No-carrier-added 6-[^18F] fluoro-L-DOPA(6-FDOPA) was synthesized via a multistep procedure from a commercial available precursor,6-nitroveratraldehyde,The total synthesis time was 75min,with a radiochemical yield of (...No-carrier-added 6-[^18F] fluoro-L-DOPA(6-FDOPA) was synthesized via a multistep procedure from a commercial available precursor,6-nitroveratraldehyde,The total synthesis time was 75min,with a radiochemical yield of (10±3)%,high radiochemical purity(>99%) and high enantiomeric purity(>95%).The biodistributions of 6-FDOPA in normal and unilateral PD model rats were measured.The results from normal rats showed the expected high concentration of radioactivity in striatum and low distrbutions in cerebrum,cortex and cerebellum.The ration of the radioactivity in striatum to cerebellum reached a peak value(5.9) at 60 min.In unilateral PD model rate.whose substania nigra of the right side had been damaged by pre-treated with 6-OHDA,the radioactive concentration in striatum of the damaged side was significantly lower than that of the undamaged side or that of both sides in striatum of control groups.展开更多
With the development of the PK-PD model,its application in veterinary antimicrobials has also received great attention.This paper expounded the theory of PK-PD model,and made a brief analysis of the dosing regimens of...With the development of the PK-PD model,its application in veterinary antimicrobials has also received great attention.This paper expounded the theory of PK-PD model,and made a brief analysis of the dosing regimens of various antibiotics according to the parameters of antimicrobial drugs,in order to optimize the clinical drug delivery plan and promote the rational use of clinical antibiotics.展开更多
提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各...提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各个子区域.采用该模型对氧化铝陶瓷板在热冲击载荷作用下的损伤行为进行了模拟分析,计算结果表明,采用该混合模型获得的裂纹萌生及扩展与实验研究结果吻合良好,验证了该模型的正确性.该PD-FEM混合模型继承了PD处理不连续问题的优势,同时,由于FEM的引入,大大提高了PD方法在研究材料热力耦合损伤问题时的求解效率.展开更多
目的:探讨粪菌移植(fecal microbiota transplantation,FMT)能否提高抗程序性细胞死亡蛋白1(anti-programmed cell death protein 1,PD-1)疗法治疗卵巢癌荷瘤小鼠的效果及可能的作用机制。方法:随机将20只5周龄的C57bl/6 SPF雌鼠分为4组...目的:探讨粪菌移植(fecal microbiota transplantation,FMT)能否提高抗程序性细胞死亡蛋白1(anti-programmed cell death protein 1,PD-1)疗法治疗卵巢癌荷瘤小鼠的效果及可能的作用机制。方法:随机将20只5周龄的C57bl/6 SPF雌鼠分为4组,每组5只,分别为对照组(NC组)、FMT组、PD-1组、联合治疗(FMT联合PD-1)组。每组小鼠予广谱抗生素统一处理2周,构建假无菌小鼠模型。第0天,腹腔注射ID8-luc细胞,构建卵巢癌荷瘤小鼠模型。在药物治疗前后,分别给小鼠进行1次动物活体成像(in-vivo imaging system,IVIS),评价治疗效果。第30天即实验结束后,小鼠脱颈处死,取腹膜肿瘤组织进行HE和免疫组化染色,观察肿瘤组织病理变化。结果:联合治疗组比PD-1组治疗卵巢癌荷瘤小鼠效果更好,并且降低了肿瘤细胞PD-L1表达(P<0.05)和增加了肿瘤微环境(the tumor microenvironment,TME)中CD8+T细胞浸润(P<0.05)。结论:FMT通过增加肿瘤微环境中CD8+T细胞的浸润来提高PD-1单抗治疗卵巢癌荷瘤小鼠的效果。展开更多
In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in health...In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment,and provide a new method for the research to the clinical pharmacy of special patients.Based on the drug-specific properties,such as log D,plasma protein binding collected by the published literature,the WB-PBPK model and the PD model were established.After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation,the WB-PBPK model could be optimized.After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects,the PD model could be optimized.The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment.All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects(Cmax and AUC were less than 1.3-fold).The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization,and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully.The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.展开更多
目的:基于药动学(pharmacokinetics,PK)/药效学(pharmacodynamics,PD)模型和蒙特卡洛模拟(Mote Carlo simulation,MCS),分析大肠埃希菌所致脓毒症休克患者抗感染治疗方案的优化过程,为临床感染患者构建合理有效的治疗方案提供参考。方法...目的:基于药动学(pharmacokinetics,PK)/药效学(pharmacodynamics,PD)模型和蒙特卡洛模拟(Mote Carlo simulation,MCS),分析大肠埃希菌所致脓毒症休克患者抗感染治疗方案的优化过程,为临床感染患者构建合理有效的治疗方案提供参考。方法:一患者因不明原因发热入院,初步诊断为尿路感染和脓毒症休克。入院后第一时间完善了相关实验室检查,随后采用PK/PD模型和MCS依据微生物培养结果及其药敏试验确定最优的抗感染治疗方案。结果:入院第3天,微生物培养检出大肠埃希菌,随后的药敏试验提示其对美罗培南、亚胺培南敏感,而对头孢哌酮-舒巴坦钠中介;采用PK/PD模型和MCS对拟定的几个抗感染治疗方案进行分析,结果发现美罗培南(1 g,q8h)和亚胺培南(0.5 g,q6h)的达标概率(probability of target attainment,PTA)均为100.00%,而头孢哌酮-舒巴坦钠(3 g,q12h)的PTA为1.14%,头孢哌酮-舒巴坦钠(3 g,q8h)的PTA为7.65%;最终,临床选择了美罗培南(1 g,q8h)治疗,1周后患者的感染指征基本消失。结论:PK/PD模型和MCS两个工具可以较好地帮助临床药师预测抗感染治疗方案的可能效果,从而更好地协助医生制定和优化治疗方案,进而最大程度保证患者的治疗效果。展开更多
[目的]建立芍药内酯苷的药动学-药效学(PK-PD)模型。[方法]首先采用液质联用法测定大鼠脑缺血再灌注损伤模型给予辛芍组方后的不同时间点所得血浆样本中芍药内酯苷的药物浓度,获得药时曲线;同时采用试剂盒测定不同时间点所得血浆样本中...[目的]建立芍药内酯苷的药动学-药效学(PK-PD)模型。[方法]首先采用液质联用法测定大鼠脑缺血再灌注损伤模型给予辛芍组方后的不同时间点所得血浆样本中芍药内酯苷的药物浓度,获得药时曲线;同时采用试剂盒测定不同时间点所得血浆样本中的超氧化物歧化酶(SOD)和乳酸脱氢酶(LDH)含量,获得时效曲线。然后用Win Non Lin软件采用房室模型的分析方法对芍药内酯苷的药代动力学参数进行拟合,获得PK参数。在此基础之上,固定相关的药代动力学参数,对时效关系进行拟合,得到相关的PD参数,根据PD参数,建立辛芍组方中芍药内酯苷的PK-PD模型。[结果]当以SOD为药效指标时,可得辛芍组方中芍药内酯苷的PK-PD模型为E=21.04+(7.16×Ce)/(Ce+372.4);当以LDH为药效指标时,可得辛芍组方中代表成分芍药内酯苷的PK-PD模型为E=216.83-(37.31×Ce)/(Ce+0.04)。[结论]SOD和LDH的浓度与芍药内酯苷的浓度存在一定的相关性。芍药内酯苷可通过提高SOD、降低LDH发挥抗氧化作用来实现保护脑缺血再灌注损伤。展开更多
基金Supported by the National Nature Sciences Foundation(10075073)
文摘No-carrier-added 6-[^18F] fluoro-L-DOPA(6-FDOPA) was synthesized via a multistep procedure from a commercial available precursor,6-nitroveratraldehyde,The total synthesis time was 75min,with a radiochemical yield of (10±3)%,high radiochemical purity(>99%) and high enantiomeric purity(>95%).The biodistributions of 6-FDOPA in normal and unilateral PD model rats were measured.The results from normal rats showed the expected high concentration of radioactivity in striatum and low distrbutions in cerebrum,cortex and cerebellum.The ration of the radioactivity in striatum to cerebellum reached a peak value(5.9) at 60 min.In unilateral PD model rate.whose substania nigra of the right side had been damaged by pre-treated with 6-OHDA,the radioactive concentration in striatum of the damaged side was significantly lower than that of the undamaged side or that of both sides in striatum of control groups.
基金Supported by China UK Technology and Innovation Project ICUK
文摘With the development of the PK-PD model,its application in veterinary antimicrobials has also received great attention.This paper expounded the theory of PK-PD model,and made a brief analysis of the dosing regimens of various antibiotics according to the parameters of antimicrobial drugs,in order to optimize the clinical drug delivery plan and promote the rational use of clinical antibiotics.
文摘提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各个子区域.采用该模型对氧化铝陶瓷板在热冲击载荷作用下的损伤行为进行了模拟分析,计算结果表明,采用该混合模型获得的裂纹萌生及扩展与实验研究结果吻合良好,验证了该模型的正确性.该PD-FEM混合模型继承了PD处理不连续问题的优势,同时,由于FEM的引入,大大提高了PD方法在研究材料热力耦合损伤问题时的求解效率.
文摘In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment,and provide a new method for the research to the clinical pharmacy of special patients.Based on the drug-specific properties,such as log D,plasma protein binding collected by the published literature,the WB-PBPK model and the PD model were established.After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation,the WB-PBPK model could be optimized.After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects,the PD model could be optimized.The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment.All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects(Cmax and AUC were less than 1.3-fold).The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization,and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully.The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.
文摘目的:探讨“冬病夏治”全方配伍和无白芥子配伍延胡索乙素在模型家兔“肺俞”穴皮下药代动力学特征及药代动力学-药效动力学(PK-PD)模型的相关性。方法:支气管哮喘模型家兔随机分成延胡索单方组、缺白芥子组、全方组,微透析技术收集14 h穴位皮下透析液,液相色谱-质谱法(Liquid Chromatography Mass Spectrometry,LCMS)法检测方中君药延胡索主要成分延胡索乙素浓度,获得药代动力学参数;酶联免疫吸附试验(ELISA)法检测对应时间点模型动物血清中IgE水平,获得药效学参数;对药动学、药效学参数进行PK-PD模型拟合。结果:白芥子配伍后的药峰浓度(C_(max))、药时曲线下面积(AUC_(0-t))、平均滞留时间(MRT_(0-t))均显著增加(P<0.01,P<0.01,P<0.05),达峰时间(T_(max))提前(P<0.01);“浓度-时间-效应”三维曲线表明,方中有白芥子配伍时,药效出现更快、消退更慢,起效时间晚于峰浓度,具有一定滞后性。结论:动力学参数、PK-PD模型结果表明,白芥子配伍能够改变“方中君药”——延胡索的主要成分延胡索乙素穴位局部的皮下分布,促进方中君药有效成分快速吸收,延长滞留时间,在方剂中起到主药、改善其他药物分布的“双重”作用。
文摘[目的]建立芍药内酯苷的药动学-药效学(PK-PD)模型。[方法]首先采用液质联用法测定大鼠脑缺血再灌注损伤模型给予辛芍组方后的不同时间点所得血浆样本中芍药内酯苷的药物浓度,获得药时曲线;同时采用试剂盒测定不同时间点所得血浆样本中的超氧化物歧化酶(SOD)和乳酸脱氢酶(LDH)含量,获得时效曲线。然后用Win Non Lin软件采用房室模型的分析方法对芍药内酯苷的药代动力学参数进行拟合,获得PK参数。在此基础之上,固定相关的药代动力学参数,对时效关系进行拟合,得到相关的PD参数,根据PD参数,建立辛芍组方中芍药内酯苷的PK-PD模型。[结果]当以SOD为药效指标时,可得辛芍组方中芍药内酯苷的PK-PD模型为E=21.04+(7.16×Ce)/(Ce+372.4);当以LDH为药效指标时,可得辛芍组方中代表成分芍药内酯苷的PK-PD模型为E=216.83-(37.31×Ce)/(Ce+0.04)。[结论]SOD和LDH的浓度与芍药内酯苷的浓度存在一定的相关性。芍药内酯苷可通过提高SOD、降低LDH发挥抗氧化作用来实现保护脑缺血再灌注损伤。
