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
In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball ...In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball software combining PK and PD parameters with 10000 simulation runs to calculate the probability of target attainment(PTA)and cumulative fraction of response(CFR)for the seven clinically common dosing regimens of ceftriaxone(1 g qd,1.5 g qd,1 g bid,2 g qd,1 g tid,1.5 g bid,and 2 g bid).A%fT≥50 as the target value expected to achieve satisfactory clinical efficacy and a dosing regimen with an obtained CFR≥90%or the ability to achieve the highest PTA was used as a reasonable choice for empirical antimicrobial therapy,i.e.the clinically optimal regimen.All eight pathogenic bacteria had a CFR>90%when the dosing regimen was 2 g bid and 1 g tid,seven pathogenic bacteria had a CFR>90%when the dosing regimen was 1 g bid and 1.5 g bid,except for Pseudomonas aeruginosa,and all pathogenic bacteria had a CFR<90%when the dosing regimen was 1 g qd and 1.5 g qd.The dosing regimens of 2 g bid and 1 g tid were effective against all eight pathogenic bacteria infections,and 1 g bid and 1.5 g bid dosing regimens were effective against the other seven pathogenic bacteria except for Pseudomonas aeruginosa.展开更多
目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积...目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积反应分数(CFR)。结果奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌(抑菌靶值下模拟),都能达到CFR>90%;对于金黄色葡萄球菌(杀菌靶值下模拟),仅600 mg po q24h和多剂量C组(负荷剂量450 mg po q12h,维持剂量450 mg poq24h)达到CFR>90%;但对大肠埃希菌,所有给药方案的CFR均不达标。结论奥马环素的说明书推荐给药方案(负荷剂量200 mg iv,维持剂量300 mg po q24h)对肺炎链球菌、金黄色葡萄球菌有较好的治疗效果;但对大肠埃希菌,6种给药方案均达不到预期疗效。展开更多
Peridynamics(PD)is an effective method for simulating the spontaneous initiation and propagation of tensile cracks in materials.However,it faces great challenges in simulating compression-shear cracking of geomaterial...Peridynamics(PD)is an effective method for simulating the spontaneous initiation and propagation of tensile cracks in materials.However,it faces great challenges in simulating compression-shear cracking of geomaterials due to the lack of efficient contact-friction models.This paper introduces an original contact-friction model that leverages twin mesh and potential function principles within PD to model rock cracking under tensile and compressive stresses.The contact detection algorithm,based on space segmentation axis-aligned bounding box(AABB)tree data structure,is used to address the significant challenge of highly efficient contact detection in compression and shear problems.In this method,the twin mesh and potential function are utilized to quantify contact detection and contact degree,as well as friction behavior.This is in contrast to the distance and circular contact area model,which lacks physical significance in the classical PD method.As demonstrated by the tests on specimens containing cracks,the proposed model can capture 8 types of secondary fractures,reduce the contact detection error by about 29%e56%,and increase the contact retrieval efficiency by over 1600 times compared to the classic PD models.This significantly enhances the capability of PD to simulate the initiation,expansion,and coalescence of intricate compression-shear cracks.展开更多
Metal nanoclusters(MNCs)possess distinct chemical properties due to their diverse electronic structures.As a class of promising model catalysts,it is of importance to explore the relationship between their structures ...Metal nanoclusters(MNCs)possess distinct chemical properties due to their diverse electronic structures.As a class of promising model catalysts,it is of importance to explore the relationship between their structures and properties.However,it is still challenging to get highly active and stable MNCs as surface ligands can hinder their activities,while a complete lack of surface ligand protection can lead to instability.To address this concern,here a series of Pd_(6)nanoclusters(NCs)with varying ligand amounts were synthesized by using Pd_(6)(SC_(6)(C_(2))H_(17))_(12)as precursor and single-walled carbon nanotube(s-CNT)as carrier through treating the composite at different temperatures and times.展开更多
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.
基金2019 Second Hospital of Hebei Medical University Pro ject(Grant No.2h2019042)。
文摘In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball software combining PK and PD parameters with 10000 simulation runs to calculate the probability of target attainment(PTA)and cumulative fraction of response(CFR)for the seven clinically common dosing regimens of ceftriaxone(1 g qd,1.5 g qd,1 g bid,2 g qd,1 g tid,1.5 g bid,and 2 g bid).A%fT≥50 as the target value expected to achieve satisfactory clinical efficacy and a dosing regimen with an obtained CFR≥90%or the ability to achieve the highest PTA was used as a reasonable choice for empirical antimicrobial therapy,i.e.the clinically optimal regimen.All eight pathogenic bacteria had a CFR>90%when the dosing regimen was 2 g bid and 1 g tid,seven pathogenic bacteria had a CFR>90%when the dosing regimen was 1 g bid and 1.5 g bid,except for Pseudomonas aeruginosa,and all pathogenic bacteria had a CFR<90%when the dosing regimen was 1 g qd and 1.5 g qd.The dosing regimens of 2 g bid and 1 g tid were effective against all eight pathogenic bacteria infections,and 1 g bid and 1.5 g bid dosing regimens were effective against the other seven pathogenic bacteria except for Pseudomonas aeruginosa.
文摘目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积反应分数(CFR)。结果奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌(抑菌靶值下模拟),都能达到CFR>90%;对于金黄色葡萄球菌(杀菌靶值下模拟),仅600 mg po q24h和多剂量C组(负荷剂量450 mg po q12h,维持剂量450 mg poq24h)达到CFR>90%;但对大肠埃希菌,所有给药方案的CFR均不达标。结论奥马环素的说明书推荐给药方案(负荷剂量200 mg iv,维持剂量300 mg po q24h)对肺炎链球菌、金黄色葡萄球菌有较好的治疗效果;但对大肠埃希菌,6种给药方案均达不到预期疗效。
基金supported by the National Natural Science Foundation of China(Grant No.52278333)the China Scholarship Council(CSC)and the Science and Technology Department of Liaoning Province(Grant No.2024JH2/102500069).
文摘Peridynamics(PD)is an effective method for simulating the spontaneous initiation and propagation of tensile cracks in materials.However,it faces great challenges in simulating compression-shear cracking of geomaterials due to the lack of efficient contact-friction models.This paper introduces an original contact-friction model that leverages twin mesh and potential function principles within PD to model rock cracking under tensile and compressive stresses.The contact detection algorithm,based on space segmentation axis-aligned bounding box(AABB)tree data structure,is used to address the significant challenge of highly efficient contact detection in compression and shear problems.In this method,the twin mesh and potential function are utilized to quantify contact detection and contact degree,as well as friction behavior.This is in contrast to the distance and circular contact area model,which lacks physical significance in the classical PD method.As demonstrated by the tests on specimens containing cracks,the proposed model can capture 8 types of secondary fractures,reduce the contact detection error by about 29%e56%,and increase the contact retrieval efficiency by over 1600 times compared to the classic PD models.This significantly enhances the capability of PD to simulate the initiation,expansion,and coalescence of intricate compression-shear cracks.
基金financially supported by the Natural Science Foundation of Guangxi,China(Nos.2019GXNSFGA245003 and 2021GXNSFBA220058)the National Natural Science Foundation of China(Nos.22272036 and 22362008)+2 种基金Guangxi Technology Base and Talent Subject,China(GUIKE AD23026272)Guangxi Normal University Research Grant,China(No.2022TD)Innovation Project of Guangxi Graduate Education(No.XYCSR2023018)。
文摘Metal nanoclusters(MNCs)possess distinct chemical properties due to their diverse electronic structures.As a class of promising model catalysts,it is of importance to explore the relationship between their structures and properties.However,it is still challenging to get highly active and stable MNCs as surface ligands can hinder their activities,while a complete lack of surface ligand protection can lead to instability.To address this concern,here a series of Pd_(6)nanoclusters(NCs)with varying ligand amounts were synthesized by using Pd_(6)(SC_(6)(C_(2))H_(17))_(12)as precursor and single-walled carbon nanotube(s-CNT)as carrier through treating the composite at different temperatures and times.
