ObjectivesNirmatrelvir/ritonavir (N/R) is an effective antiviral for treating COVID-19. However, evidence supporting therapeutic drug monitoring (TDM) for N/R remains limited, potentially increasing the risk of adverse reactions and compromising efficacy. This study aims to identify factors influencing N/R plasma exposure and to develop and internally validate a machine learning model for predicting N/R concentrations, thereby supporting individualized therapy.MethodsWe retrospectively analyzed data from 139 patients who received N/R at two centers. Baseline clinical and laboratory variables were collected, and steady-state trough concentrations of nirmatrelvir and ritonavir were measured on day 3 of treatment. Logistic regression was used to examine the association between drug concentration and prognosis. After excluding highly correlated features, a random forest model identified key factors affecting drug exposure. An XGBoost regression model was then constructed with the selected features, and its predictive performance was evaluated using mean absolute error (MAE), mean squared error (MSE), root mean squared error (RMSE), and R². Five-fold cross−validation was applied for internal validation.ResultsNirmatrelvir trough concentration was not predictive of patient outcomes (AUC = 0.467). Six factors were consistently identified as important determinants of N/R exposure: estimated glomerular filtration rate (eGFR), creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lymphocyte count (Lymph), and procalcitonin (PCT). Ultimately, the evaluation of the predictive model resulted in a mean absolute error (MAE) of 0.717, mean squared error (MSE) of 1.328, root mean squared error (RMSE) of 1.152, and coefficient of determination (R-squared) of 0.779. The prediction model performs well and can provide risk prediction for medication management for N/R, as well as assist in personalized medication.ConclusionsWe identified a set of variables that affect the treatment of N/R through therapeutic drug monitoring and established a machine learning model capable of predicting N/R concentrations with satisfactory performance. These findings provide a basis for integrating TDM with multivariable prediction tools to personalize N/R dosing and improve medication safety.

Purpose:To identify predictive metabolic biomarkers for immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICIs) using metabolomics, supporting early detection and intervention. Patients and Methods:Fifty-five ICI-treated cancer patients from Changxing People's Hospital were divided into irAEs-positive (34 cases) and irAEs-negative (21 cases) groups after 12-month follow-up. Pretreatment serum samples were analyzed by untargeted UPLC-MS metabolomics. PCA, OPLS-DA, and KEGG pathway enrichment were used to screen differential metabolites and key pathways. Results:Seventy significant differential metabolites (eg, ursodeoxycholic acid, uric acid) were identified. β-Alanine metabolism, pentose phosphate pathway, and coenzyme A biosynthesis were closely correlated with irAEs. Five metabolites showed AUC 0.7-0.9 with favorable predictive performance. Conclusion:Metabolomics reveals specific metabolites and metabolic pathways linked to ICI-induced irAEs, providing potential biomarkers for early prediction and new insights into irAEs pathogenesis to optimize clinical management.

Azithromycin is widely used to treat infections caused by susceptible bacteria and is the first-line treatment for mycoplasma pneumonia in pediatric patients. However, in clinical practice, large between-patient variability has been observed. Several population pharmacokinetic studies have been conducted to identify covariates and guide individualized therapy. This study evaluated published population pharmacokinetic studies and explored the significant covariates. The PubMed, Embase, and Web of science databases were systematically searched from their inception to 30 May 2024. Information on study design, characteristics, and final model parameters was extracted and compared. Time-concentration curves and forest plots were used to examine pharmacokinetic characteristics and identify covariates, respectively. Fifteen population pharmacokinetic studies were included in the review: three involved preterm neonates, two involved children, two involved pregnant/non-pregnant women, and eight involved adults. The median apparent clearance value was higher for adults (1.66 L/h/kg) than for children (1.28 L/h/kg) and preterm neonates (0.187 L/h/kg). For all populations, body weight significantly influenced the apparent clearance and distribution volume. In children, age and liver function influenced azithromycin clearance; whereas for women, clearance was reduced by 38% in case of pregnancy, non-African descent, and oral contraceptive use. Azithromycin was shown to distribute across plasma, tissues, and cells, with notable concentration differences. The azithromycin dose regimen is determined based on body weight. However, for children and women, additional predictors should be considered for individualized therapy. Further azithromycin population studies of the dose-exposure-response relationship are needed to achieve accurate dose adjustments.

Off-target effects, which arise from drug interactions in nontarget tissues, can lead to unfavored side effects. The treatment efficacy of vancomycin (Vanco) in Gram-positive bacterial infections is often compromised by the frequent occurrence of Vanco-induced vascular injury. However, the potential targets and underlying molecular mechanisms of this phenomenon remain unclear. Here, we developed multidimensional two-photon imaging for dynamic tracking of fluorescently labeled Vanco in vivo, characterizing the molecular behavior of Vanco in situ after administration and providing the first direct evidence of its interactions with vascular wall. Morphological analysis combined with colocalization imaging identified elastin within the vascular wall as the molecular target. After binding, Vanco underwent self-assembly into forming irregular nanoaggregates, primarily driven by electrostatic and hydrophobic forces. This persistent binding and self-assembly on the elastic lamina resulted in significant endothelial cytotoxicity and subsequent apoptosis, suggesting a mechanistic link to the vascular injury observed in clinical settings. Taken together, our findings revealed off-target molecular interactions between Vanco and vascular elastin in situ, highlighting the importance of considering unintended drug-vascular interactions.

Tumor senescence, a double-edged sword, can suppress tumor growth but also promote immune evasion if not properly cleared. Herein, a cell membrane-coated ZIF-8@MnOx nanoplatform co-loaded with doxorubicin (DOX) and piperlongumine (PL), termed mPDZM, is developed to remodel the senescence-mediated immune response in hepatocellular carcinoma. PL synergizes with DOX to amplify intracellular oxidative stress, which promotes both the killing of tumor cells and the clearance of senescent cells. The biomimetic ZIF-8@MnOx nanoplatform potentiates the efficacy of DOX and PL by integrating targeted delivery, hypoxia relief, and redox homeostasis disruption. mPDZM remodels the immunosuppressive microenvironment by regulating SASP release, inducing immunogenic cell death, and activating the STING signaling pathway. In vivo, mPDZM exhibits preferential tumor accumulation and minimal systemic toxicity. mPDZM treatment leads to significant tumor suppression both in the senescent and non-senescent tumor models. Moreover, mPDZM effectively promotes CD8+ T cell and NK cell infiltration, while reducing immunosuppressive Treg cells and M2-like macrophages. In combination with anti-PD-L1 therapy, mPDZM further potentiates antitumor immunity and induces a robust abscopal effect against distant tumors. Collectively, these findings unveil a new paradigm that integrates senescence modulation with immune activation via a biomimetic nanotherapeutic platform and offers a promising combinatorial approach to overcome immune resistance in solid tumors.

[This corrects the article DOI: 10.3389/fphar.2024.1406247.].

Polymyxin B (PMB) serves as the last-line drug for treating multidrug-resistant Gram-negative bacterial infections. However, its clinical application is limited due to significant nephrotoxicity and neurotoxicity. In recent years, smart drug delivery systems have emerged as a research hotspot, aiming to optimise the functions and therapeutic effects of PMB. This article systematically reviews the structural characteristics and antibacterial mechanisms of PMB, as well as the challenges it faces in treating drug-resistant bacterial infections. The progress in smart delivery strategies for PMB is also discussed, including multidrug-resistant delivery, anti-biofilm technologies, targeted delivery, local administration, and synergistic treatment strategies. These strategies offer new directions for the precise treatment of PMB by increasing local drug concentration, reducing toxicity, enhancing the antibacterial spectrum, and inhibiting drug resistance.

The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment.

Introduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the influence of IQC on preventing the THP-induced cardiotoxicity in vivo and in vitro.Methods: The optimal concentration and time required for IQC to prevent THP-induced cardiomyocyte damage were determined by an MTT assay. The protective effect was further verified in H9c2 and HCM cells using dichlorodihydrofluorescein diacetate fluorescent probes, MitoTracker Red probe, enzyme-linked immunosorbent assay, JC-1 probe, and real time-quantitative polymerase chain reaction (RT-qPCR). Rats were administered THP to establish cardiotoxicity. An electrocardiogram (ECG) was performed, and cardiac hemodynamics, myocardial enzymes, oxidative stress indicators, and hematoxylin-eosin staining were studied. Voltage-dependent anion channel 1 (VDAC1), adenine nucleotide translocase 1 (ANT1), and cyclophilin D (CYPD) were detected by qRT-PCR, and the Phlpp1/AKT/Bcl-2 axis proteins were detected by western blot, confirming that IQC markedly increased cell viability and superoxide dismutase (SOD) levels, diminished the levels of ROS and MDA, and elevated mitochondrial function and apoptosis in vivo and in vitro.Results: Results showed that IQC reduced THP-induced myocardial histopathological injury, electrocardiogram (ECG) abnormalities, and cardiac dysfunction in vivo. IQC also decreased serum levels of MDA, BNP, CK-MB, c-TnT, and LDH, while increasing levels of SOD and GSH. We also found that IQC significantly reduced VDAC1, ANT1, and CYPD mRNA expression. In addition, IQC controlled apoptosis by modulating Phlpp1/AKT/Bcl-2 signaling pathways. IQC markedly increased H9c2 and HCM cell viability and SOD levels, diminished the levels of ROS and MDA, and elevated mitochondrial function in H9c2 and HCM cells to defend against THP-induced cardiomyocyte apoptosis in vitro. The AKT inhibitor IMQ demonstrated that IQC lacked antioxidant and anti-apoptotic properties. Moreover, our data showed that IQC regulates Phlpp1 expression, thereby influencing the expression levels of p-AKT, cytochrome c, caspase-3, caspase-9, Bcl-2, and Bax.Discussion: In conclusion, our results indicate that IQC protects the changes in mitochondrial membrane permeability in cardiomyocytes by regulating the Phlpp1/AKT/Bcl-2 signaling pathway, inhibits the release of cytc from the mitochondrial inner membrane to the cytoplasm, forms apoptotic bodies, induces cell apoptosis, and reduces THP induced cardiotoxicity.

In the research of clinical medicine, life sciences, tissue engineering, and emerging fields like organoids, in vitro cell culture technology represents the fundamental step, with widely recognized advantages of three-dimensional (3D) culture substrates over traditional two-dimensional culture. Further review and exploration of the preparation methods and materials for 3D cell scaffolds is of great significance for the interdisciplinary field of medicine and engineering. As the maturity of 3D micro-structures machining technologies, various paths that can prepare micro-scaffolds for cell culture have been proposed. The two-photon polymerization (TPP) has attracted significant interest among them due to the advantages of high resolution, without mask, simple process and wide range of materials. The key factor of two-photon polymerization is the cross-linking of the suitable materials, which formed versatile scaffolds to influence cell proliferation, differentiation and arrangement. This review features a comprehensive account on the latest advancements in TPP-based 3D micro-scaffolds for cell culture, organoids, life science and tissue engineering. After a brief introduction of processing principle of TPP, the review discusses critically various 3D cell scaffolds based on TPP-materials and structures including protein-based biomaterials, hybrid inorganic–organic materials, photoresist materials, resin materials, synthetic degradable materials and other common hydrogel materials. Subsequently, the applications of TPP-based scaffold in biomedical sciences also are reviewed. Finally, current weaknesses and fabrication limitations for the 3D cell scaffolds fabricated by TPP-based materials applied currently are summarized. In addition, we have further put forward our own views on the future development direction and industry trends in the field of TPP manufacturing of cell scaffolds. We believe that the advancement of design and preparation technology of 3D cell scaffolds will bring new creative points for fields such as organoids, tissue engineering, life science and medical-engineering integration.

Purpose:Nirmatrelvir/ritonavir (N/R) is the first drug to receive emergency authorization for the treatment of COVID-19 infection. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of potential covariates and explore dosing regimen. Patients and Methods:Sparse data of serum concentrations of N/R were obtained from 129 patients with COVID-19 infection receiving oral 300/100 mg N/R twice daily for 5 days. Plasma samples were assayed using ultra-high-performance liquid chromatography-tandem mass spectrometry. The PopPK model was developed using a nonlinear mixed effects approach utilizing the NONMEM 7.4 software. Monte Carlo simulation was conducted to optimize the dosage regimen. Results:A one-compartment model with first-order absorption and first-order elimination provided the best fit for the data. Allometric scaling of parameters on creatinine clearance (CrCl) and body weight were identified as covariates that significantly influenced exposure-efficacy after oral administration of nirmatrelvir. Monte Carlo simulation using the final model generated concentration-time profiles for virtual patients (1,000 per group) with varying renal functions and body weight. Furthermore, we developed a web-based dashboard to visualize the dynamic changes in nirmatrelvir concentration and provide individualized dosage regimens. Conclusion:This study showed that dosing regimen optimization of nirmatrelvir should be based on CrCl and body weight. Moreover, a web-based dashboard has been developed to facilitate individualized pharmacotherapy.

The EPIC III study showed that 52% of patients admitted to the intensive care unit (ICU) have infectious diseases and that the incidence of ICU-acquired infections is increasing, leading to longer ICU stays and higher mortality rates. Multiple-site decontamination, a type of selective decontamination program, has been associated with a reduction in the incidence of ICU-acquired infection and decreased mortality rates in some critically ill patients. However, the standardized implementation and actual effectiveness of multiple-site decontamination require further investigation.

Objective: Antibiotic utilization stands as the strongest modifiable determinant for Clostridioides difficile infection (CDI). However, previous studies have relied on aggregated antibiotic categories, leaving prescribers without detailed comparative risk information for individual antibiotics. The objective of this study was to estimate the risk of CDI comprehensively across specific antibiotics. Methods: Two methodologies were integrated to access and rank the risk of CDI associated with individual antibiotics or classes. Initially, a network comparison was conducted by analysing data from randomized controlled trials (RCTs). Subsequently, a real-world disproportionality analysis using the Food and Drug Adverse Event Reporting System (FAERS) database complemented and enriched the findings from RCTs. Results: The network comparison, encompassing 61 RCTs with 25,931 patients, revealed that exposure to cefepime [odds ratio (OR) 2.56, 95% confidence interval (CI) 1.20-5.44; P = 0.02] and imipenem/cilastatin (OR 3.86, 95% CI 1.61-9.29; P = 0.003) exhibited higher frequencies of CDI compared with piperacillin/tazobactam. No significant differences were observed between the carbapenems, albeit a trend indicating higher incidence of CDI with imipenem/cilastatin compared with meropenem (OR 3.89, 95% CI 0.94-16.09). In the FAERS disproportionality analysis, nearly all antibiotics displayed associations with CDI, and CDI risk signals often clustered within the majority of antibiotic classes. Among these, lincomycin demonstrated the strongest association (OR 112.17, 95% CI 51.68-243.43). Additionally, oral third-generation cephalosporins tended to exhibit higher CDI risk signals than other antibiotics. Conclusions: The findings unveiled substantial diversity in the risk of CDI, both within and between antibiotic classes, providing valuable guidance for clinicians in antibiotic prescription decisions and for initiatives aimed at antibiotic stewardship. (c) 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The primary aim of the study is to discuss the potential interactions between venetoclax and common drugs used in department of hematology and the corresponding effects on the efficacy and safety of venetoclax treatment. Here, we report an acute myeloid leukemia patient treated with venetoclax and posaconazole, and the dose of venetoclax was adjusted due to drug interactions. Clinical pharmacists actively participated in treatment of this patient to provide pharmacy care to assist clinicians to identify the venetoclax-induced liver function impairment and give timely management. The case reported here is hoped to provide reference for clinical venetoclax treatment in patients with such disease. Clinical pharmacists should actively participate in clinical treatment, actively screen potential drug interactions, strengthen cooperation and communication with doctors, provide patients with high-quality pharmaceutical services, and establish clinical pharmacists' status in the multidisciplinary treatment of tumor.