Ceritinib is a first-line drug for treating non-small cell lung cancer, but its clinical use is limited by severe hepatotoxicity. The mechanism underlying ceritinib-induced liver injury remains unclear. This study aimed to clarify this mechanism and evaluate the protective effect of magnesium isoglycyrrhizinate (MgIG). Hepatocytes were treated with ceritinib to assess cell viability and morphology using the CCK-8 assay and bright-field microscopy, respectively. Mitochondrial damage was evaluated by measuring membrane potential, ultrastructure, and NADH-CoQ reductase activity. Intracellular reactive oxygen species (ROS) levels were detected by DCFH-DA staining and flow cytometry. Western blotting was used to quantify oxidative stress- and pyroptosis-related proteins. Liver injury was assessed by serum ALT and AST levels and histopathological analysis. We found that ceritinib induced hepatocyte death by disrupting mitochondrial function and structure, leading to ROS accumulation, oxidative stress, NF-κB signaling activation and subsequent pyroptosis. MgIG treatment restored NADH-CoQ reductase activity, reduced ROS levels, and inhibited NF-κB activation, thereby attenuating oxidative stress and pyroptosis. These protective effects were confirmed in the animal model. In conclusion, ceritinib-induced hepatotoxicity is mediated by mitochondrial dysfunction, which triggers ROS-driven oxidative stress and pyroptosis. MgIG effectively mitigates this toxicity both in vitro and in vivo.

AIMS:The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of linezolid in patients with diabetic foot infections (DFIs) remain insufficiently characterized. This study aimed to develop a population PK model, optimize dosing regimens and establish individualized dosing software for linezolid. METHODS:Clinical characteristics, microbiological data and linezolid concentrations were retrospectively collected from 88 patients with DFIs, comprising 173 linezolid plasma concentrations and 247 microbial isolates. Population PK modelling and Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) and cumulative fraction of response (CFR). The final model was integrated into individualized dosing software. RESULTS:Linezolid pharmacokinetics were best described by a one-compartment model with first-order elimination. The typical clearance (CL) and volume of distribution (V) were 1.69 L/h and 17.4 L, respectively, with creatinine clearance (CrCL) identified as the primary covariate on CL. For isolates with MIC ≤2 μg/mL, simulations suggested 400 mg q12h for patients with CrCL ≤30 mL/min and 600 mg q12h for those with CrCL ≥30 mL/min. A regimen of 600 mg q12h achieved CFR ≥90% for major pathogens, including Staphylococcus aureus, Streptococcus agalactiae and Enterococcus faecalis, while 600 mg q24h was sufficient for Staphylococcus lugdunensis. The individualized dosing software demonstrated good agreement between observed and predicted concentrations. CONCLUSIONS:Renal function significantly affects linezolid pharmacokinetics in patients with DFIs. This study provides model-informed dosing strategies and a validated tool to support individualized linezolid therapy.

Unsaturated fatty acids (UFAs) play a crucial physiological role in human body. However, the concentration- related changes and prognostic significance of UFAs in epilepsyremain unclear. An optimized ultra- performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was developed to measure six key UFAs: oleic acid (OA), linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Subsequently, the levels of these six UFAs were determined in 40 healthy individuals and 49 epilepsy patients. The diagnostic value of UFAs and clinical examination indicators were assessed using statistical analysis and the support vector machine (SVM) algorithm. The results showed that the UPLC-MS/MS method successfully quantified the levels of OA, LA, AA, ALA, EPA, and DHA in both the healthy individuals and epilepsy patients. Compared with the healthy group, the levels of ALA, AA, and DHA were significantly elevated in the epilepsy group (P < 0.05). Pearson correlation analysis revealed a strong positive correlation among the UFAs in the epilepsy group. The orthogonal partial least squares-discriminant analysis (OPLS-DA) model showed that DHA and EPA were more important than cholesterol in distinguishing between two groups, although the separation was not complete. The SVM model achieved better separation, with an area under the curve (AUC) of 0.95 when including the six UFAs. The EPA/DHA ratio was identified as a key feature, with a significant contribution to the model's performance. Removing the six UFAs from the model reduced the AUC to 0.91, highlighting the predictive value of UFAs for epilepsy. In conclusion, ALA, AA, and DHA, are altered in epilepsy patients. The EPA/DHA ratio was found to be a key predictive indicator for epilepsy. The use of UFAs in conjunction with clinical examination data improved the predictive power of the SVM model, suggesting that UFAs have potential as biomarkers for epilepsy.

An Ultra Performance Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (UPL-MS/MS) method for simultaneous determination of 8, 11, 12, 20- hydroxyeicosatetraenoic acids (HETEs) and 13 s-hydroxyoctadecadienoic acid (13 s-HODE) in plasma was developed and optimized. The chromatographic separation of 8, 11, 12, 20-HETEs and 13 s-HODE was achieved on a Peptide Bridged Ethylene Hybrid Particles (BEH) C18 column (2.1 mm × 150 mm, 1.7 μm) with mobile phase A (Water containing 0.1% formic acid) and mobile phase B (acetonitrile containing 0.1% formic acid). HETEs and 13 s-HODE were quantified using multiple reaction monitoring mode. The developed UPLC-MS/MS method was applied to determine the plasma samples of 32 paraquat (PQ) poisoning patients, 20 diquat (DQ) poisoning patients and 38 healthy subjects. The results showed that the 8, 11, 12, 20-HETEs and 13 s-HODE have good linearity (R2 > 0.99) from 0.1-500 ng/mL. The levels of HETEs and 13 s-HODE were dramatically increased in PQ and DQ poisoning patients. There were high correlation between 8, 11, 12, 20-HETEs and 13 s-HODE. Orthogonal partial least squares discrimination analysis showed that three groups were distributed in different areas and separated well. In conclusion, a sensitive UPLC-MS/MS method had been developed and validated for determination of 8, 11, 12, 20-HETEs and 13 s-HODE in plasma of PQ and DQ patients.

OBJECTIVE:This study aims to optimize carbapenem dosing strategies in febrile neutropenic (FN) patients by evaluating the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) using Monte Carlo simulations based on published population PK (PopPK) models and real-world covariate data. METHODS:A systematic review of published PopPK studies on carbapenems in FN patients was conducted to obtain relevant PK parameters. In parallel, retrospective clinical data from FN patients treated at the First Affiliated Hospital of Wenzhou Medical University between January 2022 and April 2024 were collected to provide covariates for Monte Carlo simulation. Monte Carlo simulations were then performed to evaluate the PTA for various dosing regimens. Dosing regimens were assessed based on achieving a PTA of ≥ 90%. RESULTS:A total of 96 studies were screened, of which 4 met the inclusion criteria. Separately, real-world covariate data were obtained from 163 FN patients to inform the Monte Carlo simulations. The simulation results showed that standard label dosages of carbapenems administered over 0.5-h infusions failed to consistently achieve a PTA ≥ 90% at the current CLSI breakpoint of 1 mg/L for Enterobacterales. Notably, increasing the dose did not consistently improve PTA, whereas extending the infusion duration to 3 h or using continuous infusion strategy markedly enhanced the likelihood of attaining the PK/PD target. CONCLUSION:Standard carbapenem dosing with 0.5-h infusions may lead to suboptimal exposure in FN patients. Prolonging the infusion duration is an effective strategy to improve PTA and optimize efficacy.

We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and m/z 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC0-t of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.

Introduction:Alectinib is a widely used first-line ALK inhibitor for fusion-positive non-small cell lung cancer. However, its clinical use is limited by hepatotoxicity, and its mechanism remains unclear. This study aims to elucidate how alectinib induces liver injury and to explore a potential protective strategy. Methods:In vitro, AML-12 hepatocytes were incubated with alectinib to determine cell viability and morphology by using CCK-8 assay and optical microscopy, respectively. Necrosis was assessed by flow cytometry after Annexin V-FITC/PI staining. Mitochondrial damage was analyzed by measuring membrane potential, ultrastructure, and respiratory chain complex activities using JC-1 staining under fluorescence microscopy, transmission electron microscopy, and assay kits, respectively. Intracellular reactive oxygen species (ROS) levels were detected using DCFH-DA staining and flow cytometry. Pyroptosis- and oxidative stress-related proteins (NLRP3, GSDMD-N, P20, cleaved IL-1β, Nrf2, HO-1) were quantified by Western blot. In vivo, C57BL/6J mice were divided into control, alectinib treatment, and alectinib plus magnesium isoglycyrrhizinate (MgIG) treatment groups. Serum ALT and AST were measured to assess liver function. Hepatic oxidative stress was evaluated by SOD and MDA levels. Inflammatory cytokines including IL-1β and TNF-α were measured by corresponding kits. Liver histopathology was examined by hematoxylin-eosin staining. Results:We found alectinib could induce the death of AML-12 hepatocytes. Alectinib impaired both the function and structure of mitochondria and caused a significant increase in ROS levels. The excessive accumulation of ROS triggered oxidative stress and finally resulted in cell pyroptosis in AML-12 cells. MgIG was found to alleviate mitochondrial damage and reduce ROS levels, restore the Nrf2/HO-1 signaling pathway, thereby inhibiting oxidative stress and pyroptosis caused by alectinib. Conclusion:Alectinib induces elevated ROS levels in hepatocytes by damaging mitochondria and causing oxidative stress in hepatocytes, which results in cell pyroptosis and ultimately hepatotoxicity, whereas MgIG can treat alectinib-induced hepatic injury by restoring mitochondrial function and structure.

Objective: Serum lactic acidosis has been reported as a serious adverse effect associated with linezolid. This study aims to explore the risk factors of linezolid‐induced lactic acidosis. Methods: Patients admitted to a 3600‐bed university hospital, who received linezolid treatment and had at least one steady‐state concentration of linezolid, were retrospectively reviewed to analyze the incidence of linezolid‐induced lactic acidosis. Meanwhile, univariate and multivariate logistic regression analyses were conducted to determine the risk factors of lactic acidosis. Results: A total of 95 adult patients were included in the study. 18.95% (18 out of 95) of patients developed lactic acidosis during linezolid treatment. Importantly, patients who concurrently used linezolid and metformin had a high risk of developing lactic acidosis (90.9%, 10 out of 11). After excluding these patients from the original database, 9.52% (8 out of the 84) of the patients developed lactic acidosis. In the population not receiving concurrent metformin treatment, univariate analysis showed that patients who developed lactic acidosis had higher linezolid C min and serum creatinine levels or lower creatinine clearance, and multivariate analysis showed that C min (OR: 1.114; 95% CI: 1.012–1.226; p = 0.027) was an independent risk factor for lactic acidosis. Conclusion: The concurrent use of linezolid and metformin raises the risk of lactic acidosis. Therapeutic drug monitoring of linezolid based on C min is recommended for decreasing the risk of lactic acidosis during linezolid treatment.

ABSTRACT:Omadacycline is a novel aminomethylcycline antibiotic that retains its antibacterial activity against strain-specific efflux pumps and ribosomal protective protein mechanisms of tetracycline resistance. To determine the concentration of omadacycline in human plasma, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to provide a basis for therapeutic monitoring of omadacycline in clinical settings. The experimental approach involves using an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm), with a mobile phase of 0.1% aqueous formic acid:acetonitrile (90:10, vol/vol), a flow rate of 0.3 mL·min -1 , a column temperature of 40°C, and an injection volume of 0.1 μL. Protein precipitation was employed as pretreatment, using acetonitrile as the precipitant. Minocycline was used as an internal standard. Omadacycline and internal standard were monitored in positive ion mode with the following mass transition pairs: mass/charge (m/z) = 557.1→ 470.1 for omadacycline, and m/z = 458.3→ 440.9 for IS, respectively. The established method showed a good linearity in the range of 0.01-10 mcg/mL of omadacycline (Y = 0.4603X + 0.0452, r 2 = 0.999), with the lower limit of quantification of 0.01 mcg/mL. Method validation included accuracy, precision, matrix effect, recovery, carryover, dilution integrity, and stability, all of which met the requirements of the US Food and Drug Administration for the validation of bioanalytical methods. This method has been successfully applied to therapeutic drug monitoring in patients.

INTRODUCTION:This study aimed to reevaluate the clinical efficacy and safety of omadacycline in treating acute bacterial infections. METHODS:We searched PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials up to 1 January 2024, including only randomized controlled trials comparing OMC with other antibiotics in adults. Primary outcomes were clinical and microbiological responses; secondary outcomes included adverse events. RESULTS:Seven RCTs with 2957 patients met the inclusion criteria. OMC showed a slightly better clinical response at the post-therapy evaluation phase in the clinically evaluable population (RR = 1.03, 95% CI = 1.01-1.05, I2 = 0%). Microbial eradication rates for Gram-positive and Gram-negative infections showed no significant differences between OMC and comparators. Safety analysis revealed no significant differences in overall AEs, treatment-related AEs, serious AEs, or drug discontinuation due to AEs. However, OMC had a lower risk of diarrhea (RR: 0.48, 95% CI = 0.23-1.00, I2 = 65%). All-cause mortality did not differ significantly between OMC and comparators. CONCLUSIONS:OMC is a safe and effective treatment for acute bacterial infections, comparable to other antibiotics. REGISTRATION:This study has been registered in the online systematic review database (Prospective Register of Systematic Reviews [PROSPERO]), and the registration number is CRD42024575416.

This study aims to investigate the impact of therapeutic drug monitoring (TDM) on the microbiological eradication rate in patients with Staphylococcus aureus bacteremia. Demographic information and laboratory data were collected for patients who were diagnosed with Staphylococcus aureus bacteremia during their hospital stays from January 2021 to May 2024. A total of 105 patients were included in the TDM group and 208 patients in the non-TDM group. The Chi-squared test showed a significantly higher microbiological eradication rate in the TDM group compared to the non-TDM group before (p<0.001) and after (p=0.003) propensity score matching. Subgroup analysis showed that the eradication rate was significantly higher in the TDM group for patients with either methicillin-sensitive Staphylococcus aureus bacteremia (p<0.001) or methicillin-resistant Staphylococcus aureus bacteremia (p=0.007). Moreover, for patients with multi-site infections, the microbiological eradication rate was significantly higher in the TDM group for either methicillin-sensitive Staphylococcus aureus bacteremia (p<0.001) or methicillin-resistant Staphylococcus aureus bacteremia (p<0.001). Although the drugs undergoing TDM in this study-vancomycin, daptomycin, linezolid, and teicoplanin-are primarily used for treating methicillin-resistant Staphylococcus aureus bacteremia, TDM for these agents can also significantly improve the microbiological eradication rate in methicillin-sensitive Staphylococcus aureus bacteremia. Furthermore, multivariate logistic regression analysis confirmed that TDM is an independent protective factor for microbiological eradication rate (p<0.001). In conclusion, this study demonstrates that performing TDM in patients with Staphylococcus aureus bacteremia can indeed enhance the microbiological eradication rate, thereby improving patient outcomes.

Bruton’s tyrosine kinase inhibitors have been demonstrated preliminary efficacy in diffuse large B-cell lymphoma (DLBCL). To compare the safety and efficacy of zanubrutinib plus rituximab and lenalidomide (ZR2) and R-CHOP-like for elderly patients with newly diagnosed DLBCL, we conducted this single-center prospective study. Patients were treated with 6 cycles of ZR2 or R-CHOP-like regimen for the first-line treatment. The primary endpoint was complete response ratio (CRR). The secondary outcome measures were progression-free survival (PFS), overall survival (OS), and adverse events. Between June 15, 2020, and March 11, 2023, 30 patients with ZR2 and 60 patients with R-CHOP-like were enrolled. There were no significant differences observed in CRR (P = 0.878), PFS (P = 0.555) and OS (P = 0.769) between ZR2 and R-CHOP-like group. While, patients in ZR2 group had the following features: significantly older (P = 0.002), more unfit (P < 0.001) and higher prognosis risk scores (P = 0.025). The incidence of grade ≥ 3 anemia (P = 0.008) and pneumonia (P = 0.001) was significantly lower in ZR2 group. Patients with germinal center B-cell-like subtype (GCB), large masses or TP53 mutations had a satisfactory remission rate in ZR2 group (57.1

OBJECTIVE:This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US. METHODS:Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio. RESULTS:The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year. CONCLUSION:For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.

Liver fibrosis (LF) is a common sequela to diverse chronic liver injuries, leading to rising rates of cirrhosis and hepatocellular carcinoma (HCC). As the medicinal and edible homologous material, traditional teas have exhibited promising applications in the clinical management of liver fibrosis. Here, we generated a liver fibrosis mouse model to explore the potent therapeutic ability of Ampelopsis grossedentata (AG) tea on this condition by multi-omics analysis. The biochemistry results pointed towards mitigated increases of ALT, AST, TBIL, and ALP triggered by BDL in the AG-treated group. Examination using H&E and Sirius Red staining revealed severe liver injuries, inflammation infiltration, amplified fibrosed regions, and the creation of bile ducts, all of which were fallout from BDL. Immunohistochemistry findings also implicated a noteworthy upregulation of the HSC activation marker alpha-smooth muscle actin (alpha-SMA) and the fibrosis marker collagen I in the BDL group. However, these symptoms demonstrated a significant improvement in the group treated with 100 mg/kg AG. Findings from the Western Blot test corroborated the prominent elevation of TNF-alpha, col1a1, alpha-SMA, and TGF-beta, instigated by BDL, while AG treatment meaningfully modulated these proteins. Furthermore, our study underscored the potential involvement of several microbiota, such as Ruminococcaceae UCG-014, Eubacterium Ruminantium, Ruminococcus 1, Christensenellaceae R-7, Acetatifactor, Dubosiella, Parasutterella, Faecalibaculum, and Defluviitaleaceae UCG-011, in the progression of liver fibrosis and the therapeutic efficacy of AG. This investigation shows that during the process of AG ameliorating BDL-induced liver fibrosis, bile acid derivatives such as CDCA, TCDCA, 3-DHC, UCA, DCA, among others, play significant roles. In this study, we identified that several non-bile acid metabolites, such as Deltarasin, Thr-Ile-Arg, etc., are entailed in the process of AG improving liver fibrosis.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

Abstract: Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum, has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.

BackgroundLenalidomide is a thalidomide analog that has immunomodulatory and anti-angiogenic properties. The ECOC-ACRIN E1412 Phase II trial demonstrated that lenalidomide, when combined with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), extended survival in diffuse large B-cell lymphoma (DLBCL) patients. This study aimed to evaluate the cost-effectiveness of combining lenalidomide with R-CHOP (R2-CHOP) versus R-CHOP alone as the initial treatment for DLBCL from the perspective of the Chinese healthcare system.MethodsWe developed a 5-year partitioned survival model to compare the cost-effectiveness of R2-CHOP versus R-CHOP alone. The clinical data came from the ECOG-ACRIN E1412 clinical trial. The costs of drugs and examinations were obtained from publicly available Chinese medical databases and literatures. Model robustness was assessed by sensitivity analysis and scenario analysis. And subgroup analysis was also performed. Key outcomes include total cost, quality-adjusted life years, and the incremental cost-effectiveness ratio (ICER).ResultsOver a 5-year time horizon, the basic analysis results of the partitioned survival model showed that the ICER of $35,159.06 per QALY for R2-CHOP compared to R-CHOP. Deterministic sensitivity analysis revealed that the price of lenalidomide is the main factor affecting cost-effectiveness. Probabilistic sensitivity analysis indicated a 67.9% chance of lenalidomide plus R-CHOP being cost-effective at the willingness-to-pay threshold, compared to R-CHOP alone. Scenario analysis showed R2-CHOP scenarios to be cost-effective for 10–30 years. And subgroup analysis showed that treating activated B cell-like type DLBCL with R2-CHOP was more cost-effective.ConclusionIn the Chinese healthcare system, R2-CHOP is a cost-effective approach for DLBCL compared to R-CHOP, but the costs of lenalidomide and rituximab warrant attention.

AIM:Our study is to investigate the effects of triazole antifungal drugs on the pharmacokinetics of lorlatinib in rats.METHODS:The samples were precipitated with methanol. Chromatographic separation was performed on a ultra-performance liquid chromatography (UPLC) system using a BEH C18 column. The mobile phase consisted of 0.1% formic acid water and methanol. Lorlatinib and crizotinib (internal standard) were detected in multiple reaction monitoring mode. The fragment ions were 407.3-228.07 for lorlatinib and m/z 450.3-260.0 for crizotinib. Lorlatinib and different triazole antifungal drugs were given to Sprague Dawley rats by gavage, and blood was collected from the tail vein at a certain time point. The validated UPLC-MS/MS method was applied to a drug interaction study of ketoconazole, voriconazole, itraconazole, and posaconazole with lorlatinib in rats.RESULTS:Ketoconazole and voriconazole significantly inhibited lorlatinib metabolism. When administration with ketoconazole and voriconazole, the area under the curve from time zero to infinity of lorlatinib increased by 49.0% and 104.3%, respectively; the clearance decreased by 40.0% and 40.0%, respectively. While itraconazole and posaconazole did not affect lorlatinib pharmacokinetics.CONCLUSION:The UPLC-MS/MS-based assay is helpful to further understand the pharmacokinetics of lorlatinib in rats, and confirmed the findings that the combination of lorlatinib with CYP3A inhibitors should be avoided as predicted by our pre-clinical studies.

As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ poisoning continues to present a medical challenge. In this study, the objective was to investigate the early metabolic changes in serum metabolism and identify the key metabolic pathways involved in patients with PQ poisoning. Quantitative analysis was conducted to determine the relevant metabolites. Additionally, experiments were carried out in both plasma and cell to elucidate the mechanisms underlying metabolic disorder and cell death in PQ poisoning. The study found that polyunsaturated fatty acids (PUFAs) and their metabolites, such as arachidonic acid (AA) and hydroxy eicosatetraenoic acids (HETEs), were significantly increased by non-enzymatic oxidative reaction. Reactive oxygen species (ROS) production increased rapidly at 2 h after PQ poisoning, followed by an increase in PUFAs at 12 h, and intracellular glutathione, cysteine (Cys), and Fe2+ at 24 h. However, at 36 h later, intracellular glutathione and Cys decreased, HETEs increased, and the expression of SLC7A11 and glutathione peroxidase 4 (GPX4) decreased. Ultrastructural examination revealed the absence of mitochondrial cristae. Deferoxamine was found to alleviate lipid oxidation, and increase the viability of PQ toxic cells in the low dose. In conclusion, unsaturated fatty acids metabolism was the key metabolic pathways in PQ poisoning. PQ caused cell death through the induction of ferroptosis. Inhibition of ferroptosis could be a novel strategy for the treatment of PQ poisoning.