Drug Design, Development and Therapy最新文献

Purpose: This study aims to provide a reference for the introduction and utilization of oxazolidinone drugs in medical institutions, based on the authoritative Chinese guideline, Rapid Guideline for Drug Evaluation and Selection in Chinese Medical Institutions (2nd Edition) (Rapid Guideline).

Patients and methods: Based on the Rapid Guideline, this study conducted a comprehensive literature search across relevant databases, including the China National Knowledge Infrastructure (CNKI), PubMed, Embase, and the Cochrane Library, as well as drug labels and relevant clinical guidelines. A health technology assessment (HTA) was then performed on three oxazolidinone drugs across five dimensions: pharmaceutical properties, efficacy, safety, economy, and other attributes.

Results: The final evaluation results from highest to lowest were tedizolid (83.52 points), linezolid (80.02 points), and contezolid (72.79 points). The evaluation results of tedizolid across the five dimensions were as follows: pharmaceutical properties (25.5 points), efficacy (25 points), safety (17.5 points), economy (9.02 points), and other attributes (6.5 points). For linezolid, the scores were pharmaceutical properties (25 points), efficacy (25 points), safety (18 points), economy (5.02 points), and other attributes (7 points). For contezolid, the scores were pharmaceutical properties (24 points), efficacy (22 points), safety (18.5 points), economy (4.29 points), and other attributes (4 points).

Conclusion: Based on the comprehensive evaluation across five key dimensions, the recommended prioritization of oxazolidinone antibiotics is as follows: tedizolid, linezolid, and contezolid. The ranking was primarily driven by tedizolid's once-daily dosing and lowest total course cost, linezolid's pediatric indication and widespread availability, and contezolid's superior safety profile, although its overall score was limited by higher cost and lack of guideline recommendations. This study recommends the selection of tedizolid, linezolid, and contezolid for use in medical institutions during the introduction and application of oxazolidinone antibiotics.

Esophageal cancer remains a major global health burden, ranking seventh in cancer-related mortality. The prognosis is poor with five-year survival rates below 5% for metastatic disease. Tumor heterogeneity and the development of treatment resistance have limited durable responses to conventional chemotherapy. The emergence of biomarker-driven therapies has begun to transform management and enable more personalized treatment approaches. This narrative review summarizes current clinical strategies for esophageal cancer, emphasizing clinically validated biomarkers -HER2, PD-L1, CLDN18.2, and MMR/MSI status-that inform therapeutic selection for advanced metastatic disease. Both esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) are addressed; however, this review centers on biomarker-directed therapies for EAC, reflecting its predominance in Western populations and recent therapeutic progress. We highlight pivotal phase II and III clinical trials that have established the current landscape of esophageal cancer treatment. In addition, we review key early phase clinical data for promising new modalities such as antibody-drug conjugates, novel monoclonal antibodies, and cellular therapies-highlighting their biomarker associations and mechanisms of action. Finally, we discuss the ongoing challenges-including elucidating tumor heterogeneity, improving biomarkers, targeting novel tumor intrinsic vulnerabilities, overcoming treatment resistance, and preventing esophageal cancer development-and identify key research directions that present unique opportunities for the development of new biomarker-driven treatments for esophageal cancer.

Copper dyshomeostasis and the resulting induction of cuproptosis, a novel regulated cell death pathway driven by mitochondrial copper overload, play a critical role in renal pathophysiology. Cuproptosis is characterized by FDX1-mediated copper reduction, irreversible aggregation of lipoylated TCA cycle enzymes, such as dihydrolipoamide S-acetyltransferase, and destabilization of iron‒sulfur cluster proteins, leading to proteotoxic mitochondrial collapse. The kidney's high vulnerability arises from its filtration and metabolic functions. This review consolidates evidence linking cuproptosis to various renal disorders, including acute kidney injury (eg, sepsis-induced, cisplatin-induced, and ischemia-reperfusion injury), diabetic nephropathy through mitochondrial dysfunction and immune dysregulation, and chronic kidney disease involving podocyte damage or context-dependent dysregulation in fibrosis and clear cell renal cell carcinoma. Notably, cuproptosis and ferroptosis interact synergistically through shared mechanisms, where glutathione depletion or iron overload exacerbates both pathways, while mitochondrial dysfunction and lipid peroxidation create a self-perpetuating injury cycle. Emerging diagnostic strategies utilize cuproptosis-related biomarkers for early detection, supported by various prediction models. In therapeutic contexts, copper chelators, transporter modulators, and dual-pathway inhibitors targeting both cuproptosis and ferroptosis mitigate renal damage in preclinical models. Dietary interventions that modulate copper bioavailability also hold promise. However, challenges remain, including identifying renal cell type-specific mechanisms, developing noninvasive biomarkers, optimizing kidney-targeted nanotherapeutics, and preventing iatrogenic copper deficiency. Future research may focus on translational applications and the physiological roles of cuproptosis in renal repair. Targeting cuproptosis offers a promising avenue for innovative diagnostics and treatments in nephrology.

Purpose: To evaluate the association between early supratherapeutic tacrolimus exposure (trough concentration >20 ng/mL within the first postoperative week) and graft outcomes in kidney transplant recipients, and to develop a prediction model for this early high exposure.

Patients and methods: This single-center retrospective cohort study included 210 kidney transplant recipients (105 exposed, 105 non-exposed) after propensity score matching. Renal function (eGFR, cystatin C) and infection rates over the first year were compared using linear mixed-effects models with multiple imputation. A Cox proportional hazards model with LASSO variable selection was developed to predict the risk of high exposure.

Results: The exposed group had significantly lower eGFR at 7 days, 1, and 3 months (adjusted mean differences: -11.32, -10.20, -10.75 mL/min/1.73 m²) and higher cystatin C (0.83, 0.36, 0.36 mg/L). At 1 year, eGFR remained lower (-7.54 mL/min/1.73 m², P=0.038) and cystatin C higher (0.40 mg/L, P=0.043) in the exposed group. The 1-year infection rate was higher in the exposed group (80.0% vs 52.3%; adjusted OR=4.27, P<0.001). The prediction model identified CYP3A5 *3/*3 genotype (HR=2.19), elevated C-reactive protein on day 1 (HR=1.27), and higher weight-adjusted tacrolimus dose (HR=1.58) as key predictors (C-index=0.716; optimism-corrected C-index=0.728).

Conclusion: Early high tacrolimus exposure is associated with impaired renal function and increased infection risk in the first year after transplantation. A prediction model incorporating genetic, inflammatory, and dosing factors could aid in early risk stratification.

Abdominal aortic aneurysms (AAAs) are life-threatening cardiovascular disorders with limited treatment options, largely due to an incomplete understanding of their molecular and cellular pathogenesis. A comprehensive elucidation of the mechanisms driving AAA initiation, progression, and rupture is critical for developing novel therapeutic interventions. Emerging research has highlighted the central role of inflammatory processes in AAA pathophysiology, including dysregulated extracellular matrix (ECM) remodeling, chronic vascular inflammation, immune cell infiltration, and vascular smooth muscle cell (VSMC) dysfunction. These pathological processes are regulated by complex signaling pathways with divergent roles in AAA progression: while NF-κB, MAPK, STAT, and Notch signaling exacerbate disease pathogenesis, AMPK, PPAR-γ, and Nrf2 pathways exert protective effects. Notably, the PI3K/Akt and TGF-β signaling cascades demonstrate context-dependent dual roles, capable of either promoting or inhibiting AAA development. This comprehensive review synthesizes current knowledge of AAA pathophysiology with emphasis on druggable targets within these signaling networks. We critically evaluate emerging therapeutic strategies including miRNA-based interventions, nanoparticle-mediated drug delivery systems, and stem cell therapies that offer promising approaches for precision modulation of disease-specific pathways. By integrating current mechanistic understanding with therapeutic development, this review aims to provide a framework for designing effective pharmacological strategies that could transform AAA management from surgical intervention to medical prevention, addressing a critical unmet clinical need.

Drug repurposing, or repositioning, has emerged as a pivotal strategy in pharmaceutical research, offering a promising approach to uncover new therapeutic uses for existing drugs. While traditional de novo drug discovery typically requires 10-17 years and investments exceeding $2 billion with only 11% of Phase I candidates reaching approval, drug repurposing can reduce development timelines to 3-12 years at substantially lower costs, with approval rates reaching approximately 30% for de-risked compounds. The current review evaluates recent approaches, benefits, challenges and successful examples of drug repurposing. Relevant literature related to the advantages and obstacles associated with drug repurposing were reviewed. Additionally, the review demonstrates computational and data-driven methods, as well as traditional and novel examples of repurposed drugs across different therapeutic fields. Drug repurposing offers a faster and cost-effective approach to new therapies, particularly for critical conditions, such as rare diseases, neurodegenerative disorders and cancer. These advantages overcome the shortcomings of traditional drug development. Successful examples include the repurposing of dimethyl fumarate, chloroquine and daptomycin, which addressed a range of medical indications beyond the original drug uses. Collectively, these findings demonstrate that drug repurposing provides a viable solution for accelerating the process of drug discovery and addressing urgent medical needs. The integration of advanced computational methods and enhancing collaborative research projects would allow further expansion of treatment options and supporting timely solutions for critical and rare medical conditions.

Self-nanoemulsifying drug delivery systems (SNEDDS) have been widely developed as a practical approach to enhance the bioavailability of poorly water-soluble drugs through nanoscale emulsification. To improve the stability and practicality of liquid systems, solidification is commonly performed to obtain solid SNEDDS (S-SNEDDS) by incorporating appropriate solid carriers. Among various options, mesoporous materials have attracted significant attention due to their high surface area, tunable pore sizes, and excellent adsorption capacity. This review aims to summarize and critically analyze recent advances in mesoporous-based S-SNEDDS, focusing on formulation design, solidification strategies, and associated biopharmaceutical outcomes. The review is based on research articles published between 2020 and 2025 retrieved from reputable scientific databases (PubMed, ScienceDirect, Taylor & Francis, Springer, Scopus, and Web of Science) and selected for their relevance to mesoporous carriers and S-SNEDDS development. Findings reveal that carriers such as mesoporous magnesium alumino-metasilicate (eg, Neusilin^®) and mesoporous silica (eg, Syloid^®) have primarily been reported in studies employing physical adsorption. These systems generally exhibit favorable micromeritic properties and solid-state characteristics, suggesting successful drug incorporation within the carrier matrix and improved physical stability. These systems consistently demonstrate enhanced dissolution and permeation, and subsequently translate into superior pharmacokinetic and pharmacodynamic performances. Overall, the solidification of SNEDDS using mesoporous carriers successfully yields systems with desirable physical properties and improved in vitro and in vivo performances. Future research should address regulatory considerations for mesoporous excipients, deepen mechanistic insights into drug-carrier interactions, and include comparative evaluations among different carriers to support clinical and industrial advancement.

Obesity itself induces macroscopic, microscopic, and functional changes in the lungs, potentially making obese individuals more susceptible to acute and chronic pulmonary diseases. Apart from direct contribution to the course of the disease, obesity-induced alterations of the respiratory tract may influence the delivery and efficacy of inhaled formulations. The review examined obesity-induced changes in healthy lungs and the link between obesity and the prevalence and severity of chronic respiratory diseases. Fat accumulation at the tissue and cellular levels, as well as an increased thickness of the smooth muscle layer and an increase in the extracellular matrix, caused a reduction in lung compliance, resistance, reactance, and lung volumes. Conversely, airway hyperreactivity and closure increased, and ventilation/perfusion mismatch was observed. Changes in deposition, metabolization, and permeation across the respiratory barrier in obese lungs may alter the availability of inhaled drugs. Obesity-induced lung alterations may in part explain the higher reported doses of the bronchodilators and anticholinergics in obese compared to normal-weight asthma patients. Based on the observed changes, formulations with smaller particle sizes that require lower airflow may be more effective for obese patients with obstructive lung diseases.

Background: Despite advances in pharmacological interventions for rheumatoid arthritis (RA), a subset of patients continues to experience disease activity, highlighting the need for adjunctive therapeutic strategies.

Objective: To assess the therapeutic efficacy of paroxetine when administered as adjuvant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA).

Methods: In this randomized, double-blind, clinical trial, one hundred patients were randomized in 1:1 ratio to receive either csDMARDs including methotrexate plus placebo (control group) or paroxetine (paroxetine group). The primary endpoint was the change in Disease Activity Score using 28 joint counts (DAS-28) [Tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP), visual analogue scale (VAS)] at three months. Secondary endpoints included multidimensional health assessment questionnaire [morning stiffness (MS), pain, fatigue, physical functioning (PF)].

Results: After treatment, both groups demonstrated significant within-group improvements in TJC, SJC, VAS, and DAS-28, with superior improvements observed in the paroxetine group (p = 0.016, 0.0006, 0.03, and 0.005, respectively). CRP showed no significant change in the control group (p = 0.933). Paroxetine group showed significant reductions in MS, pain, and fatigue (p = 0.024, 0.03, and 0.006, respectively) compared with the control group, while PF were significant within groups but not between groups (p = 0.208). Adverse events were comparable, except for a higher incidence of decreased libido in the paroxetine group.

Conclusion: Adjunctive paroxetine significantly improved clinical and patient-reported outcomes in mild and moderate RA patients and was generally well tolerated, supporting its potential as an effective adjunctive therapy. The relatively small single-center sample, the exclusion of severe RA patients, the short disease duration, the low seropositivity, absence of mental health assessment, the possibility of overlapping with secondary pain mechanisms (eg, central sensitization or early fibromyalgia features) may limit the generalizability of the findings to broader and more diverse patient populations.

Trial registration identifier: NCT06231745.

Purpose: Remimazolam is an ultrashort-acting benzodiazepine, which has been indicated to be effective in endoscopic surgery and general anaesthesia. Research on its use in outpatient dental procedures remains limited. This triple-blinded randomized clinical trial was designed to determine whether the quality of postoperative recovery is better with continuous intravenous remimazolam administration compared with midazolam administration for impacted wisdom tooth extraction in patients with dental anxiety.

Patients and methods: This study was a randomized, parallel triple-blinded, superiority trial conducted between 30 April 2022 and 24 June 2024. Participants aged ≥18 years who exhibited dental anxiety and who were eligible for impacted wisdom tooth extraction in an outpatient setting were included in this study. Participants were randomly assigned at a 1:1 ratio to receive either a continuous intravenous infusion of remimazolam or midazolam. The primary outcome was the time to recover full alertness. The secondary outcome was postoperative anterograde amnesia.

Results: A total of 150 participants were randomized in this study, with 75 patients assigned to the remimazolam group and 75 patients assigned to the midazolam group. The time to complete alertness was significantly shorter in the remimazolam group than in the midazolam group (3.0 ± 3.6 min vs 4.7 ± 5.2 min, mean difference, -1.9 min; 95% CI, -3.3min to -0.4 min; P = 0.013). The odds of immediate and delayed anterograde amnesia were much reduced with remimazolam administration compared with midazolam administration (immediate: 0.14, 95% CI, 0.05 to 0.34, delayed: 0.07, 95% CI, 0.03 to 0.15, both P < 0.001).

Conclusion: For patients with dental anxiety, remimazolam offers not only faster recovery, but also a much better restoration of memory function compared with midazolam.

Trial registration: https://clinicaltrials.gov/study/NCT05350085.