Munropenn7190

Background The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands 10 mg for patients with body weight 4 kg. Conclusion The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0-59 days.Quality control of Chinese medicine (CM) is mainly based on chemical testing, which sometimes shows weak correlation to pharmacological effects. Thus, there is a great demand to establish bioactivity-based assays to ensure the quality of CM. The aim of the present study was to establish a bioassay-based approach to evaluate the biological activity of Xuesaitong injection (XST) based on an in vivo zebrafish model. Zebrafish larvae with arachidonic acid (AA)-induced thrombus were applied to evaluate anti-thrombosis effects of XST and explore the potential mechanism of XST. Analysis of major components in normal and abnormal XST samples was performed by high performance liquid chromatography (HPLC). The results indicate that XST could significantly restore heart red blood cells (RBCs) intensity of thrombotic zebrafish in a dose-dependent manner, whilst decreasing RBCs accumulation in the caudal vein. The results were confirmed using a green fluorescence protein (GFP)-labeled zebrafish thrombosis model. Moreover, we could show that XST downregulates the expression of the fibrinogen alpha chain (fga) gene to inhibit the coagulation cascade during the process of thrombosis in zebrafish. Notoginsenoside R1, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rd, which were considered to be the major components of XST, also showed moderate anti-thrombosis efficacy. Further results showed that the zebrafish thrombosis model could efficiently distinguish five abnormal batches of XST from 24 normal batches. Furthermore, the inhibition rates of different batches were correlated with the content level of major components. Our results suggested that the proposed zebrafish thrombosis model could be successfully used to evaluate the batch-to-batch consistency of XST, which provided an alternative way for the quality control of CM.Endoplasmic reticulum (ER) stress is often closely linked to autophagy, hypoxia signaling, mitochondrial biogenesis and reactive oxygen species (ROS) responses. Understanding the interaction between ER stress, mitochondrial function and autophagy is of great importance to provide new mechanisms for the pathology, prevention and treatment of cardiovascular diseases. Our previous study has reported that Panax notoginseng saponins (PNS) protection against thapsigargin (TG)-induced ER stress response and associated cell apoptosis in cardiac myocytes is calcium dependent and mediated by ER Ca2+ release through RyR2. However, whether its protection upon ER stress and associated apoptosis is related to mitochondrial function and autophagy remains largely unknown. Here, we investigated the roles of PNS played in TG-induced mitochondrial function, ROS accumulation and autophagy. https://www.selleckchem.com/products/b102-parp-hdac-in-1.html We also assessed its effects on Ca2+ homeostasis, ER stress response and associated cell death in the presence of autophagy inhibition. PNS-pl injury, ROS accumulation and disruption of Ca2+ homeostasis. Last but not least, inhibition of autophagy abolishes PNS protection against TG-induced ER stress response and associated apoptosis. In summary, PNS protection against ER stress response and associated apoptosis is related to the regulation of mitochondrial injury and ROS overproduction via modulation of autophagy. These data provide new insights for molecular mechanisms of PNS as a potential preventive approach to the management of cardiovascular diseases.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counter-regulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified.