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AIM: To establish a method for quantitation of cefepime and avibactam in M-H broth, and applicated in the in vitro dynamic PK/PD model. METHODS: The cefepime was also determined using the high-performance liquid chromatography method (HPLC), the avibactam was also determined using the liquid chromatography-mass spectrometry (LC-MS/MS), an in vitro dynamic PK/PD model was established to study the PK/PD relationship of cefepime/avibactam against carbapenem resistant Klebsiella pneumoniae (CRKP). RESULTS: The linear ranges of cefepime and avibactam were good at (0.5-20) and (0.1-25) μg/mL (r=0.999), and the lower limit concentrations were 0.5 and 0.1 μg/mL. The extraction recoveries of cefepime and avibactam in M-H broth were 88.0%-101.7% and 90.9%-95.2%, the relative standard deviation of intra-day precision and inter-day precision were less than 5.2%. The concentration-time curves were well simulated by the PK/PD model. All observed concentrations in each experiment were in the range of 20% of the targeted values. For the CRKP of MIC=8 μg/mL and MIC=16 μg/mL, the colony decreased to 2.783Log10 CFU/mL and 1.325Log10 CFU/mL at the cefepime/avibactam 2.5 g q8 h administration after 24 h. CONCLUSION: The determination method of cefepime and avibactam in broth established in this study has high sensitivity and good stability. For the CRKP with MIC≤8 μg/mL,cefepime/avibactam showed that good anti-CRKP activity under routine administration in vitro dynamic PK/PD model.
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AIM: To provide reference for clinical application of warfarin PPK/PD model, the prediction accuracy of warfarin PPK/PD model and 6 dose models established by multiple linear regression were compared. METHODS: Clinical data of inpatients who took warfarin tablets for oral anticoagulant therapy in our hospital were collected, and the predictive values were simulated by PPK/PD model and other 6 models, respectively. SPSS 23.0 software was used for paired t-test of measured value and predicted value. MAE and percentage of prediction deviation were used to evaluate the results, and the prediction deviation box-plot was drawn to compare the total data, different dose groups and different genotypes. RESULTS: A total of 50 patients were included in the study. Among 7 models, only PPK/PD model, Wen et al., and Du Liping et al.'s model had no statistical difference in predicted values and measured values (P>0.05). The prediction accuracy of PPK/PD model was higher among the total data, low and medium doses, and patients with different genotypes.The prediction accuracy of Wen et al. 's model and Li Chuanbao et al.'s model was higher in the high-dose group. CONCLUSION: The PPK/PD model of warfarin has good clinical prediction performance, which is expected to provide reference for accurate administration of warfarin.
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In recent years， the role of quantitative pharmacological models in applicable population of drugs and dose optimization has been widely recognized. In order to improve the efficiency of clinical development and optimize clinical rational drug use， quantitative pharmacological models are being gradually introduced into the research of traditional Chinese medicine （TCM）. There are various types of quantitative pharmacological models， among which the following three models are commonly used：①Population pharmacokinetic （PPK） model， which is mainly used to explore the pharmacokinetic characteristics in different populations.②Pharmacokinetic-pharmacodynamic （PK-PD） model， which is used to reveal the internal relationship among dose， time and efficacy. ③PPK-PD model， which integrates both the characteristics of PPK model and PK-PD model. The paper summarizes the application of the above three models in TCM， and extracts the main ideas and methods of TCM model research， in order to provide reference for clinical research and rational use of TCM.
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Objective: To investigate the pharmacokinetic and pharmacodynamic changes of Yangyin Tongnao Granules (YTG) in cerebral ischemia reperfusion rats after the compatibility of main effective parts (total alkaloids, total flavonoids, total saponins and total phenolic acids). Methods: By using the orthogonal design to research the main effective parts of YTG, nine different dosage ratios combinations were formed, which were used for oral administration in cerebral ischemia reperfusion rats. High performance liquid chromatography-diode array detector (HPLC-DAD) was used to determine the concentration of puerarin, ferulic acid, and ligustrazine in rat plasma at different time points. The non-compartmental model was used to fit the pharmacokinetic parameters by Drug and Statistics (DAS) 3.2.6 software. The total quantum statistical moment analysis method and comprehensive evaluation method were used to evaluate the total pharmacokinetic characteristics. Meanwhile, the content of superoxide dismutase (SOD) and catalase (CAT) were determined by enzyme-linked immunosorbent assay (ELISA) kits. Finally, the PK-PD model and the quantitative equations between drug concentration and efficacy were obtained. Results: The pharmacokinetic characteristics of puerarin, ferulic acid and ligustrazine in cerebral ischemia-reperfusion rats were different. Total statistical moment and comprehensive score study showed that different combinations had different effects on ACUT, mean retention time (MRT), and comprehensive evaluation. The effective parts inhibited the reduction of oxidation indexes such as SOD and CAT. Sigmoid-Emax models were adopted in all PK-PD models, and the fitting results had a good correlation with the measured data. The R values were more than 0.85. Conclusion: Compatibility of YTG activity parts had a certain effect on their pharmacokinetic behaviors and antioxidation in model rats. The total quantum statistical moment analysis and comprehensive evaluation method can be used to study the pharmacokinetics of multi-component traditional Chinese medicine prescriptions. PK-PD model could be used to predict and evaluate the correlation between pharmacokinetics and pharmacodynamics of traditional Chinese medicine prescriptions.
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Objective: To establish a pharmacokinetic (PK)-pharmacodynamic (PD) model of Periploca forrestii. Methods: The right hindfoot footpad of rats were 0.1 mL complete Freund's Adjuvant (CFA) to establish adjuvant arthritis (AA) rat model. Rats were ig P. forrestii extract (87 g/kg, twice a day for 14 d) and blood were collected via tail vein at 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after the last administration. The concentrations of 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid in plasma samples were detected by HPLC-mass spectrometry (HPLC-MS/MS) to obtain the drug concentration-time curve. The level of interleukin-1β (IL-1β), rheumatoid factor (RF), tumor necrosis factor-α (TNF-α) in plasma samples were determined by kit to obtain the time-effect curve. WinNonLin software was used to fit the PK parameters of P. forrestii, and the time-effect relationship was fitted to obtain the PD parameters. According to the PD parameters, the PK-PD model of P. forrestii was established. Results: The PK-PD model of P. forrestii according to the WinNonLin software was fitted in accordance with the Inhibitory Effect Sigmoid E0 model, in which the blood concentrations of 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid could be calculated based on the potency values, and the potency values could be calculated based on the blood concentrations. Conclusion: There was a correlation between the concentrations of IL-1β, RF, TNF-α and 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid and 5-O-caffeoylquinic acid. These three components in P. forrestii extract could inhibit the secretion of IL-1β, RF and TNF-α to treat rheumatiod arthritis.
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Xenograft mice are preclinical animal models of tumors and are widely utilized in anti-tumor research. PK/PD modeling of anti-tumor agents is an approach that can capture the time profile of the "dose-plasma concentration-biomarker level-tumor volume" process based on experimental data from xenograft mice using a non-linear mixed-effect model. PK/PD modeling can help optimize the dosing regimen for anti-tumor therapy, evaluate any synergistic effect and help identify an optimal schedule for combination therapy, as well as providing a preliminary estimate of a drug's efficacy and anti-tumor potency in the human body. PK/PD modeling can also help by quantitatively explaining the mechanism of the tumor-inhibitory effect as indicated by changes in biomarker levels after a drug acts on its target. This article provides a systematic summary of the background, application range, and limitations of the mainstream anti-tumor agent PK/PD models. Recent advances in model structure development are reviewed in detail. Finally, we discuss promising applications of PK/PD models in anti-tumor medicine development from the perspective of a drug's mechanism of action, optimization of combination therapy schedules, and their clinical translation.
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Studies on the effective material basis of Chinese materia medica (CMM), which is critical for clarifying the mechanism of action and control quality. The main research methods on the effective material basis of CMM were reviewed through consulting relevant literature in this paper. It mainly includes the serum pharmaceutical chemistry, spectrum-effect and PK/PD model research.
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In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.
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Objective To investigate the alterations of tight junction proteins in duodenal mucosa from 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease(PD) model. Methods Rats were subjected with 6-OHDA in bilateral substantia nigra (SN) as PD model. The location and quantitative detecting techniques inclu-ding immunohisto- chemistry and western blotting were used to determine the expressions and alterations of tight junction proteins (claudin-1, occludin, ZO-1). Results Claudin-1, occludin and ZO-1 were highly expressed in the duodenal mucosa of PD models, where the expressions of occluding (P<0.001) and ZO-1 (P<0.001) were much lower, while the expression of claudin-1 had no alteration. Conclusions The down-regulated expres-sion of occludin and ZO-1 was detected in duodenal mucosa of PD models, which might be related to duodenal ulcer in PD.
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In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.
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Objective To investigate the alterations of tight junction proteins in duodenal mucosa from 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease(PD) model. Methods Rats were subjected with 6-OHDA in bilateral substantia nigra (SN) as PD model. The location and quantitative detecting techniques inclu-ding immunohisto- chemistry and western blotting were used to determine the expressions and alterations of tight junction proteins (claudin-1, occludin, ZO-1). Results Claudin-1, occludin and ZO-1 were highly expressed in the duodenal mucosa of PD models, where the expressions of occluding (P<0.001) and ZO-1 (P<0.001) were much lower, while the expression of claudin-1 had no alteration. Conclusions The down-regulated expres-sion of occludin and ZO-1 was detected in duodenal mucosa of PD models, which might be related to duodenal ulcer in PD.
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We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy--dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HTreceptor and thermogenesisthe stimulation of 5-HTreceptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SCvalue (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.
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e: Vancomycin is a glycopeptide antibiotic separated from streptomycete, having been used as the ifrst choice to treat methicillin-resistant Staphylococcus aureus infection so far. The studies show that because of the individual difference in the metabolism of vancomycin, it is dififcult to get the trough concentration of pediatric patients severely ill or complicatedly in-fected to reach the target range (15—20 mg/L). However, with the help of therapeutic drug monitoring (TDM) of vancomycin and the pharmacokinetic/pharmacodynamic parameter (PK/PD) mode, the PK/PD parameters to achieve the precise control can be acquired by using the Bayes feedback. By a stretched review from clinical medication guide of vancomycin to the latest evidence from research, this paper fully demonstrates that renal function, weight, age, and disease state are the principal parameters to impact pediatric patient’s vancomycin metabolism and that the area under the concentration-time curve divided by the minimum inhibitory concentration (AUC/MIC)≥400 is the better cut-off value to determine vancomycin efifcacy and toxicity.
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Aim To study the dopaminergic neuroprotection of quercetin-3-O-sophoroside and total flavonoids derived from Poacynum hendersonni in MPTP-induced mice model of Parkinson's disease.Methods To inject MPTP intraperitoneal to C57/bl6 mouse at 30 mg·kg~(-1)·d~(-1) 5 days for PD model preparation, qercetin-3-O-sophoroside(25 mg·kg~(-1))and total flavonoids(250 mg·kg~(-1))were treated through intragastric administration 7 days before.Watching the mice behavior change through autonomic activities and pole test after final treatment, dopamine content in striatum was determined with fluorescence photometer.The neurons pathological change in substantia nigra(SN)was observed by pafaffin slice and immunohistochemistry staining to analyze the dopaminergic neuroprotective effects of Poacynum hendersonni.Results Treatment of quercetin-3-O-sophoroside for 7 days in advance, can improve PD mice motivation and dopamine concentration in striatum, tyrosine hydroxylase immune-reactive neurons in SN increased as well.Conclusion Quercetin-3-O-sophoroside can attenuate the impairment of MPTP in mice model of PD.
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Objective To study the effect of Busui Jiannao Prescription on ethology, GSH content and GSH-PX activity in brain of PD model rats. Methods Forty-five the aging pure C57BL rats were divided into a negative injury group, a model group, and a Chinese medicine group. PD animal model were established by injection with MPTP and were treated with Busui Jiannao Prescription by intragastric administration. Score changes of PD model rats in the test of pole-climbing and suspending were observed. GSH content and GSH-PX activity were further measured. Results After treating with Busui Jiannao Prescription, the test scores in pole-climbing and suspending were improved, GSH content and GSH-PX activity in substantia nigra were increased. Conclusion Busui Jiannao Prescription can regulate the behavior coordination and repair the damage of dopaminergic neurons in the substantia nigra of PD model rats.
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Pharmacokinetic/pharmacodynamic (PK/ PD) modelling plays more and more important role in the study of pharmacology. This paper recommends some new research progress including PK models, PD models, four basic attributes of PK/PD model, population PK/PD model , physiological PK/PD model, and some questions aboututilization of Sheiner effect compartment model.
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Aim To study the neuroprotective effect of Acteoside against MPTP-induced mouse model of Parkinsons disease (PD) and its mechanism. Methods The behavioral testing of C57 mice was assessed using spontaneous movement and rotarod test. DA levels in striatum were measured using HPLC-EC. Dopaminergic neurons in the substantia nigra were observed by immunohistochemical staining with an anti-Tyroxine hydroxylase (TH) antibody. Moreover, the mechanism of the neuroprotective effect of acteoside was investigated using Western blot analysis with an anti-?-synuclein antibody in the substantia nigra and striatum. Results ① Compared with control, MPTP lesion significantly reduced the number of spontaneous movement and latent period of mice on the rotating rod (both P