Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus.

Despite the availability of effective vaccines and treatments for SARS-CoV-2, managing COVID-19 in patients with systemic lupus erythematosus (SLE) remains challenging, particularly considering drug-drug interactions (DDIs). Here, we present a case of DDIs between Tacrolimus (Tac) and nirmatrelvir/ritonavir (NMV/r) in a 32-year-old male with SLE. Following self-administration of NMV/r and resumption of Tac after 5 days, the patient experienced acute nephrotoxicity and neurotoxicity, accompanied by supratherapeutic Tac levels, despite Tac being withheld during NMV/r. The primary cause of this acute toxicity is attributed to ritonavir's inhibitory effect on both CYP3A4 enzymes and P-glycoprotein. Upon admission, Tac was discontinued, and supportive therapies were initiated. Phenytoin, a CYP3A4 inducer, was administered to lower Tac levels under the guidance of clinical pharmacists, effectively alleviating the patient's acute toxic symptoms. The half-life of Tac during the treatment of phenytoin was calculated to be 55.87 h. And no adverse reactions to phenytoin were observed. This case underscores the persistence of enzyme inhibition effects and demonstrates the effectiveness and safety of utilizing CYP3A4 enzyme inducers to mitigate Tac concentrations. Furthermore, it emphasizes the importance of healthcare providers and patients being vigilant about DDIs in Tac recipients. Lastly, it highlights the indispensable role of pharmacist involvement in clinical decision-making and close monitoring in complex clinical scenarios. Although our findings are based on a single case, they align with current knowledge and suggest the potential of individualized combination therapy in managing challenging COVID-19 cases in immunocompromised patients.

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

PURPOSE: To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. METHODS: Patients > 60 years of age, who received intravenous linezolid (600 mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). RESULTS: A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. CONCLUSION: The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300 mg every 12 h).

Pharmacokinetic interactions between tacrolimus and Wuzhi capsule in liver transplant recipients: Genetic polymorphisms affect the drug interaction.

Wuzhi capsule (WZC), a commonly used Chinese patent medicine to treat various types of liver dysfunction in China, increases the exposure of tacrolimus (TAC) in liver transplant recipients. However, this interaction has inter-individual variability, and the underlying mechanism remains unclear. Current research indicates that CYP3A4/5 and drug transporters influence the disposal of both drugs. This study aims to evaluate the association between TAC dose-adjusted trough concentration (C/D) and specific genetic polymorphisms of CYP3A4/5, drug transporters and pregnane x receptor (PXR), and plasma levels of major WZC components, deoxyschisandrin and γ-schisandrin, in liver transplant patients receiving both TAC and WZC. Liquid chromatography-tandem-mass spectrometry was used to detect the plasma levels of deoxyschisandrin and γ-schisandrin, and nine polymorphisms related to metabolic enzymes, transporters and PXR were genotyped by sequencing. A linear mixed model was utilized to assess the impact of the interaction between genetic variations and WZC components on TAC lnC/D. Our results indicate a significant association of TAC lnC/D with the plasma levels of deoxyschisandrin and γ-schisandrin. Univariate analysis demonstrated three polymorphisms in the genes ABCB1 (rs2032582), ABCC2 (rs2273697), ABCC2 (rs3740066), and PXR (rs3842689) interact with both deoxyschisandrin and γ-schisandrin, influencing the TAC lnC/D. In multiple regression model analysis, the interactions between deoxyschisandrin and both ABCB1 (rs2032582) and ABCC2 (rs3740066), post-operative day (ß < 0.001, p < 0.001), proton pump inhibitor use (ß = -0.152, p = 0.008), body mass index (ß = 0.057, p < 0.001), and ABCC2 (rs717620, ß = -0.563, p = 0.041), were identified as significant factors of TAC lnC/D, accounting for 47.89% of the inter-individual variation. In summary, this study elucidates the influence of the interaction between ABCB1 and ABCC2 polymorphisms with WZC on TAC lnC/D. These findings offer a scientific basis for their clinical interaction, potentially aiding in the individualized management of TAC therapy in liver transplant patients.

Development and Validation of a Dynamic Nomogram for Predicting 3-Month Mortality in Acute Ischemic Stroke Patients with Atrial Fibrillation.

Background: Acute ischemic stroke (AIS) in patients with atrial fibrillation (AF) carries a substantial risk of mortality, emphasizing the need for effective risk assessment and timely interventions. This study aimed to develop and validate a practical dynamic nomogram for predicting 3-month mortality in AIS patients with AF. Methods: AIS patients with AF were enrolled and randomly divided into training and validation cohorts. The nomogram was developed based on independent risk factors identified by multivariate logistic regression analysis. The prediction performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, decision curve analysis (DCA), and Kaplan-Meier survival analysis. Results: A total of 412 patients with AIS and AF entered final analysis, 288 patients in the training cohort and 124 patients in the validation cohort. The nomogram was developed using age, baseline National Institutes of Health Stroke Scale score, early introduction of novel oral anticoagulants, and pneumonia as independent risk factors. The nomogram exhibited good discrimination both in the training cohort (AUC, 0.851; 95% CI, 0.802-0.899) and the validation cohort (AUC, 0.811; 95% CI, 0.706-0.916). The calibration plots, DCA and Kaplan-Meier survival analysis demonstrated that the nomogram was well calibrated and clinically useful, effectively distinguishing the 3-month survival status of patients with AIS and AF, respectively. The dynamic nomogram can be obtained at the website: https://yanxiaodi.shinyapps.io/3-monthmortality/. Conclusion: The dynamic nomogram represents the first predictive model for 3-month mortality and may contribute to managing the mortality risk of patients with AIS and AF.

Effect of Tacrolimus Time in Therapeutic Range on Postoperative Recurrence in Patients Undergoing Liver Transplantation for Liver Cancer.

BACKGROUND AND OBJECTIVE: Liver cancer is the second highest cause of cancer-related deaths worldwide. It is commonly treated with liver transplantation, where tacrolimus is typically used as an antirejection immunosuppressant. The purpose of this study was to evaluate the effect of tacrolimus time in therapeutic range (TTR) on liver cancer recurrence in liver transplant recipients and to compare the performance of TTRs calculated according to the target ranges recommended in published guidelines. METHODS: A total of 84 patients who underwent liver transplantation for liver cancer were retrospectively included. Tacrolimus TTR was calculated using linear interpolation from the date of transplantation until recurrence or the last follow-up according to target ranges recommended in the Chinese guideline and international expert consensus. RESULT: Twenty-four recipients developed liver cancer recurrence after liver transplantation. The CTTR (TTR calculated according to the Chinese guideline) for the recurrence group was significantly lower than that of the nonrecurrence group (26.39% vs. 50.27%, P < 0.001), whereas the ITTR (TTR calculated according to the international consensus) was not significantly different between the two groups (47.81% vs. 56.37%, P = 0.165). Multivariate survival analysis revealed that age, microvascular invasion, hepatocellular carcinoma, CTTR, and mean tacrolimus trough concentration were independent predictors of liver cancer recurrence after liver transplantation. CONCLUSIONS: TTR predicts liver cancer recurrence in liver transplant recipients. The range of tacrolimus concentrations recommended in the Chinese guideline was more beneficial than that recommended in the international consensus for Chinese patients undergoing liver transplantation for liver cancer.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

Integrated untargeted and targeted proteomics to unveil plasma prognostic markers for patients with acute paraquat poisoning: A pilot study.

Paraquat (PQ) is a widely used but strongly toxic herbicide, which can induce multiple organ failure. The overall survival rate of the poisoned patients was only 54.4% due to lack of specific antidotes. Besides, the definite pathogenic mechanism of PQ is still not fully understood. In this pilot study, untargeted and targeted proteomics were integrated to explore the expression characteristics of plasma protein in PQ poisoned patients, and identify the differentially expressed proteins between survivors and non-survivors. A total of 494 plasma proteins were detected, and of which 47 were upregulated and 44 were downregulated in PQ poisoned patients compared to healthy controls. Among them, five differential plasma proteins (S100A9, S100A8, MB, ACTB and RAB11FIP3) were further validated by multiple reaction monitoring (MRM)-based targeted proteomic approach, and three of them (S100A9, S100A8 and ACTB) were confirmed to be correlated with PQ poisoning. Meanwhile, 84 dysregulated plasma proteins were identified in non-survivors compared with survivors. Moreover, targeted proteomic and ROC analysis suggested that ACTB had a good performance in predicting the prognosis of PQ poisoned patients. These findings highlighted the value of label-free and mass spectrometry-based proteomics in screening prognostic biomarkers of PQ poisoning and studying the mechanism of PQ toxicity.

Mid-dosing interval concentration is important for polymyxin B exposure and acute kidney injury in critically ill patients.

This study aimed to evaluate the association between polymyxin B (PMB) exposure and acute kidney injury (AKI) and analyze the risk factors for PMB-induced AKI in critically ill patients. Plasma concentrations of PMB were determined using an ultraperformance liquid chromatography-tandem mass spectrometer in intensive care unit patients who were administered PMB. Univariate and multivariate analyses were conducted to identify risk factors. A receiver operating characteristic curve was constructed to assess the discriminant power of the factors and to identify the cutoff value for AKI. The white blood cell count and estimated area under the concentration-time curve (AUC) of patients administered PMB were independent risk factors for PMB-induced AKI, where AUC were calculated using a first-order pharmacokinetic equation based on the mid-dosing interval concentration (C1/2t ) and peak concentration. The area under the receiver operating characteristic curve of the final model was 0.805 (95% confidence interval, 0.690-0.921). The cutoff value for the combined predictor was 0.57. Alternatively, when using C1/2t , which was strongly correlated with AUC, as the only independent risk factor, the analysis showed that the 3.47 µg/ml threshold provides favorable differentiation between the AKI and non-AKI groups. These results provide insightful information for therapeutic drug monitoring-guiding PMB dosing in clinical practice.

Metabolic alteration of circulating steroid hormones in women with gestational diabetes mellitus and the related risk factors.

Background: Abnormally changed steroid hormones during pregnancy are closely related to the pathological process of gestational diabetes mellitus (GDM). Our aim was to systematically profile the metabolic alteration of circulating steroid hormones in GDM women and screen for risk factors. Methods: This study was a case-control study with data measured from 40 GDM women and 70 healthy pregnant women during their 24-28 gestational weeks. 36 kinds of steroid hormones, including 3 kinds of corticosteroids, 2 kinds of progestins, 5 kinds of androgens and 26 kinds of downstream estrogens in serum were systematically measured using a combined sensitive UPLC-MS/MS method. The flux of different metabolic pathways of steroid hormones was analyzed. Logistic regression and ROC curve model analyses were performed to identify potential steroid markers closely associated with GDM development. Results: Serum corticosteroids, progestins and almost all the estrogen metabolites via 16-pathway from parent estrogens were higher in GDM women compared with healthy controls. Most of the estrogen metabolites via 4-pathway and more than half of the metabolites via 2-pathway were not significantly different. 16α-hydroxyestrone (16OHE1), estrone-glucuronide/sulfate (E1-G/S) and the ratio of total 2-pathway estrogens to total estrogens were screened as three indicators closely related to the risk of GDM development. The adjusted odds ratios of GDM for the highest quartile compared with the lowest were 72.22 (95% CI 11.27-462.71, P trend <0.001) for 16OHE1 and 6.28 (95% CI 1.74-22.71, P trend <0.05) for E1-G/S. The ratio of 2-pathway estrogens to total estrogens was negatively associated with the risk of GDM. Conclusion: The whole metabolic flux from cholesterol to downstream steroid hormones increased in GDM condition. The most significant changes were observed in the 16-pathway metabolism of estrogens, rather than the 2- or 4-pathway or other types of steroid hormones. 16OHE1 may be a strong marker associated with the risk for GDM.

Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis.

Non-alcoholic steatohepatitis (NASH) is emerging as a serious liver disorder characterized by hepatic steatosis and liver inflammation. Nicotinamide adenine dinucleotide (NAD+) and NAD+-dependent deacetylase, SIRT1, play important roles in lipid metabolism in non-alcoholic fatty liver disease (NAFLD). However, their effects on liver inflammation and homeostasis of bile acids (BAs), the extensively proved pathophysiological actors in NASH, have not been fully understood. NASH animal model was induced by a methionine-choline-deficient (MCD) diet in C57BL/6J mice and intraperitoneally injected with NAD+ precursor, an agonist of upstream rate-limiting enzyme NAMPT or downstream SIRT1, or their vehicle solvents. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model. Induction of NAMPT/NAD+/SIRT1 axis could remarkably alleviate the aggravated inflammation in the liver of NASH mice, accompanied by decreased levels of total BAs throughout the enterohepatic system and a switch of BA synthesis from the classic pathway to the alternative pathway, resulting in less production of pro-inflammatory 12-OH BAs. The expressions of key enzymes including cyp7a1, cyp8b1, cyp27a1 and cyp7b1 in BA synthesis were significantly modulated after NAMPT/NAD+/SIRT1 axis induction in both animal and cell models. The levels of pro-inflammatory cytokines in liver were significantly negatively correlated with the intermediates in NAD+ metabolism, which may also be related to their regulation on BA homeostasis. Our results indicated that induction of NAMPT/NAD+/SIRT1 axis may be a potential therapeutic strategy for NASH or its complications related with BAs.

Pharmacokinetic/Pharmacodynamic Target Attainment of Tigecycline in Patients with Hepatic Impairment in a Real-World Setting.

BACKGROUND: This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of various tigecycline dosing regimens in real-world patients with impaired liver function. METHODS: The clinical data and serum concentrations of tigecycline were extracted from the patients' electronic medical records. Patients were classified into Child-Pugh A, Child-Pugh B, and Child-Pugh C groups, according to the severity of liver impairment. Furthermore, the minimum inhibition concentration (MIC) distribution and PK/PD targets of tigecycline from the literature were used to obtain a proportion of PK/PD targets attainment of various tigecycline dosing regimens at different infected sites. RESULTS: The pharmacokinetic parameters revealed significantly higher values in moderate and severe liver failure (groups Child-Pugh B and Child-Pugh C) than those in mild impairment (Child-Pugh A). Considering the target area under the time-concentration curve (AUC 0-24 )/MIC ≥4.5 for patients with pulmonary infection, most patients with high-dose (100 mg, every 12 hours) or standard-dose (50 mg, every 12 hours) for tigecycline achieved the target in groups Child-Pugh A, B, and C. Considering the target AUC 0-24 /MIC ≥6.96 for patients with intra-abdominal infection, when MIC ≤1 mg/L, more than 80% of the patients achieved the target. For an MIC of 2-4 mg/L, only patients with high-dose tigecycline in groups Child-Pugh B and C attained the treatment target. Patients experienced a reduction in fibrinogen values after treatment with tigecycline. In group Child-Pugh C, all 6 patients developed hypofibrinogenemia. CONCLUSIONS: Severe hepatic impairment may attain higher PK/PD targets, but carries a high risk of adverse reactions.

Insight into Nephrotoxicity and Processing Mechanism of Arisaema erubescens (Wall.) Schott by Metabolomics and Network Analysis.

Background: Arisaematis Rhizome (AR) has been used as a damp-drying, phlegm-resolving, wind-expelling, pain-alleviating, and swelling-relieving drug for thousands of years. However, the toxicity limits its clinical applications. Therefore, AR is usually processed (Paozhi in Chinese) prior to clinical use. In this study, the integration of ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry-based metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism. Materials and Methods: Extracts of crude and processed AR products (1g/kg) were intragastrically administered to rats once daily for four consecutive weeks. The renal function was evaluated by blood urea nitrogen, creatinine, interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), super oxide dismutase (SOD), the ratio of glutathione/glutathione disulfide (GSH/GSSH), glutathione peroxidase (GSH-Px) and histopathological examination. Furthermore, the chemical composition of AR was clarified by ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry, after which the integration of metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism. Results: Crude AR caused renal damage by stimulating inflammation and oxidative stress, as confirmed by the increased production of IL-1ß, TNF-α and MDA, and decreased levels of SOD, GSH/GSSH and GSH-Px. Processing with ginger juice, alumen and bile juice alleviated the damage to kidney. Metabolomics results showed that a total of 35 potential biomarkers enriched in amino acid metabolism, glycerophospholipid metabolism, fatty acid-related pathways, etc. were deduced to be responsible for the nephrotoxicity of AR and the toxicity-reducing effect of processing. Conclusion: This work provided theoretical and data support for the in-depth study of the processing mechanism, showing that processing reduces AR nephrotoxicity through multiple metabolic pathways.

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies.

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81 × (CLCR/121.38)0.806 × (1-POS × 0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Pharmacist-Driven Dosing Services and Pharmaceutical Care Increase Probability of Teicoplanin Target Concentration Attainment and Improve Clinical and Economic Outcomes in Non-Critically Ill Patients.

INTRODUCTION: Pharmacist-driven (PD) dosing and monitoring services have been shown to improve the clinical and economic outcomes in patients treated with different antibiotics, other than teicoplanin. This study investigates the impact of PD dosing and monitoring services on the clinical and economic outcomes of non-critically ill patients receiving teicoplanin treatment. METHODS: A single-center retrospective study was conducted. Patients were divided into the PD group and the non-PD (NPD) group. Primary outcomes included the achievement of target serum concentration, and a composite endpoint of all-cause mortality, intensive care unit (ICU) admission, and sepsis or septic shock development during hospitalization or within 30 days of hospital admission. The cost of teicoplanin, overall medication cost, and total cost during hospital stay were also compared. RESULTS: A total of 163 patients from January to December 2019 were included and assessed. Seventy patients were assigned to the PD group and 93 to the NPD group. The PD group had a higher percentage of patients reaching the target trough concentration (54% versus 16%, p < 0.001). Around 26% of the patients in the PD group and 50% of the patients in the NPD group met the composite endpoint during their hospital stay (p = 0.002). The PD group exhibited a significantly lower incidence of sepsis or septic shock, shorter hospital stays, reduced drug costs, and lower total expenses. CONCLUSIONS: Our study demonstrates that pharmacist-driven teicoplanin therapy can improve the clinical and economic outcomes for non-critically ill patients. TRIAL REGISTRATION: https://www.chictr.org.cn ; identifier, ChiCTR2000033521.

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Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.

Serum proteomics analysis of biomarkers for evaluating clinical response to MTX/IGU therapy in early rheumatoid arthritis.

Methotrexate (MTX) and iguratimod (IGU) are conventional synthetic disease modifying antirheumatic drugs widely used in the treatment of Rheumatoid arthritis (RA) in China. Although MTX combined with IGU can significantly inhibit the progression of RA, some patients do not respond to the treatment. The purpose of this study is to explore the difference of serum protein expression between RA patients with good and poor response to the combined therapy by label-free quantitative proteomic approach. From the proteomics data, a total of 782 proteins in the serum of RA patients were detected, and of which 9 were upregulated and 18 were downregulated in the good response group compared to poor response group. Among them, four significantly differentially expressed proteins (RELN, LDHA, MRC1 and TKT) were further validated by multiple reaction monitoring (MRM)-based quantification approach, and three of them (RELN, LDHA and MRC1) were confirmed to be correlated with the response to MTX/IGU therapy. Logistic regression and ROC analysis indicated that the combination of RELN, LDHA and MRC1 had good performance in evaluating the response. This result proved the different serum proteins signature fingerprint between response group and non-response group; and highlighted the potential of the label-free and mass spectrometry-based quantitative proteomic approach in screening biomarkers for evaluating clinical response to MTX/IGU therapy in RA.

Lower tacrolimus time in therapeutic range is associated with inferior outcomes in adult liver transplant recipients.

Previous studies on solid organ transplantation have reported that a low time in therapeutic range (TTR) of tacrolimus increases the risk of poor outcomes. However, the reproducibility of the findings in liver transplantation has not yet been confirmed. The TTR, coefficient of variation (CV) and standard deviation (SD) were calculated for 207 adult liver transplant patients from the date of transplantation until the first episode of acute rejection (AR), graft loss, acute kidney injury (AKI), biliary complications, infection or the last follow-up. Kaplan-Meier curves, log-rank tests and Cox regression analyses were performed. Sixty-one (29.5%) patients reached the composite endpoint of AR, biliary complications and graft loss. The log-rank test indicated that the low TTR group had an increased risk of the composite endpoint (P < 0.001), AKI (P < 0.001) and infection (P < 0.001). Multivariate Cox regression analyses revealed that a 10% decrease in TTR was associated with an increased hazard for composite endpoint (hazard ratio [HR]: 1.185, P = 0.010), AKI (HR: 1.355, P < 0.001) and infection (HR: 1.357, P < 0.001). Unexpectedly, SD and CV demonstrated no association with the above-mentioned inferior outcomes. Compared with SD and CV, the TTR of tacrolimus was more correlated with inferior outcomes and may be a novel indicator for predicting the prognosis of liver transplantation.

Sensitive colorimetric sensing of glutathione and H2O2 based on enhanced peroxidase mimetic activity of MXene@Fe3O4.

The peroxidase-like activity of MXene@Fe3O4 nanocomposites and the relevant colorimetric application have been investigated for the first time. According to a kinetic study, MXene@Fe3O4 nanocomposites displayed higher peroxidase activity than their individual components, and the catalytic process followed a ping-pong mechanism. The improved peroxidase-like activity of the MXene@Fe3O4 nanocomposites was obtained due to the synergetic impact of the Fe3O4 and MXene phases, the huge ion-accessible interface, and quick electron transfer channels in the nanocomposites. In the presence of hydrogen peroxide (H2O2), the MXene@Fe3O4 nanocomposites can catalyze the reaction of the colorless substrate 3, 3, 5, 5-tetramethylbenzidine (TMB) into oxidized TMB which revealed a blue color at 652 nm. After the introduction of glutathione (GSH), the blue color was gradually fading owing to the hydroxyl radical scavenging effect of glutathione. A colorimetric detection platform based on the peroxidase-like activity of the MXene@Fe3O4 nanocomposites was developed for H2O2 and GSH with a detection limit of 0.4 µM and 0.5 µM, respectively. The calibration plot for glutathione detection is calculated by absorbance difference at 652 nm, which ranged from 0.5 to 10 µM with a detection limit of 0.2 µM. The recoveries of GSH with different concentrations ranged from 93.76 to 108.50% and the relative standard deviation from 0.30 to 5.96%. This work significantly extends the application of MXene@Fe3O4 nanocomposites in the construction of colorimetric sensors and reveals a satisfactory result in real sample analysis.