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BackgroundMethotrexate is widely recommended as a first‐line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate‐induced nephrotoxicity is a severe adverse reaction, of which the mechanisms remain unclear.MethodsAn untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia patients with delayed methotrexate excretion, with or without acute kidney injury, was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro HK‐2 cell assays further verified the candidate metabolites, and explored the mechanisms underlying the nephrotoxicity of methotrexate.ResultsFour metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione was confirmed as a candidate metabolite involved in the toxicity of methotrexate. We further explored the role of glutathione deprivation‐induced ferroptosis on methotrexate cytotoxicity, and it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe2+ accumulation, and altered the expression of ferroptosis‐related proteins in HK‐2 cells. These methotrexate‐induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate‐induced cytotoxicity in HK‐2 cells.ConclusionsOur findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Background: Ibrutinib, one Food and Drug Administration-approved, orally available, small-molecule Bruton tyrosine kinase (BTK) inhibitor, is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). YouTube is increasingly used for health purposes.However, videos for ibrutinib on YouTube have not been previously evaluated. This study assessed the accuracy and quality of YouTube videos on ibrutinib, to better understand the information shown on a dominant media platform. Methods:The first 150 video results returned by the YouTube search engine in response to the keyword "ibrutinib" were included (up to June 27, 2022). Typically used predefined inclusion and exclusion criteria were applied to screen the videos based on our needs. A 5-point Global Quality Scale (GQS) determined whether the videos would be useful to patients or not, and the quality of content was analyzed by five content-specific items. The quality of the included videos was classified as "low", "moderate", or "excellent" according to GQS and content score. The median and interquartile range were used to describe the values and Kruskal-Wallis test were used in the analysis.Results: A total of 99 videos with a median of 237 views met the inclusion criteria. The videos were categorized into educational videos (n=6, 6.07%), personal experience and blog (n=3, 3.03%) and interviews videos (n=90, 90.9%). Almost half of the videos were classified as moderate (n=51, 51.51%), followed by excellent (n=25, 25.26%) and low (n=23, 23.23%). Between the groups, no statistically significant differences were observed in the numbers of dislikes, comments, posted days, percentage positivity and viewing rate (P>0.05). There were marked differences in the length, likes, views, viewers' interaction and likeability (P<0.05).Conclusions: YouTube could be an effective source for different groups of people to obtain helpful information about ibrutinib. The physicians, pharmacists, nurses and healthcare organizations should prepare and upload more comprehensible and reliable videos with evidence-based information.

Background: Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanism remains unclear. Methods: An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia with delayed methotrexate excretion with or without acute kidney injury was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro assays further confirmed the candidate metabolites and the mechanisms underlying the nephrotoxicity of methotrexate. Results: Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione is confirmed as an candidate metabolite involved in the toxicity of methotrexate. Based on the depletion of glutathione mediated cell death, it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. Conclusions: Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

What is Known and Objective: Carbapenem-resistant Gram-negative bacterial pathogens continue to threaten public health. Avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor, has been approved for use with ceftazidime (CAZ) mainly against carbapenem-resistant Enterobacteriaceae. Therapeutic drug monitoring (TDM) is urgently needed to optimize dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. This study aims to develop and validate a rapid, simple, and economical LC-MS/MS method for simultaneous determination of CAZ/AVI in human plasma.Methods: Samples were processed by simple protein precipitation, and gradient elution strategy was applied to separate CAZ and AVI on a reverse-phase C18 column; with subsequent detection by the mass spectrometer in a positive and negative ion switching mode. Plasma samples from patients were analysed.Results and Discussion: A 4-min run of LC-MS/MS was developed. The precision, trueness, matrix effect, extraction recovery, carry-over, dilution integrity, and stability were all acceptable for a bioanalytical method. The method was successfully applied to the determination of CAZ and AVI in patients, and a considerable PK variability of CAZ/AVI was observed among patients.What is New and Conclusion: A robust, rapid, simple, and economical LC-MS/MS method for the simultaneous determination of CAZ and AVI was developed. The considerable PK variability of CAZ/AVI among patients demonstrates the clinical significance of TDM.