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Objective:To explore the effect of augmented renal clearance(ARC)on 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio(AUC 24/MIC)of vancomycin and prognosis in critical children, thus to provide proposal for individual dosage regimen. Methods:Sixty-five critical children treated with vancomycin, who suffered from sepsis/septic shock, were brought into this retrospective cohort study.According to estimate glomerular filtration rate, these children were divided into ARC group ( n=27) and normal group ( n=38). The influencing factor of AUC 24/MIC of vancomycin and therapy prognosis for two groups were detected and analyzed. Results:There were no significant differences between two groups in basic setting (age, sex, weight), scores of pediatric sequential organ failure assessment and pediatric risk of mortality Ⅲ, infection markers (C-reactive protein and procalcitonin), glutamic-pyruvic transaminase, hypoproteinemia, usage of diuretic and vasoactive agent( P>0.05). The patients from ARC group showed lower levels than those from normal group in AUC 24/MIC of vancomycin[375.2(300.8, 489.4) vs. 443.6(412.3, 593.2), Z=2.263, P=0.024] and it′s target achievement ratio (TAR)(40.7% vs. 76.3%, χ2=8.440, P=0.005). When usage of diuretic and vasoactive agent, the AUC 24/MIC of ARC group was lower than that of normal group( P<0.05). But there was no significant difference between ARC group and normal group regarding hypoproteinemia( P>0.05). The days of body temperature steady at least 48 hours[7.0(5.5, 9.0)d vs. 6.0(5.0, 8.0)d], the length of hospital stay[39.0(21.0, 58.0)d vs. 20.5(16.0, 28.0)d], the length of PICU stay[14.0(9.0, 31.5)d vs. 10.0(5.0, 15.0)d] were longer than those in normal group( P<0.05). There were no significant differences between ARC group and normal group regarding days of ventilation and infectious markers decreased at least 50%, as well as 28-days mortality( P>0.05). The multivariable analysis showed that the presence of ARC, hypoproteinemia, use of diuretics and vasoactive agent were significantly associated with AUC 24/MIC of vancomycin( P<0.05). Conclusion:ARC may down regulate levels of AUC 24/MIC and TAR of vancomycin.During ARC period, the usage of diuretic and vasoactive agent could affect the AUC 24/MIC of vancomycin.Individual dosage regimen should be employed for critical children suffered with ARC.
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Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.
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AIM: To study the ways of calculating area under the plasma concentration-time curve (AUC) in non-compartment model pharmacokinetics by comparing the accuracy & precision of every method. METHODS: Three methods were used to calculate the area under 0-T curve (AUC
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As a glycopeptide antibiotic,vancomycin is the first choice for treatment of methicilin-resistant staphylococcus aureus (MRSA) infection.Because of the metabolic individual difference,if children were given the dose according to the instruction,few patients can achieve the valley concentration as recommended in the guideline.So it's necessary for optimizing individual vancomycin dosage regimen with the help of therapeutic drug monitoring (TDM) and population pharmacokinetics model-nonlinear mixed effect model (NONMEM),in order to realiz the combination of effect and safety.This article will introduce the population pharmacokinetics model of vancomycin in children and discuss about major parameters influencing vancomycin metabolism,including age,body mass index,renal function,health condition,and drug combination.With rational therapeutic drug monitoring and optimizing parameters of NONMEM,we hope to realize area under concentration-time curve/minimum inhibit concentration (AUC/MIC) ratio ≥400,and to provide the reference for safe and rational pediatric dosage regimen.
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Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators may attenuate PCSK9-induced low-density lipoprotein receptor (LDLR) degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol (LDL-C). A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In addition, five compounds , , , ()-, and ()- showed better performance in the low-density lipoprotein, labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound , selected for evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human related gene (hERG) inhibition assay indicated the potential druggability for compound , which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.
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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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Oral administration is the most commonly used route for drug treatment. Intestinal cytochrome P450 (CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation, while leaving the passage of other drugs unimpeded. A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species, including the identification of the CYP enzymes expressed, their regulation, and the relative importance of intestinal metabolism compared to hepatic metabolism, is important for improving bioavailability of current drugs and new drugs in development. Here, we briefly review the expression of drug-metabolizing P450 enzymes in the small intestine of humans and several preclinical animal species, and provide an update of the various factors or events that regulate intestinal P450 expression, including a cross talk between the liver and the intestine. We further compare various clinical and preclinical approaches for assessing the impact of intestinal drug metabolism on bioavailability, and discuss the utility of the intestinal epithelium-specific NADPH-cytochrome P450 reductase-null (IECN) mouse as a useful model for studyingroles of intestinal P450 in the disposition of orally administered drugs.
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Objective To establish an HPLC method for evaluating deoxyschizandrin in rat plasma; To explore deoxyschizandrin metabolic processes in blood.Methods The blood microdialysis probe was implanted into the right atrial enlargement through right jugular vein to detect the concentration of deoxyschizandrin in blood. Chromatographic conditions for detecting of dialysis fluid were as follows: mobile phase was methanol-acetonitrile- water (40:35:25); flow rate was 1 mL/min; column temperature was 30℃; UV detection wavelength was 254 nm. The data obtained after being calculated by the recovery rate of the probe in vivo were dealt with DAS 2.0 software. Pharmacokinetic parameters were calculated, and the concentration-time related curves were plotted.Results The deoxyschizandrin curve was linear (r=0.999 5) within the range of 2–500μg/mL. The RSD of intra-day pecision and inter-day pecision were both <3%. The stability of the solution was good in 12 hours at roomtemperature. ke was (0.364±0.047)/h; t1/2 was (1.637±0.302)h; Tmax was (0.612±0.194)h; Cmax was (165.92±28.830)μg/mL; AUC0-t was (240.793±25.540)μg?h/mL; AUC0-∞ was (282.710±30.727)μg?h/mL.Conclusion The method is convenient to perform, and the retention time of HPLC is short. This method is suitable for detecting the content of deoxyschizandrin in dialysis fluid, which can also be used to investigate the metabolic processes of deoxyschizandrin in the rat blood.
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A simple and effective high-performance liquid chromatography with diode-array detection method coupled with a liquid-liquid extraction pretreatment has been developed for determining the pharmacokinetics and tissue distribution of a novel structurally modified derivative (8-acetamino-isocorydine) of isocorydine. According to the in vivo experiments data calculations by DAS 2.0 software, a two-compartment metabolic model was suitable for describing the pharmacokinetic of 8-acetamino-isocorydine in rats. 8-Acetamino-isocorydine was absorbed well after oral administration, and the absolute bioavailability was 76.5%. The half-life of 8-acetamino-isocorydine after intravenous and oral administration was 2.2 h and 2.0 h, respectively. In vivo, 8-acetamino-isocorydine was highly distributed in the lungs, kidney and liver; however, relatively little entered the brain, suggesting that 8-acetamino-isocorydine could not easily pass through the blood brain barrier. Our work describes the first characterization of the pharmacokinetic parameters and tissue distribution of 8-acetamino-isocorydine. The acquired data will provide useful information for the in vivo pharmacology of 8-acetamino-isocorydine, and can be applied to new drug research.
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OBJECTIVE: To provide a method for calculating mean residence time of drugs in central compartment (MRTC).