙和胡蔓藤碱丁及其药动学与生物利用度研究

目的 建立一种检测大鼠血浆中蔓藤碱乙和胡蔓藤碱丁的UPLC-MS/MS法，并研究大鼠口服和舌下静脉给药方式下胡蔓藤碱乙和胡蔓藤碱丁的药动学差异。方法 大鼠分别灌胃和舌下静脉注射蔓藤碱乙和胡蔓藤碱丁，在一定时间内取血，离心获得血清；士的宁为内标，通过UPLC-MS/MS来测定血清中蔓藤碱乙和胡蔓藤碱丁的浓度，绘制药-时曲线，计算药动学参数。结果 经灌胃给药5 mg·kg^–1，胡蔓藤碱乙的t_1/2为(5.7±1.2) h，AUC_(0-t)为(59.6±20.1) ng·h·mL^–1，CL/F为(89.1±30.5) L·h^–1·kg^–1，C_max为(18.3±5.3) ng·mL^–1；经舌下静脉给药1 mg·kg^–1后，胡蔓藤碱乙的t_1/2为(1.5±0.3) h，AUC_(0-t)为(140.2±37.4) ng·h·mL^–1，CL为(7.6±2.3) L·h^–1·kg^–1，C_max为(114.9±36.0) ng·mL^–1。经灌胃给药5 mg·kg^–1，胡蔓藤碱丁的t_1/2为(4.7±4.1) h，AUC_(0-t)为(44.3±5.1) ng·h·mL^–1，CL/F为(100.3±11.7) L·h^–1·kg^–1，C_max为(13.0±4.0) ng·mL^–1；经舌下静脉给药0.1 mg·kg^–1后，胡蔓藤碱丁的t_1/2为(1.1±0.4) h，AUC_(0-t)为(72.9±19.1) ng·h·mL^–1，CL为(1.4±0.4) L·h^-1·kg^–1，C_max为(43.7±6.8) ng·mL^–1。胡蔓藤碱乙的生物利用度为8.5%；胡蔓藤碱丁的生物利用度为1.2%。结论 胡蔓藤碱乙、胡蔓藤碱丁吸收迅速，半衰期较短。     

UPLC-MS/MS检测大鼠血浆中阿帕替尼的浓度及其药动学研究

目的 采用UPLC-MS/MS建立快速检测大鼠血浆中阿帕替尼浓度的方法,并应用于药动学研究。方法 大鼠血浆样本用乙腈沉淀蛋白,液质联用技术检测浓度,流动相为乙腈-水（含0.1%甲酸）,梯度洗脱,流速为0.3 mL·min^-1,柱温40℃,内标为氯唑沙宗;质谱条件：电喷雾离子化源（ESI）,负离子监测模式,检测离子对阿帕替尼为m/z 396.2→210.0和m/z 396.2→158.0,氯唑沙宗m/z 168.0→132.0。结果 阿帕替尼和内标氯唑沙宗的保留时间分别为1.07 min和1.40 min,线性范围为10~2 000 ng·mL^-1（r²=0.993）,检测限为1 ng·mL^-1,准确度为90.65%~111.50%,基质效应为89.14%~104.65%,平均回收率>86%,日内、日间精密度RSD均<10%。常温下放置24 h、冻融2次和-80℃冻存30 d的RSD均<10%。药动学研究结果显示,大鼠单次灌胃阿帕替尼76.5 mg·kg^-1,AUC_（0-t）为（6 114.41±645.99）ng·mL^-1·h,CL_z/F为（12.21±1.08）L·h^-1·kg^-1,V_z/F为（75.70±38）L·kg^-1,T_1/2为（4.23±1.94）h,T_max为（2±0.71）h,C_max为（1 377.7±284.54）μg·L^-1。结论 该法操作简便,重复性好,准确可靠,适用于大鼠血浆中阿帕替尼的浓度检测及其药动学研究。     

冠心病患者氯吡格雷群体药动学-药效学模型研究

目的 建立冠心病患者氯吡格雷群体药动学-药效学模型,为尽早诊断和干预氯吡格雷抵抗提供临床依据.方法 前瞻性收集使用双联抗血小板治疗冠心病的患者101例,分别以患者体内氯吡格雷活性代谢产物(clopidogrel active metabolite,Clop-AM)浓度和血小板最大聚集率(maximum platelet...     

High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

The purpose of present study was to develop a population pharmacokinetic model of high dose methotrexate (HD‐MTX) infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination. It is also the purpose to propose a limited sampling strategy (LSS) for the estimation of the time above the threshold (0.2 µmol·L^?1). A total 82 patients with lymphoid malignancy were involved in the study. A pharmacokinetic model was developed using nonlinear mixed‐effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross‐validation. Bayesian estimation was evaluated. The pharmacokinetics of HD‐MTX was described by a two‐compartment model. The pharmacokinetic parameters and the inter‐individual variability were as follows: the clearance CL, 7.45 L·h^?1 (inter‐individual variability 50.6%), the volume of the central and peripheral compartment V₁, 25.9 L (22.5%), V₂, 9.23 L (97.8%), respectively, and the intercompartmental clearance Q, 0.333 L·h^?1 (70.4%). The influence of serum creatinine on CL and weight on V₁ was retained in the final model. The protocol involved one sampling time at 44 h after the start of the infusion, allowing one to predict the time at which the MTX concentration reached the expected threshold (0.2 µmol·L^?1). Serum creatinine and weight showed significant influence on methotrexate CL and V₁, respectively. Furthermore, a Bayesian estimation based on the covariates and 44 h sample was developed, allowing prediction of the individual methotrexate pharmacokinetic parameters and the time to 0.2 µmol·L^?1. Copyright © 2009 John Wiley & Sons, Ltd.     

Renal Function and Methotrexate Clearance in Children With Newly Diagnosed Leukemia

Study Objectives . To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance. Design . Prospective, unblinded observational study in consecutive patients. Setting . A research hospital. Patients . Thirty-eight children newly diagnosed with acute lymphoblastic leukemia. Interventions . The patients received either high-dose methotrexate 1 g/m² intravenously over 24 hours or low-dose methotrexate 30 mg/m² orally every 6 hours for six doses; both regimens were followed by an intensive six-drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy. Measurements and Main Results . The GFR was determined from ^99mTc-DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high-dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m²) and after induction therapy (120 ml/min/1.73 m²) were not significantly different (p=0.26) but were highly variable (range 49–274 ml/min/1.73 m²). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p=0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58–155 ml/min/m²) was significantly (p=0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance. Conclusions . The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.     

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers

AIMS

To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy.

METHODS

The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation–estimation method.

RESULTS

The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h⁻¹ (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h⁻¹ (RSE 16.9%) and absorption rate constant 0.758 h⁻¹ (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)^1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC_0–t.

CONCLUSIONS

The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC_0–t was developed from the final model and can be used routinely to optimize individual dosing.     

聚乙二醇-达沙替尼结合物的合成及初步药效研究

目的 合成2种聚乙二醇-达沙替尼结合物（JK120303和JK120304）,并评价结合物JK120303和JK120304在K562人慢性髓系白血病皮下瘤模型中的抗肿瘤作用。方法 将达沙替尼用缬氨酸衍生后分别和mPEG-二肽酸和4arm-PEG-乙酸反应得到聚乙二醇-达沙替尼结合物,于NOD/SCID小鼠右侧背部皮下接种K562细胞,建立人慢性髓系白血病异种移植动物皮下模型,根据相对肿瘤增殖率进行疗效评价。结果 合成得到2个聚乙二醇-达沙替尼结合物。结合物JK120303（2.5 mg·kg^-1和5 mg·kg^-1）的药效优于达沙替尼（5 mg·kg^-1）,结合物JK120304（2.5 mg·kg^-1和5 mg·kg^-1）的药效与达沙替尼（5 mg·kg^-1）相当。结论 聚乙二醇-达沙替尼结合物JK120303药效优于达沙替尼,值得进一步研究。     

Ranitidine pharmacokinetics in continuous ambulatory peritoneal dialysis

Summary Ranitidine kinetics in renal failure were evaluated in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD). On separate occasions each patient received either 50 mg intravenously (i.v.) or 150 mg orally of ranitidine HCl. Following i.v. administration, the plasma concentration vs time curve was best described by a two compartment model with firstorder elimination. The mean ± SD distribution and elimination rate constants were 2.47±0.78 and 0.098±0.013 h, respectively. The area under the serum concentration vs time curve after the i.v. dose was 5979±2870 μg·h· 1⁻¹, resulting in a mean volume of distribution of 76.81 and a total body clearance of 126 ml·min⁻¹. Following oral administration the observed maximum plasma concentration was 904±483 μg·l⁻¹ at 4.2±1.8 h, and the bioavailability was 69.7±35.6%. The peritoneal clerance of ranitidine was 3.2±0.7 and 2.6±0.6 ml·min⁻¹ for the i.v. and oral groups, respectively. The amount of drug removed by dialysis was 561.2±336.2 μg for the i.v. and 1197.1±602.3 μg for the oral group. Four patients in the i.v. group had urine output during the study period with renal ranitidine clearance values of 9.9±9.9 ml· min⁻¹. Two patients in the oral group had urine output and corresponding renal ranitidine clearance values of 5.1 and 20.1 ml·min⁻¹. A dosage regimen for ranitidine is proposed based on ranitidine kinetics in patients undergoing CAPD.     

Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820

Summary  The aim of this study was to assess the population pharmacokinetics (PopPK) of the novel oral anti-cancer agent E7820. Both a non-linear mixed effects modeling analysis and a non-compartmental analysis (NCA) were performed and results were compared. Data were obtained from a phase I dose escalation study in patients with malignant solid tumors or lymphomas. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to the start of subsequent cycles. A one compartment model with linear elimination from the central compartment was shown to give adequate fit, while absorption was described using a turnover model. Final population parameter estimates of basic PK parameters obtained with the PopPK method were (RSE): clearance, 6.24 L/h (7.1%), volume of distribution, 66.0 L (8.5%), mean transit time to the absorption compartment, 0.638 h (6.5%). The intake of food prior to dose administration slowed absorption (2.8-fold, RSE 13%) and increased relative bioavailability of E7820 by 36% (RSE 14%), although the effect on C _max and AUC was not significant. Comparison with the NCA approach showed approximately equal PK parameter estimates and food effect measures, although specific advantages of PopPK included efficiency in use of data and more appropriate assessment of variability.     

Influence of a Bacterial Lipopolysaccharide on the Pharmacokinetics of Tobramycin in Rats

Abstract— The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg^?1) and inulin (100 mg kg^?1) were administered intravenously 2 h after administration of 50,250 or 500 μg kg^?1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 μg kg^?1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.     

乌灵菌发酵液抗辐射功能研究

目的 研究乌灵菌发酵液对小鼠抗辐射功能的影响。方法 通过迟发型超敏反应（delayed type hypersensitivity,DTH）、脾淋巴细胞增殖转化试验、血清溶血素和凝集素水平检测、碳粒廓清试验观察乌灵菌发酵液对免疫功能的影响;通过检测辐射损伤小鼠外周血液学指标、骨髓有核细胞数、骨髓细胞微核率与血清及脏器中的脂质过氧化产物丙二醛（MDA）含量观察乌灵菌发酵液对氧化应激与造血功能的影响。结果 与正常组相比,乌灵菌发酵液3,0.6 g·kg^-1剂量组DTH反应明显增强（P<0.01）,脾淋巴细胞增殖转化功能、血清溶血素、碳粒廓清指数及胸腺系数显著提高（P<0.05或P<0.01）;与模型组相比,给药组骨髓有核细胞数与骨髓细胞微核率无明显差异,血清与心脏MDA含量显著降低（P<0.05或P<0.01）,白细胞数量显著增加（P<0.01）,结论 乌灵菌发酵液可能通过增强机体免疫调节能力与造血功能来发挥抗辐射功效。     

毛菊苣水提取物急性毒性及其保肝作用研究

摘要：目的 初步探讨毛菊苣水提物（文中简写为MS）的急性毒性,并通过D-氨基半乳糖盐酸盐(D-GaIN)、卡介苗联合脂多糖(BCG LPS)和异硫氰酸-1-萘酯（ANIT）致小鼠肝损伤实验研究探讨MS的保肝作用。方法 急毒实验：将小鼠随机分为给药组和空白对照组,并观察记录14d 内小鼠死亡情况、体质量和摄食量等,14 d 后处死并做大体解剖,观察其各主要脏器是否异常。保肝实验：将小鼠分成空白对照组、模型组、阳性对照组（联苯双酯组/护肝片组）及MS 0.13 g?kg-1 和 0.26 g?kg-1剂量组,采用D-GaIN建立化学性肝损伤模型,BCG LPS建立免疫性肝损伤模型,ANIT建立小鼠黄疸性肝炎模型,经眼球采血,测定血清中丙氨酸氨基转移酶（alanine transaminase,ALT）、天门冬氨酸氨基转移酶（aspartate aminotransferase,AST）、总胆红素（total bilirubin,TBIL）和直接胆红素（direct bilirubin,DBIL）水平,同时测定肝脏指数,并取肝脏做常规HE切片观察。结果 急毒实验：本品给小鼠单次给药最大给药量为150 g（生药）?kg-1（为70kg成人每日每公斤体重用量的500倍）未出现死亡及其他急性毒性反应。保肝实验：在D-GaIN致小鼠化学性肝损伤模型中,MS 0.26 g?kg-1剂量组能显著抑制D-GaIN 所致的血清ALT、AST和TBIL活性升高（p<0.05或p<0.01）;在免疫性肝损伤模型中,MS各剂量组均可显著抑制（p<0.01）BCG LPS所致的小鼠血清ALT、AST活性升高,但对血清中TBIL的含量未见明显改变。在黄疸性肝炎模型中,MS 0.26 g?kg-1剂量组可显著抑制（p<0.01）ANIT所致的小鼠血清ALT、AST、TBIL和DBIL活性升高。此外MS 0.13 g?kg-1剂量组对小鼠血清中TBIL和DBIL的含量也有显著的抑制作用（p<0.01）。肝脏病理切片结果显示MS各剂量组对本实验中的三种肝损伤均有明显改善作用;结论 本品以最大剂量150 g（生药）?kg-1 给药对小鼠未见明显急性毒性反应。MS 对实验性肝损伤具有较好的保护作用。