This study aimed to establish a new propofol target-controlled infusion（TCI） model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and ...This study aimed to establish a new propofol target-controlled infusion（TCI） model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and propofol（10 mg/kg） was administrated intravenously. Artery blood samples were collected at various time points after injection, and plasma concentrations of propofol were measured. Pharmacokinetic modeling was performed using Win Nonlin software. Propofol TCI within the acquired parameters integrated was conducted to achieve different anesthetic depths in rabbits, monitored by narcotrend. The pharmacodynamics was analyzed using a sigmoidal inhibitory maximal effect model for narcotrend index（NI） versus effect-site concentration. The results showed the pharmacokinetics of propofol in Japanese white rabbits was best described by a two-compartment model. The target plasma concentrations of propofol required at light anesthetic depth was 9.77±0.23 μg/m L, while 12.52±0.69 μg/m L at deep anesthetic depth. NI was 76.17±4.25 at light anesthetic depth, while 27.41±5.77 at deep anesthetic depth. The effect-site elimination rate constant（ke0） was 0.263/min, and the propofol dose required to achieve a 50% decrease in the NI value from baseline was 11.19 μg/m L（95% CI, 10.25–13.67）. Our results established a new propofol TCI animal model and proved the model controlled the anesthetic depth accurately and stably in rabbits. The study provides a powerful method for exploring general anesthetic mechanisms at different anesthetic depths in vivo.展开更多
The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, wit...The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.展开更多
目的:调查常用的6种抗菌药物在本院重症患者中的治疗药物监测(therapeutic drug monitoring,TDM)靶值和药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)靶值达标情况,为重症患者抗感染治疗提供参考。方法:选取本院2021年3月~2022...目的:调查常用的6种抗菌药物在本院重症患者中的治疗药物监测(therapeutic drug monitoring,TDM)靶值和药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)靶值达标情况,为重症患者抗感染治疗提供参考。方法:选取本院2021年3月~2022年3月期间入住重症监护病房并接受TDM的危重症患者。采用非房室模型计算患者PK/PD指数,对患者临床特征、病原学结果以及纳入的6种抗菌药物血药浓度分布范围、TDM靶值和PK/PD靶值达标情况进行分析。结果:共纳入重症患者26例,均接受万古霉素、利奈唑胺、哌拉西林/他唑巴坦、美罗培南、伏立康唑、氟康唑6种抗菌药物中的2~3种联合抗感染治疗,共计100份血浆样本及204个血药浓度-时间数据。患者群体谷浓度和PK/PD指数差异大,TDM靶值和PK/PD靶值总体不达标率分别高达45.28%和55.36%。结论:6种抗菌药物在重症患者中的TDM靶值和PK/PD靶值达标率均较低,普遍存在低暴露和过暴露情况。提示应在此类患者中开展TDM,以精准调整给药剂量。展开更多
目的:探讨影响万古霉素、哌拉西林/他唑巴坦、美罗培南3种药物治疗药物监测(therapeutic drug monitoring,TDM)靶值和药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)靶值未达标的危险因素以及2种靶值和微生物疗效的关系,为精准...目的:探讨影响万古霉素、哌拉西林/他唑巴坦、美罗培南3种药物治疗药物监测(therapeutic drug monitoring,TDM)靶值和药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)靶值未达标的危险因素以及2种靶值和微生物疗效的关系,为精准用药提供科学依据。方法:纳入2021年3月至2022年3月接受万古霉素、哌拉西林/他唑巴坦、美罗培南中至少1种抗菌药物联合治疗的危重症患者。利用优化采样方案采集每位患者的3~4份血浆样本,借助非房室模型结合经典药动学理论计算PK/PD参数。采用多因素分析探究3种药物TDM靶值和PK/PD靶值未达标的相关危险因素。结果:共纳入接受万古霉素、哌拉西林/他唑巴坦或美罗培南治疗的25名危重症患者的96份血浆样本,共计151份血药浓度-时间数据。万古霉素、哌拉西林/他唑巴坦和美罗培南的谷浓度(trough concentration,Cmin)达标率低,分别为20.00%、22.22%和23.53%;万古霉素PK/PD靶值达标率、未达标率和超标率分别为20.00%、60.00%和20.00%。哌拉西林/他唑巴坦和美罗培南的PK/PD靶值达标率分别为11.11%和17.65%,未达标率分别高达88.89%和76.47%。影响因素探究发现肌酐清除率是影响3种抗菌药物Cmin和PK/PD靶值不达标的独立危险因素。细菌根除组患者的万古霉素Cmin[(15.329±7.522)mg·L^(-1)vs.(6.273±0.754)mg·L^(-1),P=0.019]和AUC0~24 h/MIC(578.47±413.86 vs.175.94±17.07,P=0.028)均显著高于细菌未根除组。结论:万古霉素、哌拉西林/他唑巴坦、美罗培南在危重症患者中的TDM靶值和PK/PD靶值达标率低,未达标率高,普遍存在低暴露和过暴露情况。提高TDM靶值和PK/PD靶值达标率均可能提高患者细菌根除率,因此十分有必要在此类患者中开展TDM,为精准给药提供参考。展开更多
目的通过对氟氧头孢体外抗菌活性数据、蛋白结合率数据、人体药代动力学参数进行药代动力学/药效学(PK/PD)相关性分析,评价不同给药方案时氟氧头孢的PK/PD参数。方法用给药间隔期药物浓度超过最低抑菌浓度的时间百分比(%f T_(>MIC))...目的通过对氟氧头孢体外抗菌活性数据、蛋白结合率数据、人体药代动力学参数进行药代动力学/药效学(PK/PD)相关性分析,评价不同给药方案时氟氧头孢的PK/PD参数。方法用给药间隔期药物浓度超过最低抑菌浓度的时间百分比(%f T_(>MIC))数据作为与氧氟头孢药效相关的PK/PD指标。用计算出的不同%fT_(>MIC)的目标达成分数(TA%)评估药效。对1 g q6 h,1 g q8 h,1 g q12 h,2 g q12 h氧氟头孢的PK/PD参数(%fT_(>MIC))相应值进行相互比较。最佳给药方案选择:用NONMEM软件,通过蒙特卡罗方法模拟各产生1000个患者群体的数据,考察每一个给药方案对于每一种菌株的药效。结果 1 g q12 h,1 g q8 h,1 g q6 h,输注1 h,对产超广谱β内酰胺酶(ESBL)大肠埃希菌70%fT_(>MIC)达到率分别为66.8%,93.8%和89.1%;对产ESBL肺炎克雷伯菌70%fT_(>MIC)达到率分别为62.3%,78.7%和81.8%。2 g q12 h给药,50%和70%fT_(>MIC)达到率与q8 h或q6 h类似。但更高的抗菌药效指标达成概率2.0 g q12 h给药不如1 g q8 h或1 g q6 h。对甲氧西林敏感金黄色葡萄球菌和甲氧西林敏感表皮葡萄球菌等都具有很好的PK/PD特点。结论氟氧头孢作为时间依赖性抗菌药物,无论缩短给药间隔还是延长输液时间,都可一定程度提高疗效。但与延长输注时间相比,尤以缩短给药间隔作用显著。展开更多
基金supported by a grant from Shenzhen Baoan Hospital Affiliated to Southern Medical University
文摘This study aimed to establish a new propofol target-controlled infusion（TCI） model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and propofol（10 mg/kg） was administrated intravenously. Artery blood samples were collected at various time points after injection, and plasma concentrations of propofol were measured. Pharmacokinetic modeling was performed using Win Nonlin software. Propofol TCI within the acquired parameters integrated was conducted to achieve different anesthetic depths in rabbits, monitored by narcotrend. The pharmacodynamics was analyzed using a sigmoidal inhibitory maximal effect model for narcotrend index（NI） versus effect-site concentration. The results showed the pharmacokinetics of propofol in Japanese white rabbits was best described by a two-compartment model. The target plasma concentrations of propofol required at light anesthetic depth was 9.77±0.23 μg/m L, while 12.52±0.69 μg/m L at deep anesthetic depth. NI was 76.17±4.25 at light anesthetic depth, while 27.41±5.77 at deep anesthetic depth. The effect-site elimination rate constant（ke0） was 0.263/min, and the propofol dose required to achieve a 50% decrease in the NI value from baseline was 11.19 μg/m L（95% CI, 10.25–13.67）. Our results established a new propofol TCI animal model and proved the model controlled the anesthetic depth accurately and stably in rabbits. The study provides a powerful method for exploring general anesthetic mechanisms at different anesthetic depths in vivo.
文摘The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.
文摘目的:调查常用的6种抗菌药物在本院重症患者中的治疗药物监测(therapeutic drug monitoring,TDM)靶值和药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)靶值达标情况,为重症患者抗感染治疗提供参考。方法:选取本院2021年3月~2022年3月期间入住重症监护病房并接受TDM的危重症患者。采用非房室模型计算患者PK/PD指数,对患者临床特征、病原学结果以及纳入的6种抗菌药物血药浓度分布范围、TDM靶值和PK/PD靶值达标情况进行分析。结果:共纳入重症患者26例,均接受万古霉素、利奈唑胺、哌拉西林/他唑巴坦、美罗培南、伏立康唑、氟康唑6种抗菌药物中的2~3种联合抗感染治疗,共计100份血浆样本及204个血药浓度-时间数据。患者群体谷浓度和PK/PD指数差异大,TDM靶值和PK/PD靶值总体不达标率分别高达45.28%和55.36%。结论:6种抗菌药物在重症患者中的TDM靶值和PK/PD靶值达标率均较低,普遍存在低暴露和过暴露情况。提示应在此类患者中开展TDM,以精准调整给药剂量。
文摘目的通过对氟氧头孢体外抗菌活性数据、蛋白结合率数据、人体药代动力学参数进行药代动力学/药效学(PK/PD)相关性分析,评价不同给药方案时氟氧头孢的PK/PD参数。方法用给药间隔期药物浓度超过最低抑菌浓度的时间百分比(%f T_(>MIC))数据作为与氧氟头孢药效相关的PK/PD指标。用计算出的不同%fT_(>MIC)的目标达成分数(TA%)评估药效。对1 g q6 h,1 g q8 h,1 g q12 h,2 g q12 h氧氟头孢的PK/PD参数(%fT_(>MIC))相应值进行相互比较。最佳给药方案选择:用NONMEM软件,通过蒙特卡罗方法模拟各产生1000个患者群体的数据,考察每一个给药方案对于每一种菌株的药效。结果 1 g q12 h,1 g q8 h,1 g q6 h,输注1 h,对产超广谱β内酰胺酶(ESBL)大肠埃希菌70%fT_(>MIC)达到率分别为66.8%,93.8%和89.1%;对产ESBL肺炎克雷伯菌70%fT_(>MIC)达到率分别为62.3%,78.7%和81.8%。2 g q12 h给药,50%和70%fT_(>MIC)达到率与q8 h或q6 h类似。但更高的抗菌药效指标达成概率2.0 g q12 h给药不如1 g q8 h或1 g q6 h。对甲氧西林敏感金黄色葡萄球菌和甲氧西林敏感表皮葡萄球菌等都具有很好的PK/PD特点。结论氟氧头孢作为时间依赖性抗菌药物,无论缩短给药间隔还是延长输液时间,都可一定程度提高疗效。但与延长输注时间相比,尤以缩短给药间隔作用显著。
