Disproportional signal of pericarditis with biological diseasemodifying antirheumatic drugs (bDMARDs) in patients with ankylosing spondylitis: a disproportionality analysis in the FAERS database.

Objective: This study aimed to investigate the potential association between biological disease-modifying antirheumatic drugs (bDMARDs) and pericarditis and uncover relevant clinical characteristics in ankylosing spondylitis (AS). Methods: Reports of pericarditis recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004-December 2022) were identified through the preferred term "pericarditis." Demographic and clinical characteristics were described, and disproportionality signals were assessed through the reporting odds ratio (ROR) and information component (IC). A significant signal was detected if the lower bound of IC (IC025) was more than zero. Results: We found 1,874 reports of pericarditis with bDMARDs (11.3% of cases with fatal outcomes). Adalimumab (IC025 3.24), infliximab (IC025 4.90), golimumab (IC025 5.40), certolizumab (IC025 5.43), etanercept (IC025 3.24), secukinumab (IC025 3.97), and ustekinumab (IC025 7.61) exhibit significant disproportionality signals compared to other medications in the FAERS database. After excluding pre-existing diseases and co-treated drugs that may increase the susceptibility of pericarditis, the disproportionality signal associated with infliximab, certolizumab, etanercept, secukinumab, and ustekinumab remained strong. Pericarditis cases associated with all bDMARDs were predominantly recorded in women aged 25-65 years. Conclusion: More reports of pericarditis were detected with AS patients on bDMARDs than with other drugs in the overall database. Further studies are warranted to investigate the underlying mechanisms and identify patient-related susceptibility factors, thus supporting timely diagnosis and safe(r) prescribing of bDMARDs.

Analyzing the correlation between quinolone-resistant Escherichia coli resistance rates and climate factors: A comprehensive analysis across 31 Chinese provinces.

BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.

Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System.

BACKGROUND AND OBJECTIVE: Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear. METHODS: A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship. RESULTS: From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria. CONCLUSIONS: This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.

The pharmacology and mechanisms of traditional Chinese medicine in promoting liver regeneration: A new therapeutic option.

BACKGROUND: The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases. PURPOSE: This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients. METHODS: We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed. RESULTS: Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review. CONCLUSION: This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.

Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features. Methods: Reports of PJP recorded in FAERS (January 2004-December 2022) were identified through the preferred term "Pneumocystis jirovecii pneumonia". Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence. Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed. Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice.

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study.

Introduction: Antibody-drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies. Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis. Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses. Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p <0.001); however, age did not exert influence on the risk of sepsis. We identified that 973 of 2,441 (39.9%) cases had acute myeloid leukemia (AML), and 766 of 2613 (29.3%) cases on ADCs died during therapy. Time-to-onset analysis indicated ADC-related sepsis is prone to occur within a month after administration. Co-administration of ADCs with colony-stimulating factors, proton pump inhibitors, H2-receptor antagonists, or CYP3A4/5 inhibitors showed to synergistically increase the risk of sepsis-related toxicities. Conclusion: Antibody-drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

Does Monitoring Total and Free Polymyxin B1 Plasma Concentrations Predict Polymyxin B-Induced Nephrotoxicity? A Retrospective Study in Critically Ill Patients.

INTRODUCTION: The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the relationships between plasma exposure of PMB1 and PMB2 and nephrotoxicity, and investigates the risk factors for PMB-induced acute kidney injury (AKI) in critically ill patients. METHODS: Critically ill patients who used PMB and met the criteria were enrolled. The total plasma concentration and plasma binding of PMB1 and PMB2 were analysed by liquid chromatography-tandem mass spectrometry and equilibrium dialysis. RESULTS: A total of 89 patients were finally included, and AKI developed in 28.1% of them. The peak concentration of PMB1 (Cmax (B1)) (adjusted odds ratio (AOR) = 1.68, 95% CI 1.08-2.62, p = 0.023), baseline BUN level (AOR = 1.08, 95% CI 1.01-1.16, p = 0.039) and hypertension (AOR = 3.73, 95% CI 1.21-11.54, p = 0.022) were independent risk factors for PMB-induced AKI. The area under the ROC curve of the model was 0.799. When Cmax (B1) was 5.23 µg/ml or more, the probability of AKI was higher than 50%. The ratio of PMB1/PMB2 decreased after PMB preparation entered into the body. The protein binding rate in critically ill patients indicated significant individual differences. Free Cmax (B) and free Cmax (B1) levels in the AKI group were significantly (p < 0.05) higher than those in the non-AKI group. Total and free concentrations of PMB in patients showed a positive correlation. CONCLUSIONS: Both the ROC curve and logistic regression model showed that Cmax (B1) was a good predictor for the probability of PMB-induced AKI. Early therapeutic drug monitoring (TDM) of PMB should be considered in critically ill patients. Compared with Cmin (B), Cmax (B) and Cmax (B1) may be helpful for the early prediction of PMB-induced AKI in critically ill patients.

Does Prolonged Infusion Time Really Improve the Efficacy of Meropenem Therapy? A Prospective Study in Critically Ill Patients.

INTRODUCTION: Meropenem is a carbapenem antibiotic, which has demonstrated excellent antimicrobial activity against gram-negative clinical isolates. It is also commonly used in critically ill patients. This study aimed to determine the pharmacokinetics/pharmacodynamics of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. METHODS: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix. RESULTS: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), and volume of peripheral compartment (V2) were 6.15 l/h, 2.83 l/h, 17.40 l, and 17.48 l, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance ≤ 60 ml/min and uric acid > 400 µmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/l, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC < 4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4 MIC, no significant statistical difference was observed in critically ill patients. CONCLUSIONS: Critically ill patients with lower creatinine clearance and higher uric acid levels tended to need a lower dosage of meropenem. Prolonged infusion time was not always beneficial for those who needed a higher therapeutic target (100% fT > MIC, 100% fT > 4 MIC) or with MIC > 4 mg/l. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients. TRIAL REGISTRATION: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Meropenem is commonly used empirically or targeted in critically ill patients for bacterial infection. Many studies have reported that prolonged infusion time can improve the efficacy of meropenem therapy. However, we are skeptical about that. Meanwhile, prolonged injections can sometimes cause mobility problems for patients. A quantitative method is used to evaluate meropenem use. It is called the population pharmacokinetic model or pharmacodynamic study. Using this method, we found two significant influencing factors of meropenem metabolism: creatinine clearance and uric acid level. It is likely that patients with a lower level of creatinine clearance and a high uric acid level tend to require lower dosages of meropenem. As for the effect of infusion time, Monte Carlo simulation was used, which can do 3000 simulations on an individual. The result was complex. We found infusion time was beneficial only when bacteria were sensitive to meropenem. The evidence suggests that prolonged injection duration sometimes does not significantly improve the outcome of antimicrobial therapy.

Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children.

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0-5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg-1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities.

Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

Population Pharmacokinetics of Polymyxin B and Dosage Optimization in Renal Transplant Patients.

Currently, polymyxin B has been widely used in the treatment of multidrug-resistant Gram-negative pathogen infections. Due to the limited pharmacokinetic/pharmacodynamic data, the optimal dosage regimen for the recently proposed therapeutic target of the area under the concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration 50-100 mg⋅h/L has not yet been established. Moreover, most studies have focused on critically ill patients, yet there have been no studies in the field of renal transplantation. To optimize the dosage strategy and reduce the risk of toxicity, a population pharmacokinetics model of polymyxin B with the Phoenix NLME program was developed in our study. A total of 151 plasma samples from 50 patients were collected in the present study. Polymyxin B plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. A one-compartment model adequately described the data, and the clearance and volume of distribution were 1.18 L/h and 12.09 L, respectively. A larger creatinine clearance was associated with increased clearance of polymyxin B (p < 0.01). Monte Carlo simulation showed that a regimen of a 75 mg loading dose with a 50 mg maintenance dose was a better option to achieve an optimal therapeutic effect (minimum inhibitory concentration ≤1 mg/L) and to reduce the incidence of side effects for patients with renal impairments. The developed model suggested that dosing adjustment should be based on renal function in renal transplant patients.

A Novel Creatinine-Based Equation to Estimate Glomerular Filtration Rate in Chinese Population With Chronic Kidney Disease: Implications for DOACs Dosing in Atrial Fibrillation Patients.

Background: Over/under-estimating renal function may increase inappropriate dosing strategy associated adverse outcomes; however, previously reported equations to estimate renal function have limited accuracy in chronic kidney disease (CKD) patients. Consequently, we intended to develop a novel equation to precisely estimate renal function and subsequently guide clinical treatment for CKD patients. Methods: A novel approach, Xiangya-s equation, to estimate renal function for CKD patients was derived by linear regression analysis and validated in 1885 patients with measured glomerular filtration rate (mGFR) < 60 ml/min/1.73 m2 by renal dynamic imaging at three representative hospitals in China, with the performance evaluated by accuracy, bias and precision. In the meanwhile, 2,165 atrial fibrillation (AF) patients who initiated direct oral anticoagulants (DOACs) between December 2015 and December 2018 were identified and renal function was assessed by estimated creatinine clearance (eCrCl). Events per 100 patient-years was calculated. Cox proportional hazards regression was applied to compare the incidence of outcomes of each group. Results: Xiangya-s equation demonstrated higher accuracy, lower bias and improved precision when compared with 12 creatinine-based and 2 CysC-based reported equations to estimate GFR in multi-ethnic Chinese CKD patients. When we applied Xiangya-s equation to patients with AF and CKD prescribed DOACs, wide variability was discovered in eCrCl calculated by the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Xiangya equation which we had developed for generally patients and Xiangya-s equations, which persisted after grouping by different renal function stages. Equation choice affected drug-dosing adjustments, with the formulas agreeing for only 1.19%, 5.52%, 33.22%, 26.32%, and 36.61% of potentially impacted patients for eCrCl cutoffs of <15, <30, 15-49, 30-49, ≥50 ml/min, respectively. Relative to CG equation, accordance in DOACs dosage was 81.08%, 88.54%, 62.25%, and 47.68% for MDRD, CKD-EPI, Xiangya and Xiangya-s equations for patients with CrCl < 50 ml/min (eCrCl cutoffs of <30, 30-49, ≥50 ml/min), respectively. Reclassification of renal function stages by Xiangya-s equation was significantly associated with stroke or systemic embolism, non-major clinically relevant bleeding and any bleeding events. Conclusion: Xiangya-s equation provides more accurate GFR estimates in Chinese CKD patients who need consecutive monitoring of renal function, which may assist clinicians in choosing appropriate drug dosages.

Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway.

Considerable attention has been raised on crizotinib- and sunitinib-induced hepatotoxicity, but the underlying mechanisms need further examination. In addition, limited therapeutic strategies exist to reduce the liver damage caused by crizotinib and sunitinib. This study investigated the mechanisms of crizotinib- and sunitinib-induced hepatotoxicity and the potential mitigation through ROS and Nrf2 signaling. Firstly, crizotinib and sunitinib reduced cell viability in human liver cells (L02 cells) and triggered dramatic liver injury in mice. Subsequently, we found that crizotinib and sunitinib activated the oxidative stress response (decreased level of GPx and SOD, and increased MDA content) in vivo. Crizotinib and sunitinib also stimulated hepatocyte mitochondrial apoptosis and necrosis in L02 cells in a dose-dependent manner. In vivo studies further confirmed that crizotinib and sunitinib decreased mitochondrial membrane potential and activated apoptosis-associated proteins (cleaved-PARP, cleaved caspase3, cytochrome c, Bcl2 and Bax). Furthermore, mechanistic investigations demonstrated that crizotinib and sunitinib accumulated ROS and inhibited Nrf2 signaling, and that ROS scavenger NAC and Nrf2 agonist tBHQ alleviated the extent of cell damage and the mitochondrial apoptosis during crizotinib- and sunitinib-induced hepatotoxicity in L02 cells. Collectively, these findings indicated that NAC and tBHQ play the crucial roles in crizotinib- and sunitinib-induced mitochondrial apoptosis via the regulation of oxidative stress.

Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity.

Nrf2 and NF-κB are important regulators of the response to oxidative stress and inflammation in the body. Previous pharmacological and genetic studies have confirmed crosstalk between the two. The deficiency of Nrf2 elevates the expression of NF-κB, leading to increased production of inflammatory factors, while NF-κB can affect the expression of downstream target genes by regulating the transcription and activity of Nrf2. At the same time, many therapeutic drug-induced organ toxicities, including hepatotoxicity, nephrotoxicity, cardiotoxicity, pulmonary toxicity, dermal toxicity, and neurotoxicity, have received increasing attention from researchers in clinical practice. Drug-induced organ injury can destroy body function, reduce the patients' quality of life, and even threaten the lives of patients. Therefore, it is urgent to find protective drugs to ameliorate drug-induced injury. There is substantial evidence that protective medications can alleviate drug-induced organ toxicity by modulating both Nrf2 and NF-κB signaling pathways. Thus, it has become increasingly important to explore the crosstalk mechanism between Nrf2 and NF-κB in drug-induced toxicity. In this review, we summarize the potential molecular mechanisms of Nrf2 and NF-κB pathways and the important effects on adverse effects including toxic reactions and look forward to finding protective drugs that can target the crosstalk between the two.

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.

AIMS: Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. METHODS: The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 µmol/L; TBIL-2: 51 µmol/L ≤ TBIL < 171 µmol/L; TBIL-3: TBIL ≥ 171 µmol/L) were performed. RESULTS: Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. CONCLUSIONS: Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Calcitonin gene­related peptide­mediated pharmacological effects in cardiovascular and gastrointestinal diseases (Review).

Calcitonin gene­related peptide (CGRP) is the predominant neurotransmitter located in sensory nerves. This peptide is extensively distributed in central and peripheral tissues. CGRP causes relaxation of cardiovascular smooth muscle cells and confers protection against ischaemic myocardium and cardiac remodeling. The pharmacological effects of nitroglycerine and rutaecarpine have been demonstrated to be associated with an increase in the synthesis and release of CGRP. In the gastrointestinal tissues, CGRP participates in the regulation of gastrointestinal function, and exerts protective effects on gastric mucosa. Rutaecarpine, capsaicin and its derivatives, such as evodiamine, decrease gastric mucosal damage induced by several factors, including increased synthesis and release of CGRP. Taken together, this review focuses on the pharmacological effects of several CGRP related canonical drugs and suggests that synthesis and secretion of CGRP exhibit significant therapeutic effects in the occurrence and development of cardiovascular and gastrointestinal diseases.

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R2  = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

Bioequivalence and Pharmacokinetic Evaluation of Two Metformin Hydrochloride Tablets Under Fasting and Fed Conditions in Healthy Chinese Volunteers.

This article aims to assess the bioequivalence of the test and the reference metformin hydrochloride tablets in healthy Chinese volunteers under fasting and fed conditions and to explore the effect of food on the pharmacokinetic (PK) profiles of both formulations. In total, 56 healthy Chinese subjects (28 in each group) were enrolled in this randomized, open, single-center, single-dose, 2-treatment, 2-sequence, 2-cycle cross clinical trial. The subjects were administrated a single dose of the test and the reference tablets at 0.25 g with a 7-day washout. Venous blood samples of all subjects were taken from predose 0 hour to postdose 24 hours according to the planned times. PK parameters for metformin were analyzed and calculated with noncompartmental methods. There were no significant differences in the PK parameters between the 2 formulations under both the fasting and the fed states. The 90% confidence intervals of 2 formulations were within 80.00%-125.00% based on Cmax , AUC0-t , and AUC0-∞ under both conditions. High-fat and high-calorie diets delayed the Tmax and reduced the AUC0-t and AUC0-∞ . No severe adverse events occurred in this study. Two metformin hydrochloride tablets were bioequivalent under both fasting and fed states; the high-fat and high-calorie diet could lower the rate and extent of absorption of metformin in healthy Chinese volunteers.