目的从文献计量角度分析药代动力学/药效动力学(pharmacokinetic/pharmacodynamic,PK/PD)研究概况。方法检索Web of Science数据库,对PK/PD研究的相关情况进行整理。结果 PK/PD研究的年发文量和引文数均呈逐年递增趋势,临床研究相关杂...目的从文献计量角度分析药代动力学/药效动力学(pharmacokinetic/pharmacodynamic,PK/PD)研究概况。方法检索Web of Science数据库,对PK/PD研究的相关情况进行整理。结果 PK/PD研究的年发文量和引文数均呈逐年递增趋势,临床研究相关杂志的载文量居前。我国的发文量居全球第15位,虽然临床前研究较多,但文章的影响力不足。结论我国发表文章的质量与国际前沿研究存在较大差距,建议要加强与国际合作,以提高我国的研究水平。展开更多
目的:分析评价不同抗菌药物给药方案对产超广谱β-内酰胺酶(extended-spectrumβ-lactamases,ESBLs)细菌的抗感染效果,为制订及优化抗菌药物治疗方案提供参考。方法:回顾性统计西安市中医医院2021—2022年产ESBLs细菌培养及药敏试验结...目的:分析评价不同抗菌药物给药方案对产超广谱β-内酰胺酶(extended-spectrumβ-lactamases,ESBLs)细菌的抗感染效果,为制订及优化抗菌药物治疗方案提供参考。方法:回顾性统计西安市中医医院2021—2022年产ESBLs细菌培养及药敏试验结果。基于药动学/药效学(PK/PD)理论,利用抗菌药物PK参数及最低抑菌浓度(minimal inhibitory cocentration,MIC)进行蒙特卡洛模拟,获得不同抗菌药物给药方案治疗产ESBLs细菌的达标概率(probability of target attainment,PTA)及累积反应分数(cumulative fraction of response,CFR),选择CFR≥90%/PTA≥90%的方案为经验性/目标性治疗产ESBLs细菌的最佳方案。结果:亚胺培南0.5 g q6h和1.0 g q8h/q6h静滴3.0 h,美罗培南0.5 g/1.0 g/2.0 g q8h静滴3.0 h,厄他培南1.0 g/2.0 g q24h静滴3.0 h,替加环素50 mg/75 mg/100 mg q12h,阿米卡星20 mg·kg^(-1)q24h,哌拉西林他唑巴坦4.5 g q8h/q6h静滴3.0 h给药方案的CFR均大于90%,推荐以上方案作为产ESLBs细菌引起的血流感染的初始经验性治疗选择,其他部位感染的给药方案应根据抗菌药物的PK特点进行调整。MIC为影响抗感染疗效的主要因素,根据MIC制订给药方案时,以PTA≥90%的方案为最优治疗选择。结论:缩短时间依赖性抗菌药物的给药间隔并延长输注时间至3.0 h,增加浓度依赖性抗菌药物的给药剂量,可显著提高PTA与CFR,达到提升抗感染治疗效果的目的。展开更多
Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of bupre...Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of buprenorphine and its analgesic effect (tail flick test) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modeling in describing this relationship. Methods: After patch application, plasma concentrations of bu- prenorphine in mice were measured for 72 hours with a validated LC/MS/MS system, and the analgesic effects were assessed by tail flick test for the period of 24 hours. A modified two- compartment open model was used to explain the PK properties of BTDS, and the PD model was characterized by slow receptor binding. Results: The peak buprenorphine level in plasma was achieved at 1-24 h and the effective therapeutic drug concentration was maintained for 72 hours. BupredermTM induced prolongation of tail-flick latency in a dose and time dependent manner. Maximum analgesic effect was attained at 3-6 h and was maintained for 24 h after patch application. Counter-clockwise hysteresis between the plasma concentration and the analgesic efficacy of BTDS was observed after BupredermTM application, indicating there was a delay between plasma concentrations and the effect observed. From the developed PK-PD model, Kd values (0.69-0.82 nM) that were derived from the pharmacodynamic parameters (Kon and Koff) are similar to the reported values (Kd = 0.76 ± 0.14 nM). Good agreement between the predicted and observed values was noted for the rate of change in analgesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4 mg/patch, respectively). Conclusions: The established PK- PD model successfully described the relationship between plasma concentration of buprenorphine and its analgesic efficacy measured by the tail flick test. Our model might be useful in estimation and prediction of onset, magnitude and time course of concentration and pharmacological effects of BTDS and will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
P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracell...P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.展开更多
The increasing antimicrobial resistance has seriously threatened human health worldwide over the last three decades.This severe medical crisis and the dwindling antibiotic discovery pipeline require the development of...The increasing antimicrobial resistance has seriously threatened human health worldwide over the last three decades.This severe medical crisis and the dwindling antibiotic discovery pipeline require the development of novel antimicrobial treatments to combat life-threatening infections caused by multidrug-resistant micro-bial pathogens.However,the detailed mechanisms of action,resistance,and toxicity of many antimicrobials remain uncertain,significantly hampering the development of novel antimicrobials.Genome-scale metabolic model(GSMM)has been increasingly employed to investigate microbial metabolism.In this review,we discuss the latest progress of GSMM in antimicrobial pharmacology,particularly in elucidating the complex interplays of multiple metabolic pathways involved in antimicrobial activity,resistance,and toxicity.We also highlight the emerging areas of GSMM applications in modeling non-metabolic cellular activities(e.g.,gene expression),identi-fication of potential drug targets,and integration with machine learning and pharmacokinetic/pharmacodynamic modeling.Overall,GSMM has significant potential in elucidating the critical role of metabolic changes in antimi-crobial pharmacology,providing mechanistic insights that will guide the optimization of dosing regimens for the treatment of antimicrobial-resistant infections.展开更多
文摘目的从文献计量角度分析药代动力学/药效动力学(pharmacokinetic/pharmacodynamic,PK/PD)研究概况。方法检索Web of Science数据库,对PK/PD研究的相关情况进行整理。结果 PK/PD研究的年发文量和引文数均呈逐年递增趋势,临床研究相关杂志的载文量居前。我国的发文量居全球第15位,虽然临床前研究较多,但文章的影响力不足。结论我国发表文章的质量与国际前沿研究存在较大差距,建议要加强与国际合作,以提高我国的研究水平。
文摘目的:分析评价不同抗菌药物给药方案对产超广谱β-内酰胺酶(extended-spectrumβ-lactamases,ESBLs)细菌的抗感染效果,为制订及优化抗菌药物治疗方案提供参考。方法:回顾性统计西安市中医医院2021—2022年产ESBLs细菌培养及药敏试验结果。基于药动学/药效学(PK/PD)理论,利用抗菌药物PK参数及最低抑菌浓度(minimal inhibitory cocentration,MIC)进行蒙特卡洛模拟,获得不同抗菌药物给药方案治疗产ESBLs细菌的达标概率(probability of target attainment,PTA)及累积反应分数(cumulative fraction of response,CFR),选择CFR≥90%/PTA≥90%的方案为经验性/目标性治疗产ESBLs细菌的最佳方案。结果:亚胺培南0.5 g q6h和1.0 g q8h/q6h静滴3.0 h,美罗培南0.5 g/1.0 g/2.0 g q8h静滴3.0 h,厄他培南1.0 g/2.0 g q24h静滴3.0 h,替加环素50 mg/75 mg/100 mg q12h,阿米卡星20 mg·kg^(-1)q24h,哌拉西林他唑巴坦4.5 g q8h/q6h静滴3.0 h给药方案的CFR均大于90%,推荐以上方案作为产ESLBs细菌引起的血流感染的初始经验性治疗选择,其他部位感染的给药方案应根据抗菌药物的PK特点进行调整。MIC为影响抗感染疗效的主要因素,根据MIC制订给药方案时,以PTA≥90%的方案为最优治疗选择。结论:缩短时间依赖性抗菌药物的给药间隔并延长输注时间至3.0 h,增加浓度依赖性抗菌药物的给药剂量,可显著提高PTA与CFR,达到提升抗感染治疗效果的目的。
文摘Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of buprenorphine and its analgesic effect (tail flick test) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modeling in describing this relationship. Methods: After patch application, plasma concentrations of bu- prenorphine in mice were measured for 72 hours with a validated LC/MS/MS system, and the analgesic effects were assessed by tail flick test for the period of 24 hours. A modified two- compartment open model was used to explain the PK properties of BTDS, and the PD model was characterized by slow receptor binding. Results: The peak buprenorphine level in plasma was achieved at 1-24 h and the effective therapeutic drug concentration was maintained for 72 hours. BupredermTM induced prolongation of tail-flick latency in a dose and time dependent manner. Maximum analgesic effect was attained at 3-6 h and was maintained for 24 h after patch application. Counter-clockwise hysteresis between the plasma concentration and the analgesic efficacy of BTDS was observed after BupredermTM application, indicating there was a delay between plasma concentrations and the effect observed. From the developed PK-PD model, Kd values (0.69-0.82 nM) that were derived from the pharmacodynamic parameters (Kon and Koff) are similar to the reported values (Kd = 0.76 ± 0.14 nM). Good agreement between the predicted and observed values was noted for the rate of change in analgesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4 mg/patch, respectively). Conclusions: The established PK- PD model successfully described the relationship between plasma concentration of buprenorphine and its analgesic efficacy measured by the tail flick test. Our model might be useful in estimation and prediction of onset, magnitude and time course of concentration and pharmacological effects of BTDS and will
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。
基金the Macao Science and Technology Development Fund(No.0067/2019/A2 and No.0075/2019/AMJ)from the Macao Special Administrative Region。
文摘P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.
文摘The increasing antimicrobial resistance has seriously threatened human health worldwide over the last three decades.This severe medical crisis and the dwindling antibiotic discovery pipeline require the development of novel antimicrobial treatments to combat life-threatening infections caused by multidrug-resistant micro-bial pathogens.However,the detailed mechanisms of action,resistance,and toxicity of many antimicrobials remain uncertain,significantly hampering the development of novel antimicrobials.Genome-scale metabolic model(GSMM)has been increasingly employed to investigate microbial metabolism.In this review,we discuss the latest progress of GSMM in antimicrobial pharmacology,particularly in elucidating the complex interplays of multiple metabolic pathways involved in antimicrobial activity,resistance,and toxicity.We also highlight the emerging areas of GSMM applications in modeling non-metabolic cellular activities(e.g.,gene expression),identi-fication of potential drug targets,and integration with machine learning and pharmacokinetic/pharmacodynamic modeling.Overall,GSMM has significant potential in elucidating the critical role of metabolic changes in antimi-crobial pharmacology,providing mechanistic insights that will guide the optimization of dosing regimens for the treatment of antimicrobial-resistant infections.
