Model-based Dose Versus Empirical Dose of Piperacillin/Tazobactam in the Treatment of Late-onset Sepsis in Preterm Neonates: a Multicentre, Randomised, Open-label, Non-inferiority Study.

This study aims to compare the clinical outcomes, safety and PD target attainment of the model-based dose and empirical dose of piperacillin/tazobactam in the treatment of LOS in premature neonates, so as to optimize the piperacillin/tazobactam dose regimen.

开始日期2023-07-31

申办/合作机构

山东大学

[+4]

TCTR20220515001 / CompletedN/AIIT

Population pharmacokinetics and Monte Carlo dosing simulations of intravenous piperacillin/tazobactam in patients on continuous ambulatory peritoneal dialysis with peritonitis

开始日期2021-04-01

申办/合作机构-

NL-OMON46163 / SuspendedN/A

An explorative study determining the hepatic cyst penetration of antibiotics (ciprofloxacin, co-trimoxazole, doxycycline and piperacillin/tazobactam) and factors affecting penetration. - PENTAC 2

开始日期2019-01-01

申办/合作机构

Radboud Universitair Medisch Centrum

100 项与 β-lactamase x GR 相关的临床结果

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100 项与 β-lactamase x GR 相关的转化医学

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0 项与 β-lactamase x GR 相关的专利（医药）

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项与 β-lactamase x GR 相关的文献（医药）

2011-12-01·Experimental Cell Research3区 · 医学

Dual Mode of glucagon receptor internalization: Role of PKCα, GRKs and β-arrestins

3区 · 医学

Article

作者: Amy Nguyen ; Cecilia G. Unson ; Lada Krilov ; Bernard Bouscarel ; Teruo Miyazaki ; Susan Ceryak ; Norman H. Lee ; Russell Williams

Glucagon levels are elevated in diabetes and some liver diseases. Increased glucagon secretion leads to abnormal stimulation of glucagon receptors (GRs) and consequent elevated glucose production in the liver. Blocking glucagon receptor signaling has been proposed as a potential treatment option for diabetes and other conditions associated with hyperglycemia. Elucidating mechanisms of GR desensitization and downregulation may help identify new drug targets besides GR itself. The present study explores the mechanisms of GR internalization and the role of PKCα, GPCR kinases (GRKs) and β-arrestins therein. We have reported previously that PKCα mediates GR phosphorylation and desensitization. While the PKC agonist, PMA, did not affect GR internalization when tested alone, it increased glucagon-mediated GR internalization by 25-40% in GR-expressing HEK-293 cells (HEK-GR cells). In both primary hepatocytes and HEK-GR cells, glucagon treatment recruited PKCα to the plasma membrane where it colocalized with GR. We also observed that overexpression of GRK2, GRK3, or GRK5 enhanced GR internalization. In addition, we found that GR utilizes both clathrin- and caveolin-mediated endocytosis in HEK-GR cells. Glucagon triggered translocation of both β-arrestin1 and β-arrestin2 from the cytosol to the perimembrane region, and overexpression of β-arrestin1 and β-arrestin2 increased GR internalization. Furthermore, both β-arrestin1 and β-arrestin2 colocalized with GR and with Cav-1, suggesting the possible involvement of these arrestins in GR internalization.

2011-09-01·Mechanisms of Development4区 · 生物学

Disruption of β-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice

4区 · 生物学

Article

作者: Jueping Shi ; Mingfeng Zhang ; Hongqi Teng ; Yanding Zhang

In this study, the role of β-arrestin 1 and β-arrestin 2 in fetal lung and liver development was examined using Arrb1(-/-)Arrb2(-/-) mouse embryos. β-Arrestin 1/2 dual-null mice died shortly after birth and morphological examination revealed an obvious pulmonary hypoplasia and severe hepatic impairment. Western blot analysis demonstrated that GR protein levels in Arrb1(-/-)Arrb2(-/-) lung and liver tissues were significantly decreased compared to wild type embryos. Expression of GR proteins was confirmed in the nuclei of type II pneumocytes of 18.5 day embryos (E18.5) by immunofluorescence. The production of hepatic glucose and mRNA level of gluconeogenic enzymes were dramatically reduced in E18.5 Arrb1(-/-)Arrb2(-/-) liver. These results suggest that GR is an important downstream effector of the β-arrestin signaling pathway involved in regulation of lung and liver development. However, no obvious changes in GR expression following in vitro modulation of β-arrestin 1/2 indicated the existence of an indirect regulatory relationship between GR and the β-arrestin signaling pathway.

2008-11-01·American Journal of Physiology-Cell Physiology3区 · 生物学

Glucagon receptor recycling: role of carboxyl terminus, β-arrestins, and cytoskeleton

3区 · 生物学

Article

作者: Bouscarel, Bernard ; Miyazaki, Teruo ; Nguyen, Amy ; Krilov, Lada ; Unson, Cecilia G.

Glucagon receptor (GR) activity and expression are altered in several diseases, including Type 2 diabetes. Previously, we investigated the mechanism of GR desensitization and internalization. The present study focused on the fate of internalized GR. Using both hamster hepatocytes and human embryonic kidney (HEK)-293 cells, we showed that internalized GR recycled to the plasma membrane within 30–60 min following stimulation of the cells with 100 nM glucagon. In HEK-293 cells and during recycling, GR colocalized with Rab4, Rab11, β-arrestin1, β-arrestin2, and actin filaments, in the cytosolic and/or perinuclear domains. Glucagon treatment triggered redistribution of actin filaments from the plasma membrane to the cytosol. GR coimmunoprecipitated with β-actin in both hepatocytes and HEK-293 cells. Downregulation of β-arrestin1 and β-arrestin2 or disruption of the cytoskeleton inhibited recycling, but not internalization of GR. Deletion of the GR carboxyl-terminal 70 amino acids abolished internalization of GR in response to glucagon while deletion of the last 40 amino acids only did not affect GR internalization and recycling. After exposure of the cells to either high concentrations or prolonged duration of glucagon, GR colocalized with lysosomes. GR degradation was inhibited by lysosomal, but not proteosomal, inhibitors. In conclusion, GR recycles through Rab4- and Rab11- positive vesicles. The actin cytoskeleton, β-arrestin1, β-arrestin2, and the receptor's carboxyl terminus are involved in recycling. Prolonged stimulation with glucagon targets GR for degradation in lysosomes. Therefore, the present study provides a better understanding of the GR recycling mechanism, which could become useful in the treatment of certain diseases, including diabetes.