OBJECTIVE To enhance the quality and efficiency of chlorogeninc acid by investigating the differences among the chlorogeninc acid polymorphs in bioavailability and solubility.METHODS Determinative method was used to a...OBJECTIVE To enhance the quality and efficiency of chlorogeninc acid by investigating the differences among the chlorogeninc acid polymorphs in bioavailability and solubility.METHODS Determinative method was used to analyze the solubility of chlorogeninc acid polymorphs;solid chlorogeninc acid in different forms were orally administered to the rats,and a HPLC method was established to determinate plasma lever of metabolite-acyclovir and the bioavailability was analyzed.RESULTS The indirect pharmacokinetic parameters of Chlorogeninc acid,as the metabolites of the form Ⅰ,Ⅱ,Ⅲ,were as follows:cmaxwas 0.37,0.34 and 0.44mg·L-1,respectively;AUC0→twas 0.71,0.76 and 0.79mg·L-1·h,respectively.CONCLUSION The solubility of form Ⅲ was larger than the other forms′.The solubility of Chlorogeninc acid polymorphs:form Ⅰ,form Ⅱ,form Ⅲ were merely the same,there was no statistically significant difference in pharmacokinetic parameters among these three forms.展开更多
OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage,and to provide an experimental basis...OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage,and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single,subcutaneous doses of PEG30-rhG-CSF at 100,200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg.PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay(ELISA).WBC,ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation.Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis so ware.RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows:the mean elimination half-life(t1/2ke) was 40.6 h(33.5~45.4 h);the mean time to reach peak concentration(Tmax) was 19.2 h(11.7~24.0 h);the drug clearance from the serum(CL) was decreased with increasing doses;the peak concentration(Cmax) and the area under the serum concentration-time curve(AUC) were increased with increasing doses.For PEG20-rhG-CSF,the half-life was shorter(12 h) and Tmax was achieved much earlier(10 h) relative to PEG30-rhG-CSF.The AUC of PEG30-rhG-CSF was much greater than that of PEG20-rhG-CSF,and the relative bioavailability with a subcutaneous injection was 158.7%.Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute neutrophil count(ANC).The time to reach ANCmax(ANCTmax) was 72 h.The maximum observed absolute neutrophil counts(ANCmax) and the area over the baseline effect curve(AOBEC) was increased with increasing doses.The effect-elimination half-life(t1/2E) ranged from 60 h to 80 h a er subcutaneous administration.The PLT count was slightly elevated 8~12 h a er s.c.injection,and declined a er 24 h.CONCLUSION The mean elimination half-life of PEG30-rhG-CSF was longer than that of PEG20-rhG-CSF at the same dose,and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF,including Cmax,ANCmax,AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.展开更多
目的分离铜绿假单胞菌噬菌体,比较其形态、裂菌特性并测定其裂解谱,根据裂解谱筛选出裂解百分比最高的噬菌体,并测定其最佳感染复数和体内代谢动力学等基本生物学特性。方法取兰州市区污水样品经0.22μm滤膜过滤,用双层琼脂平板培养法...目的分离铜绿假单胞菌噬菌体,比较其形态、裂菌特性并测定其裂解谱,根据裂解谱筛选出裂解百分比最高的噬菌体,并测定其最佳感染复数和体内代谢动力学等基本生物学特性。方法取兰州市区污水样品经0.22μm滤膜过滤,用双层琼脂平板培养法分离、纯化铜绿假单胞菌噬菌体并测定其裂解谱;纯化后的噬菌体进行扫描电镜观察;评估裂解谱后筛选出裂解百分比最高的为PaP106,分别按照感染复数(MOI)=10^(-1)、10^(-2)、10^(-3)、10^(-4)、10^(-5)、10^(-6)、10^(-7)比例加入PaP106和铜绿假单胞菌共培养后测定噬菌体滴度,确定其最佳感染复数;不同途径(腹腔、肌肉、皮下)给小鼠注射1×10^(10)pfu/m L PaP106 100μL,分别于0.5、1、3、6、12、24、36 h测定小鼠血液、肝脏、脾脏组织中噬菌体的浓度,分析噬菌体体内代谢动力学变化。结果共分离到6株形态不同的铜绿假单胞菌噬菌体,对铜绿假单胞菌耐药菌株的裂解百分比为25%—75%,其中PaP106噬菌体对铜绿假单胞菌耐药菌株的裂解百分比最高(75%),PaP106噬菌体的最佳感染复数为1×10^(-6),腹腔注射PaP106噬菌体后,其在血液、肝脏、脾脏的达峰时间短于皮下注射和肌肉注射途径。结论在分离得到的6株铜绿假单胞菌噬菌体中,PaP106噬菌体裂解性强、裂解谱宽,腹腔注射噬菌体后血液、肝脏、脾脏的分布及达峰时间最快,为今后临床治疗感染多重耐药铜绿假单胞菌提供了理论基础。展开更多
In liver transplantation, the efficacy of mycophenolate mofetil(MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid(MPA) has not been fully accepted in li...In liver transplantation, the efficacy of mycophenolate mofetil(MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid(MPA) has not been fully accepted in liver transplantation as no long-term prospective study of concentration controlled vs fixed-dose prescribing of MMF has been done. This review addressed MPA measurement, pharmacokinetic variability and reasons of this variation, exposure related to acute rejection and MMF-associated side effects in liver transplant recipients. Limited sampling strategies to predict MPA area under the concentration-time curve have also been described, and the value of clinical use needs to be investigated in future. The published data suggested that a fixed-dosage MMF regimen might not be suitable and monitoring of MPA exposure seems helpful in various clinical settings of liver transplantation.展开更多
OBJECTIVE To explain the high inter-individual variability and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride,a popula⁃tion pharmacokinetic model in Chinese pa...OBJECTIVE To explain the high inter-individual variability and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride,a popula⁃tion pharmacokinetic model in Chinese patients with schizophrenia was built based on therapeu⁃tic drug monitoring data to guide individualized therapy.METHODS Plasma concentration data(330 measurements from 121 patients)were ana⁃lyzed using a nonlinear mixed-effects model⁃ing approach with first-order conditional estima⁃tion with interaction(FOCE I).The concentra⁃tions of amisulpride were detected by HPLC-MS/MS.Age,weight,sex,combination medication history and renal function status were evaluated as main covariates.The model was internally val⁃idated using goodness-of-fit,bootstrap and nor⁃malized prediction distribution error.Recom⁃mended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model.RESULTS A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentra⁃tion in Chinese patients with schizophrenia.The population estimates of the apparent volume of distribution(V/F)and apparent clearance(CL/F)were 12.7 L and 1.12 L·h-1,respectively.Age sig⁃nificantly affected the clearance of amisulpride and the final model was as follow:CL/F=1.04×(AGE/32)-0.624(L·h-1).To avoid exceeding the lab⁃oratory alert level(640μg·L-1),the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg per day for patients aged 60 years,800 mg per day for those aged 40 years and 1200 mg per day for those aged 20 years,respectively.CON⁃CLUSION Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions.The model can be used as a suitable tool for designing individual⁃ized therapy for Chinese patients with schizo⁃phrenia.展开更多
目的探讨通过酮洛芬(KP)代谢参数的变化分析肝脏功能的可能性。方法以KP为工具药,用四氯化碳(CCl_4)和α-萘异硫氰酸酯(ANIT)建立急性肝损伤大鼠模型。体内实验,KP 20 mg·kg^(-1)iv后,测定大鼠血浆、胆汁中KP及其Ⅱ相代谢物酮洛芬...目的探讨通过酮洛芬(KP)代谢参数的变化分析肝脏功能的可能性。方法以KP为工具药,用四氯化碳(CCl_4)和α-萘异硫氰酸酯(ANIT)建立急性肝损伤大鼠模型。体内实验,KP 20 mg·kg^(-1)iv后,测定大鼠血浆、胆汁中KP及其Ⅱ相代谢物酮洛芬葡萄糖醛酸结合物(S-KPG和R-KPG)。体外微粒体孵育实验,测定KP葡萄糖醛酸化反应v_(max)和K_m。结果体内实验结果显示,与对照组相比,CCl_4肝损伤模型大鼠KPG累计胆排泄率降低[(54±18)% vs (90±7)%],ANIT肝损伤模型大鼠的KPG胆排泄几乎完全被抑制[(4.9±2.0)%]。与对照组比,CCl_4和ANIT肝损伤模型组KP药动学参数lgAUC_(0~∞)增加[(5.26±0.19),(5.05±0.10) vs (4.67±0.07)]、~t1/2β延长[(284.2±150.0),(129.0±37.0)min vs (67.8±21.7)min]、清除率降低[(0.046±0.019),(0.080±0.011)mL·min^(-1) vs (0.169±0.026)mL·min^(-1)],血浆KPG浓度明显升高。与对照组比较,ANIT肝损伤模型组血浆S-KPG的AUC_(0~∞)增高了约10倍。微粒体孵育试验表明,与对照组比,CCl_4和ANIT肝损伤模型组大鼠肝脏葡萄糖醛酸转移酶活性有轻至中度降低,v_(max):(0.9±0.5),(1.1±0.6)mmol·g^(-1)·min^(-1) vs (2.9±0.9)mmol·g^(-1)·min^(-1);K_m:(6.8±1.6),(5.4±1.5)mmol·L^(-1) vs (13.6±1.2)mmol·L^(-1)。结论急性肝损伤时KP药代动力学参数发生改变,说明可以通过考察KP的动力学参数的变化,尤其是lgAUC_(0~∞),t_(1/2β),清除率和KPGs累计胆排泄率,来反映肝功能情况。展开更多
To study the bioequivalence of Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets, a randomized cross over study was conducted in 18 healthy volunteers. A single oral dose of 1000 mg Clav ulanate Pot...To study the bioequivalence of Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets, a randomized cross over study was conducted in 18 healthy volunteers. A single oral dose of 1000 mg Clav ulanate Potassium and Amoxicillin (1:7) dispersible tablets (Tested formulation, T) or Augmentin syrup (Reference formulation, R). Concentrations in plasma were determined with high performance liquid chromatography. The main paramaters of T were: for Clavulanate Potassium and Amoxicillin, C max : 2.46±1.11 μg/m l and 18.81±7.26 μg/ml, T max : 1.12±0.23h and 1.30±0.34h, AUC (0 - 6 h) : 5.18±2.24 μg·h/ml and 45.09±14.53 μg·h/ml, t 1/2 : 1.43±0.44 h and 1.09±0.22 h., respectively. The relative bioavailability of T to R were 9 6.5±19.2 % and 98.4±26.1 % , respectively. Statistical analysis showed that th e two formulations were bioequivalent.展开更多
基金The project supported by the Ministry of Science and Technology of China(2007FY130100)the 12th Five-Year Plan project(2012ZX09301002-001-013)
文摘OBJECTIVE To enhance the quality and efficiency of chlorogeninc acid by investigating the differences among the chlorogeninc acid polymorphs in bioavailability and solubility.METHODS Determinative method was used to analyze the solubility of chlorogeninc acid polymorphs;solid chlorogeninc acid in different forms were orally administered to the rats,and a HPLC method was established to determinate plasma lever of metabolite-acyclovir and the bioavailability was analyzed.RESULTS The indirect pharmacokinetic parameters of Chlorogeninc acid,as the metabolites of the form Ⅰ,Ⅱ,Ⅲ,were as follows:cmaxwas 0.37,0.34 and 0.44mg·L-1,respectively;AUC0→twas 0.71,0.76 and 0.79mg·L-1·h,respectively.CONCLUSION The solubility of form Ⅲ was larger than the other forms′.The solubility of Chlorogeninc acid polymorphs:form Ⅰ,form Ⅱ,form Ⅲ were merely the same,there was no statistically significant difference in pharmacokinetic parameters among these three forms.
基金National High Technology Research and Development Program of China(No.2007BAI14IB04)Major State Basic Research Development Program(No.2004CB518902)
文摘OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage,and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single,subcutaneous doses of PEG30-rhG-CSF at 100,200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg.PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay(ELISA).WBC,ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation.Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis so ware.RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows:the mean elimination half-life(t1/2ke) was 40.6 h(33.5~45.4 h);the mean time to reach peak concentration(Tmax) was 19.2 h(11.7~24.0 h);the drug clearance from the serum(CL) was decreased with increasing doses;the peak concentration(Cmax) and the area under the serum concentration-time curve(AUC) were increased with increasing doses.For PEG20-rhG-CSF,the half-life was shorter(12 h) and Tmax was achieved much earlier(10 h) relative to PEG30-rhG-CSF.The AUC of PEG30-rhG-CSF was much greater than that of PEG20-rhG-CSF,and the relative bioavailability with a subcutaneous injection was 158.7%.Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute neutrophil count(ANC).The time to reach ANCmax(ANCTmax) was 72 h.The maximum observed absolute neutrophil counts(ANCmax) and the area over the baseline effect curve(AOBEC) was increased with increasing doses.The effect-elimination half-life(t1/2E) ranged from 60 h to 80 h a er subcutaneous administration.The PLT count was slightly elevated 8~12 h a er s.c.injection,and declined a er 24 h.CONCLUSION The mean elimination half-life of PEG30-rhG-CSF was longer than that of PEG20-rhG-CSF at the same dose,and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF,including Cmax,ANCmax,AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.
文摘目的分离铜绿假单胞菌噬菌体,比较其形态、裂菌特性并测定其裂解谱,根据裂解谱筛选出裂解百分比最高的噬菌体,并测定其最佳感染复数和体内代谢动力学等基本生物学特性。方法取兰州市区污水样品经0.22μm滤膜过滤,用双层琼脂平板培养法分离、纯化铜绿假单胞菌噬菌体并测定其裂解谱;纯化后的噬菌体进行扫描电镜观察;评估裂解谱后筛选出裂解百分比最高的为PaP106,分别按照感染复数(MOI)=10^(-1)、10^(-2)、10^(-3)、10^(-4)、10^(-5)、10^(-6)、10^(-7)比例加入PaP106和铜绿假单胞菌共培养后测定噬菌体滴度,确定其最佳感染复数;不同途径(腹腔、肌肉、皮下)给小鼠注射1×10^(10)pfu/m L PaP106 100μL,分别于0.5、1、3、6、12、24、36 h测定小鼠血液、肝脏、脾脏组织中噬菌体的浓度,分析噬菌体体内代谢动力学变化。结果共分离到6株形态不同的铜绿假单胞菌噬菌体,对铜绿假单胞菌耐药菌株的裂解百分比为25%—75%,其中PaP106噬菌体对铜绿假单胞菌耐药菌株的裂解百分比最高(75%),PaP106噬菌体的最佳感染复数为1×10^(-6),腹腔注射PaP106噬菌体后,其在血液、肝脏、脾脏的达峰时间短于皮下注射和肌肉注射途径。结论在分离得到的6株铜绿假单胞菌噬菌体中,PaP106噬菌体裂解性强、裂解谱宽,腹腔注射噬菌体后血液、肝脏、脾脏的分布及达峰时间最快,为今后临床治疗感染多重耐药铜绿假单胞菌提供了理论基础。
文摘In liver transplantation, the efficacy of mycophenolate mofetil(MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid(MPA) has not been fully accepted in liver transplantation as no long-term prospective study of concentration controlled vs fixed-dose prescribing of MMF has been done. This review addressed MPA measurement, pharmacokinetic variability and reasons of this variation, exposure related to acute rejection and MMF-associated side effects in liver transplant recipients. Limited sampling strategies to predict MPA area under the concentration-time curve have also been described, and the value of clinical use needs to be investigated in future. The published data suggested that a fixed-dosage MMF regimen might not be suitable and monitoring of MPA exposure seems helpful in various clinical settings of liver transplantation.
文摘OBJECTIVE To explain the high inter-individual variability and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride,a popula⁃tion pharmacokinetic model in Chinese patients with schizophrenia was built based on therapeu⁃tic drug monitoring data to guide individualized therapy.METHODS Plasma concentration data(330 measurements from 121 patients)were ana⁃lyzed using a nonlinear mixed-effects model⁃ing approach with first-order conditional estima⁃tion with interaction(FOCE I).The concentra⁃tions of amisulpride were detected by HPLC-MS/MS.Age,weight,sex,combination medication history and renal function status were evaluated as main covariates.The model was internally val⁃idated using goodness-of-fit,bootstrap and nor⁃malized prediction distribution error.Recom⁃mended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model.RESULTS A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentra⁃tion in Chinese patients with schizophrenia.The population estimates of the apparent volume of distribution(V/F)and apparent clearance(CL/F)were 12.7 L and 1.12 L·h-1,respectively.Age sig⁃nificantly affected the clearance of amisulpride and the final model was as follow:CL/F=1.04×(AGE/32)-0.624(L·h-1).To avoid exceeding the lab⁃oratory alert level(640μg·L-1),the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg per day for patients aged 60 years,800 mg per day for those aged 40 years and 1200 mg per day for those aged 20 years,respectively.CON⁃CLUSION Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions.The model can be used as a suitable tool for designing individual⁃ized therapy for Chinese patients with schizo⁃phrenia.
文摘目的探讨通过酮洛芬(KP)代谢参数的变化分析肝脏功能的可能性。方法以KP为工具药,用四氯化碳(CCl_4)和α-萘异硫氰酸酯(ANIT)建立急性肝损伤大鼠模型。体内实验,KP 20 mg·kg^(-1)iv后,测定大鼠血浆、胆汁中KP及其Ⅱ相代谢物酮洛芬葡萄糖醛酸结合物(S-KPG和R-KPG)。体外微粒体孵育实验,测定KP葡萄糖醛酸化反应v_(max)和K_m。结果体内实验结果显示,与对照组相比,CCl_4肝损伤模型大鼠KPG累计胆排泄率降低[(54±18)% vs (90±7)%],ANIT肝损伤模型大鼠的KPG胆排泄几乎完全被抑制[(4.9±2.0)%]。与对照组比,CCl_4和ANIT肝损伤模型组KP药动学参数lgAUC_(0~∞)增加[(5.26±0.19),(5.05±0.10) vs (4.67±0.07)]、~t1/2β延长[(284.2±150.0),(129.0±37.0)min vs (67.8±21.7)min]、清除率降低[(0.046±0.019),(0.080±0.011)mL·min^(-1) vs (0.169±0.026)mL·min^(-1)],血浆KPG浓度明显升高。与对照组比较,ANIT肝损伤模型组血浆S-KPG的AUC_(0~∞)增高了约10倍。微粒体孵育试验表明,与对照组比,CCl_4和ANIT肝损伤模型组大鼠肝脏葡萄糖醛酸转移酶活性有轻至中度降低,v_(max):(0.9±0.5),(1.1±0.6)mmol·g^(-1)·min^(-1) vs (2.9±0.9)mmol·g^(-1)·min^(-1);K_m:(6.8±1.6),(5.4±1.5)mmol·L^(-1) vs (13.6±1.2)mmol·L^(-1)。结论急性肝损伤时KP药代动力学参数发生改变,说明可以通过考察KP的动力学参数的变化,尤其是lgAUC_(0~∞),t_(1/2β),清除率和KPGs累计胆排泄率,来反映肝功能情况。
文摘To study the bioequivalence of Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets, a randomized cross over study was conducted in 18 healthy volunteers. A single oral dose of 1000 mg Clav ulanate Potassium and Amoxicillin (1:7) dispersible tablets (Tested formulation, T) or Augmentin syrup (Reference formulation, R). Concentrations in plasma were determined with high performance liquid chromatography. The main paramaters of T were: for Clavulanate Potassium and Amoxicillin, C max : 2.46±1.11 μg/m l and 18.81±7.26 μg/ml, T max : 1.12±0.23h and 1.30±0.34h, AUC (0 - 6 h) : 5.18±2.24 μg·h/ml and 45.09±14.53 μg·h/ml, t 1/2 : 1.43±0.44 h and 1.09±0.22 h., respectively. The relative bioavailability of T to R were 9 6.5±19.2 % and 98.4±26.1 % , respectively. Statistical analysis showed that th e two formulations were bioequivalent.