In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial re...In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.展开更多
Aim: To prospectively evaluate the acute toxicity of 3D conformal radiotherapy with dose optimization in patients with carcinoma cervix. Materials and Methods: Carcinoma cervix patients stage IIB to IIIB (n = 30) trea...Aim: To prospectively evaluate the acute toxicity of 3D conformal radiotherapy with dose optimization in patients with carcinoma cervix. Materials and Methods: Carcinoma cervix patients stage IIB to IIIB (n = 30) treated during November 2011 to May 2013 at the institution with 3D conformal chemo-radiation were included in the study. They received weekly Cisplatin 40 mg/m<sup>2</sup> for a maximum of 5 cycles. They received 46 Gy/23 fractions, 5 fractions per week of external beam radiation. In these patients dose optimization was done in order to achieve a tumor maximum dose (D<sub>max</sub>) around 105%. Various techniques were used for dose optimization which included the use of sub fields, adjusting the weightages, using wedges and the use of mixed energies. EBRT (External Beam Radiotherapy) was followed by two fractions of high dose rate intracavitary brachytherapy of 9 Gy each. Acute RTOG toxicity was assessed weekly during EBRT and 1 week post EBRT. Results: The median age of the patients was 45 (range: 30 - 55 years). All the patients completed EBRT;63.3% of the patients received all 5 cycles of chemotherapy while 26.6% of the patients received 4 cycles of chemotherapy and 10% of the patients received 3 cycles of chemotherapy. The most predominant toxicity seen was GI toxicity, diarrhea being the most common GI toxicity followed by vomiting. Neutropenia was the most common hematological toxicity. Most patients had grade 0 and grade 1 toxicity. None of the patients had grade 4 toxicity while few had grade 2 and 3 toxicity. Conclusion: 3D conformal concurrent chemo radiotherapy with D<sub>max</sub>around 105% reduces acute RTOG toxicity particularly grade 3 and 4 and improves patient compliance for concurrent chemo-radiotherapy.展开更多
Finding the optimal dose combination in two-agent dose-finding trials is challenging due to limited sample sizes and the extensive range of potential doses.Unlike traditional chemotherapy or radiotherapy,which primari...Finding the optimal dose combination in two-agent dose-finding trials is challenging due to limited sample sizes and the extensive range of potential doses.Unlike traditional chemotherapy or radiotherapy,which primarily focuses on identifying the maximum tolerated dose(MTD),therapies involving targeted and immune agents facilitate the identifica-tion of an optimal biological dose combination(OBDC)by simultaneously evaluating both toxicity and efficacy.Cur-rently,most approaches to determining the OBDC in the literature are model-based and require complex model fittings,making them cumbersome and challenging to implement.To address these challenges,we developed a novel model-as-sisted approach called uTPI-Comb.This approach refines the established utility-based toxicity probability interval design by integrating a strategically devised zone-based local and global candidate set searching strategy,which can effectively optimize the decision-making process for two-agent dose escalation or de-escalation in drug combination trials.Extensive simulation studies demonstrate that the uTPI-Comb design speeds up the dose-searching process and provides substantial improvements over existing model-based methods in determining the optimal biological dose combinations.展开更多
OBJECTIVE: To investigate the optimal dosage ratio of chlorogenic acid and gardenia glycosides in treating the rates with fatty liver disease induced by high-fat feed.METHODS: A rat model of non-alcoholic fatty liver ...OBJECTIVE: To investigate the optimal dosage ratio of chlorogenic acid and gardenia glycosides in treating the rates with fatty liver disease induced by high-fat feed.METHODS: A rat model of non-alcoholic fatty liver disease(NAFLD) was established by using a high-fat diet. According to mathematical model "uniform design", varying doses of chlorogenic acid and gardenia glycosides have been combined to form 6 medications for the treatment of NAFLD.Samples were then taken to observe pathological changes of the liver tissue(HE staining); changes in the fat metabolism pathway e.g. triglyceride(TG)and free fatty acid(FFA) content; alterations in liver function, i.e. serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST) activity; and differences in Malondialdehyde(MDA) and superoxide dismutase(SOD) content in the liver tissue. Multiple regression analysis was conducted to test the optimal dosage ratio of chlorogenic acid and gardenia glycosides.RESULTS: Fatty degeneration and vacuole-like changes of different degrees occurred in hepatic cells of the model group. Markers for fat metabolism, serum ALT and AST activities, and expression of MDA in liver tissue significantly increased, while SOD decreased. Combination of 90 mg chlorogenic acid and 90 mg Gardenia glycosides was the optimal dosage ratio of chlorogenic acid and gardenia glycosides in the treatment of rats with fatty liver induced by high-fat diet.CONCLUSION: Chlorogenic acid of 90 mg plus gardenia glycosides of 90 mg was the best combination in the treatment of fatty liver disease in rats induced by high-fat feed.展开更多
The formation of hydrogen sulfide in biofilms and sediments in sewer systems can cause severe pipe corrosions and health hazards, and requires expensive programs for its prevention. The aim of this study is to propose...The formation of hydrogen sulfide in biofilms and sediments in sewer systems can cause severe pipe corrosions and health hazards, and requires expensive programs for its prevention. The aim of this study is to propose a new control strategy and the optimal condition for sulfide elimination by intermittent nitrate dosing in sewer sediments. The study was carried out based on lab-scale experiments and batch tests using real sewer sediments. The intermittent nitrate dosing mode and the optimal control condition were investigated. The results indicated that the sulfide-intermittent-elimination strategy by nitrate dosing is advantageous for controlling sulfide accumulation in sewer sediment. The oxidation–reduction potential is a sensitive indicator parameter that can reflect the control effect and the minimum N/S（nitrate/sulfide）ratio with slight excess nitrate is necessary for optimal conditions of efficient sulfide control with lower carbon source loss. The optimal control condition is feasible for the sulfide elimination in sewer systems.展开更多
As the market competition of steel mills is severe,deoxidization alloying is an important link in the metallurgical process.To solve this problem,principal component regression analysis is adopted to reduce the dimens...As the market competition of steel mills is severe,deoxidization alloying is an important link in the metallurgical process.To solve this problem,principal component regression analysis is adopted to reduce the dimension of influencing factors,and a reasonable and reliable prediction model of element yield is established.Based on the constraint conditions such as target cost function constraint,yield constraint and non-negative constraint,linear programming is adopted to design the lowest cost batting scheme that meets the national standards and production requirements.The research results provide a reliable optimization model for the deoxidization and alloying process of steel mills,which is of positive significance for improving the market competitiveness of steel mills,reducing waste discharge and protecting the environment.展开更多
Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80--100 MeV/u carbon ions supplied by the H...Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80--100 MeV/u carbon ions supplied by the Heavy Ion Research Facility in Lanzhou （HIRFL） at the Institute of Modern Physics, Chinese Academy of Sciences since November, 2006. A passive irradiation system and a dose optimization method for radiotherapy with carbon-ion beams have been developed. Experimental verification of longitudinally therapeutic dose distributions was conducted under the condition of simulating patient treatment in the therapy terminal at HIRFL. The measured depth-dose distributions basically coincide with the expected ones. These results indicate that the irradiation system and the dose optimization method are effective in the ongoing carbon-ion radiotherapy for shallow-seated tumors at HIRFL.展开更多
Introduction:Vaccines are a cornerstone of global health,with their efficacy and safety dependent on appropriate dosage determination.Early-phase vaccination trials face significant challenges due to minimal toxicity ...Introduction:Vaccines are a cornerstone of global health,with their efficacy and safety dependent on appropriate dosage determination.Early-phase vaccination trials face significant challenges due to minimal toxicity and nonmonotonic dose response curves,creating a major obstacle in vaccine development.To address this gap,we propose a novel Bayesian phase I/II trial design for dose response curves exhibiting plateau or unimodal patterns to identify the optimal biological dose(OBD),effectively balancing efficacy and toxicity.Methods:We employ a logistic dose-efficacy design that makes dose-escalation and de-escalation decisions while simultaneously considering both efficacy and safety parameters.Extensive simulation studies evaluate the performance of this design.Results:Comparative analyses with commonly used vaccine dose-finding designs demonstrate that our method excels in identifying the optimal toxicityefficacy trade-off,offering both simplicity and accuracy.Sensitivity analyses across various prior settings confirm the robustness and efficiency of our approach.Additionally,our design provides a userfriendly framework for clinicians,with superior operating performance compared to existing designs,particularly in terms of accuracy and robustness.Discussion:Our innovative Bayesian design represents a significant advancement in addressing the inherent challenges of early-phase vaccination clinical trials,offering improved accuracy and efficacy in vaccine dosage determination.展开更多
Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administ...Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administration of doses that yield therapeutic drug concentrations at the infection site. This ensures a favorable clinical and microbiological response while avoiding antibiotic-related toxicity. Therapeutic drug monitoring (TDM) is the recommended approach for attaining these goals. However, TDM is not universally available in all intensive care units (ICUs) and for all antimicrobial agents. In the absence of TDM, healthcare practitioners need to rely on several factors to make informed dosing decisions. These include the patient's clinical condition, causative pathogen, impact of organ dysfunction (requiring extracorporeal therapies), and physicochemical properties of the antimicrobials. In this context, the pharmacokinetics of antimicrobials vary considerably between different critically ill patients and within the same patient over the course of ICU stay. This variability underscores the need for individualized dosing. This review aimed to describe the main pathophysiological changes observed in critically ill patients and their impact on antimicrobial drug dosing decisions. It also aimed to provide essential practical recommendations that may aid clinicians in optimizing antimicrobial therapy among critically ill patients.展开更多
基金Peking University Third Hospital research funding(Grant No.7476-01)
文摘In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.
文摘Aim: To prospectively evaluate the acute toxicity of 3D conformal radiotherapy with dose optimization in patients with carcinoma cervix. Materials and Methods: Carcinoma cervix patients stage IIB to IIIB (n = 30) treated during November 2011 to May 2013 at the institution with 3D conformal chemo-radiation were included in the study. They received weekly Cisplatin 40 mg/m<sup>2</sup> for a maximum of 5 cycles. They received 46 Gy/23 fractions, 5 fractions per week of external beam radiation. In these patients dose optimization was done in order to achieve a tumor maximum dose (D<sub>max</sub>) around 105%. Various techniques were used for dose optimization which included the use of sub fields, adjusting the weightages, using wedges and the use of mixed energies. EBRT (External Beam Radiotherapy) was followed by two fractions of high dose rate intracavitary brachytherapy of 9 Gy each. Acute RTOG toxicity was assessed weekly during EBRT and 1 week post EBRT. Results: The median age of the patients was 45 (range: 30 - 55 years). All the patients completed EBRT;63.3% of the patients received all 5 cycles of chemotherapy while 26.6% of the patients received 4 cycles of chemotherapy and 10% of the patients received 3 cycles of chemotherapy. The most predominant toxicity seen was GI toxicity, diarrhea being the most common GI toxicity followed by vomiting. Neutropenia was the most common hematological toxicity. Most patients had grade 0 and grade 1 toxicity. None of the patients had grade 4 toxicity while few had grade 2 and 3 toxicity. Conclusion: 3D conformal concurrent chemo radiotherapy with D<sub>max</sub>around 105% reduces acute RTOG toxicity particularly grade 3 and 4 and improves patient compliance for concurrent chemo-radiotherapy.
基金This work was supported by the Natural Science Foundation of Anhui Province(2022AH050703)the National Natural Science Foundation of China(11671375).
文摘Finding the optimal dose combination in two-agent dose-finding trials is challenging due to limited sample sizes and the extensive range of potential doses.Unlike traditional chemotherapy or radiotherapy,which primarily focuses on identifying the maximum tolerated dose(MTD),therapies involving targeted and immune agents facilitate the identifica-tion of an optimal biological dose combination(OBDC)by simultaneously evaluating both toxicity and efficacy.Cur-rently,most approaches to determining the OBDC in the literature are model-based and require complex model fittings,making them cumbersome and challenging to implement.To address these challenges,we developed a novel model-as-sisted approach called uTPI-Comb.This approach refines the established utility-based toxicity probability interval design by integrating a strategically devised zone-based local and global candidate set searching strategy,which can effectively optimize the decision-making process for two-agent dose escalation or de-escalation in drug combination trials.Extensive simulation studies demonstrate that the uTPI-Comb design speeds up the dose-searching process and provides substantial improvements over existing model-based methods in determining the optimal biological dose combinations.
基金Supported by the General Project of National Natural Science Foundation of China,Research of the Ratio Optimization between Chlorogenic Acid and Geniposide for Non-alcoholic Fatty Liver Disease,the Mechanism of Action for Epithelial-Mesenchymal Transition(No.81274155),Mechanism of Chlorogenic Acid and Geniposide for NASH by Regulating Kupffer Cells Polarization Based on Gut-liver Axis(No.81673660),the Youth Project of National Natural Science Foundation of China,Research on the mechanism of compound prescription of Chinese traditional medicine regulating endocannabinoid system in non-alcoholic steatohepatitis(No.81503529),Mechanism of treatment of nonalcoholic fatty liver disease by"HJJB"compound of Chinese traditional medicine based on insulin transduction(No.81503404)the Pilot Project of Science and Technology of Fujian Province,Study of Compound Prescription of Chinese Traditional Medicine on Fibrosis Based on Endocannabinoid System(No.2016D012)+1 种基金the TCM Project of Fujian Health Department,Clinic Research of Chinese Traditional Medicine for Nonalcoholic Fatty Liver(No.wzpw201308)the General Project of Xiamen Science and Technology Program Grant,Research of Chinese Traditional Medicine with IFNαTreatment on CHB(No.3502Z20134020)
文摘OBJECTIVE: To investigate the optimal dosage ratio of chlorogenic acid and gardenia glycosides in treating the rates with fatty liver disease induced by high-fat feed.METHODS: A rat model of non-alcoholic fatty liver disease(NAFLD) was established by using a high-fat diet. According to mathematical model "uniform design", varying doses of chlorogenic acid and gardenia glycosides have been combined to form 6 medications for the treatment of NAFLD.Samples were then taken to observe pathological changes of the liver tissue(HE staining); changes in the fat metabolism pathway e.g. triglyceride(TG)and free fatty acid(FFA) content; alterations in liver function, i.e. serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST) activity; and differences in Malondialdehyde(MDA) and superoxide dismutase(SOD) content in the liver tissue. Multiple regression analysis was conducted to test the optimal dosage ratio of chlorogenic acid and gardenia glycosides.RESULTS: Fatty degeneration and vacuole-like changes of different degrees occurred in hepatic cells of the model group. Markers for fat metabolism, serum ALT and AST activities, and expression of MDA in liver tissue significantly increased, while SOD decreased. Combination of 90 mg chlorogenic acid and 90 mg Gardenia glycosides was the optimal dosage ratio of chlorogenic acid and gardenia glycosides in the treatment of rats with fatty liver induced by high-fat diet.CONCLUSION: Chlorogenic acid of 90 mg plus gardenia glycosides of 90 mg was the best combination in the treatment of fatty liver disease in rats induced by high-fat feed.
基金supported by the National Natural Science Foundation of China (No. 50908131)the Major Science and Technology Program for Water Pollution Control and Treatment of China (No. 2011ZX07301-002)Tsinghua University Initiative Scientific Research Program (No.20121087922)
文摘The formation of hydrogen sulfide in biofilms and sediments in sewer systems can cause severe pipe corrosions and health hazards, and requires expensive programs for its prevention. The aim of this study is to propose a new control strategy and the optimal condition for sulfide elimination by intermittent nitrate dosing in sewer sediments. The study was carried out based on lab-scale experiments and batch tests using real sewer sediments. The intermittent nitrate dosing mode and the optimal control condition were investigated. The results indicated that the sulfide-intermittent-elimination strategy by nitrate dosing is advantageous for controlling sulfide accumulation in sewer sediment. The oxidation–reduction potential is a sensitive indicator parameter that can reflect the control effect and the minimum N/S（nitrate/sulfide）ratio with slight excess nitrate is necessary for optimal conditions of efficient sulfide control with lower carbon source loss. The optimal control condition is feasible for the sulfide elimination in sewer systems.
文摘As the market competition of steel mills is severe,deoxidization alloying is an important link in the metallurgical process.To solve this problem,principal component regression analysis is adopted to reduce the dimension of influencing factors,and a reasonable and reliable prediction model of element yield is established.Based on the constraint conditions such as target cost function constraint,yield constraint and non-negative constraint,linear programming is adopted to design the lowest cost batting scheme that meets the national standards and production requirements.The research results provide a reliable optimization model for the deoxidization and alloying process of steel mills,which is of positive significance for improving the market competitiveness of steel mills,reducing waste discharge and protecting the environment.
基金Supported by Century Program of Chinese Academy of Science (O506120BR0)National High Technology Research and Development Program of China (863 Program, 2006AA02Z499)
文摘Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80--100 MeV/u carbon ions supplied by the Heavy Ion Research Facility in Lanzhou （HIRFL） at the Institute of Modern Physics, Chinese Academy of Sciences since November, 2006. A passive irradiation system and a dose optimization method for radiotherapy with carbon-ion beams have been developed. Experimental verification of longitudinally therapeutic dose distributions was conducted under the condition of simulating patient treatment in the therapy terminal at HIRFL. The measured depth-dose distributions basically coincide with the expected ones. These results indicate that the irradiation system and the dose optimization method are effective in the ongoing carbon-ion radiotherapy for shallow-seated tumors at HIRFL.
基金Supported by the National Natural Science Foundation of China(Project Nos.82404383 to Mengyi Lu,82173620 and 82373690 to Yang Zhao,82204156 to Dongfang You,and 82473732 to Fang Shao).
文摘Introduction:Vaccines are a cornerstone of global health,with their efficacy and safety dependent on appropriate dosage determination.Early-phase vaccination trials face significant challenges due to minimal toxicity and nonmonotonic dose response curves,creating a major obstacle in vaccine development.To address this gap,we propose a novel Bayesian phase I/II trial design for dose response curves exhibiting plateau or unimodal patterns to identify the optimal biological dose(OBD),effectively balancing efficacy and toxicity.Methods:We employ a logistic dose-efficacy design that makes dose-escalation and de-escalation decisions while simultaneously considering both efficacy and safety parameters.Extensive simulation studies evaluate the performance of this design.Results:Comparative analyses with commonly used vaccine dose-finding designs demonstrate that our method excels in identifying the optimal toxicityefficacy trade-off,offering both simplicity and accuracy.Sensitivity analyses across various prior settings confirm the robustness and efficiency of our approach.Additionally,our design provides a userfriendly framework for clinicians,with superior operating performance compared to existing designs,particularly in terms of accuracy and robustness.Discussion:Our innovative Bayesian design represents a significant advancement in addressing the inherent challenges of early-phase vaccination clinical trials,offering improved accuracy and efficacy in vaccine dosage determination.
文摘Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administration of doses that yield therapeutic drug concentrations at the infection site. This ensures a favorable clinical and microbiological response while avoiding antibiotic-related toxicity. Therapeutic drug monitoring (TDM) is the recommended approach for attaining these goals. However, TDM is not universally available in all intensive care units (ICUs) and for all antimicrobial agents. In the absence of TDM, healthcare practitioners need to rely on several factors to make informed dosing decisions. These include the patient's clinical condition, causative pathogen, impact of organ dysfunction (requiring extracorporeal therapies), and physicochemical properties of the antimicrobials. In this context, the pharmacokinetics of antimicrobials vary considerably between different critically ill patients and within the same patient over the course of ICU stay. This variability underscores the need for individualized dosing. This review aimed to describe the main pathophysiological changes observed in critically ill patients and their impact on antimicrobial drug dosing decisions. It also aimed to provide essential practical recommendations that may aid clinicians in optimizing antimicrobial therapy among critically ill patients.
