Determination of vancomycin exposure target and individualised dosing recommendations for neonates: model-informed precision dosing.

INTRODUCTION: Few studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919). METHODS: A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target. RESULTS: Pop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0-24 hours (AUC0-24) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0-24 to minimum inhibitory concentration (AUC0-24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates. CONCLUSION: An AUC0-24 of 240-480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.

Kaempferol Protects Renal Fibrosis through Activating the BMP-7-Smad1/5 Signaling Pathway.

Renal interstitial fibrosis (RIF) is a common pathological characteristic associated with end-stage renal disease. However, treatment strategies for RIF are still very limited. In this study, we reported that kaempferol, a classic flavonoid, exhibited strong and widely inhibitory effect on the expression of fibrosis related genes in transforming growth factor beta 1 (TGF-ß1) treated NRK-52E cells. Further studies revealed that kaempferol inhibited TGF-ß1 induced epithelial-mesenchymal transition (EMT) process of NRK-52E cells and improved renal function deterioration and RIF in unilateral ureteral obstruction (UUO) rats. After exploring the underlying mechanisms, we found that kaempferol was able to activate the BMP-7-Smad1/5 pathway, rather than the TGF-ß1-Smad2/3 pathway. To further validate these results, DMH1 and BMP-7 knockdown were utilized at the cellular level and the results showed that both methods were able to antagonize the effects of kaempferol on the EMT process of NRK-52E cells induced by TGF-ß1. In UUO rats, inhibition of BMP-7 signaling by DMH1 also reversed the effects of kaempferol on renal function decline and RIF. Taken together, our findings demonstrated that kaempferol could be a good candidate for renal fibrosis treatment.

Endogenous peptide LYENRL prevents the activation of hypertrophic scar-derived fibroblasts by inhibiting the TGF-ß1/Smad pathway.

Hypertrophic scar formation is a fibroproliferative disorder caused by abnormal wound healing. At present, there are limited treatment strategies for hypertrophic scars. In this study, we identified an endogenous peptide, LYENRL, through peptidomics screening that is downregulated in scar skin tissues. The peptide exhibited concentration dependent inhibitory effects on the proliferation, migration and extracellular matrix (ECM) production of scar fibroblasts. By eukaryotic transcriptome sequencing analysis, we noted that LYENRL downregulated gene sets in scar fibroblasts were associated with the transforming growth factor-ß (TGF-ß) signaling pathway. Further experiments revealed that LYENRL was able to inhibit the activation of TGF-ß1/Smad signaling and TGF-ß1-induced activation of scar fibroblasts at the source by blocking the binding of AP-1 to the corresponding region of the Tgfb1 promoter, which in turn inhibited gene expression of Tgfb1. Taken together, we concluded that the effects of LYENRL on scar fibroblasts make it a potential peptide drug for hypertrophic scar treatment.