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Background: Sepsis and continuous renal replacement therapy (CRRT) are both responsible for the alterations of the pharmacokinetics of antibiotics. For patients with sepsis receiving CRRT, the serum concentrations of meropenem in the early phase (< 48 h) was significantly lower than that in the late phase (> 48 h). This current trial aimed to investigate whether administration of a loading dose of meropenem results in a more likely achievement of the pharmacokinetic (PK)/pharmacodynamics (PD) target (100% fT > 4 × MIC) and better therapeutic results in the patients with sepsis receiving CRRT.Methods: This is a single-blinded, single-center, randomized, controlled, two-arm, and parallel-group trial. This trial will be carried out in Guangzhou First People's Hospital, School of Medicine, South China University of Technology Guangdong, China. Adult patients (age ≥ 18 years) with critical sepsis or sepsis-related shock receiving CRRT will be included in the study. The subjects will be assigned to the control group and the intervention group (LD group) randomly at a 1:1 ratio, the estimated sample size should be 120 subjects in each group. In the LD group, the patient will receive a loading dose of 1.5-g meropenem resolved in 30-ml saline which is given via central line for 30 min. Afterward, 0.75-g meropenem will be given immediately for 30 min every 8 h. In the control group, the patient will receive 0.75-g meropenem for 30 min every 8 h. The primary objective is the probabilities of PK/PD target (100% fT > 4 × MIC) achieved in the septic patients who receive CRRT in the first 48 h. Secondary objectives include clinical cure rate, bacterial clearance rate, sepsis-related mortality and all-cause mortality, the total dose of meropenem, duration of meropenem treatment, duration of CRRT, Sequential Organ Failure Assessment (SOFA), C-reactive protein levels, procalcitonin levels, white blood cell count, and safety.Discussion: This trial will assess for the first time whether administration of a loading dose of meropenem results in a more likely achievement of the PK/PD target and better therapeutic results in the patients with sepsis receiving CRRT. Since CRRT is an important therapeutic strategy for sepsis patients with hemodynamic instability, the results from this trial may help to provide evidence-based therapy for septic patients receiving CRRT.Trial Registration: Chinese Clinical Trials Registry, ChiCTR2000032865 . Registered on 13 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=53616 . [ABSTRACT FROM AUTHOR]

Owing to the promising applications of C-dots in biomedical engineering, concerns about their safety have drawn increasing attention recently. In this study, mice were intraperitoneally injected at different C-dot concentrations (0, 6.0, 12.0 and 24.0 mg kg−1) once every 2 days for 30 days. A 1H NMR-based metabolic approach supplemented with biochemical analysis and histopathology was used for the first time to explore the toxicity of C-dots in vivo. Histopathological inspection revealed that C-dots did not induce any obvious impairment in tissues. Biochemical assays showed no significant alterations of most measured biochemical parameters in tissues and serum, except for a slight reduction of the albumin level in serum as well as AChE activity in the liver and kidneys. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis and SUS-plots disclosed that C-dots not only triggered the immune system but also disturbed the function of cell membranes as well as the normal liver clearance, indicating that the 1H NMR based metabolomics approach provided deep insights into the toxicity of C-dots in vivo and gained an advantage over traditional toxicological means, and should be helpful for the understanding of its toxic mechanism. [ABSTRACT FROM AUTHOR]

Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg−1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD+ metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects. [ABSTRACT FROM AUTHOR]

Owing to the promising applications of C-dots in biomedical engineering, concerns about their safety have drawn increasing attention recently. In this study, mice were intraperitoneally injected at different C-dot concentrations (0, 6.0, 12.0 and 24.0 mg kg -1 ) once every 2 days for 30 days. A 1 H NMR-based metabolic approach supplemented with biochemical analysis and histopathology was used for the first time to explore the toxicity of C-dots in vivo . Histopathological inspection revealed that C-dots did not induce any obvious impairment in tissues. Biochemical assays showed no significant alterations of most measured biochemical parameters in tissues and serum, except for a slight reduction of the albumin level in serum as well as AChE activity in the liver and kidneys. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis and SUS-plots disclosed that C-dots not only triggered the immune system but also disturbed the function of cell membranes as well as the normal liver clearance, indicating that the 1 H NMR based metabolomics approach provided deep insights into the toxicity of C-dots in vivo and gained an advantage over traditional toxicological means, and should be helpful for the understanding of its toxic mechanism.

Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1 H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg -1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD + metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.