Drug Design, Development and Therapy最新文献

{"title":"Optimization of Anticoagulation Strategy During Cardiopulmonary Bypass in Neonates with Congenital Heart Disease: A Randomized Controlled Trial.","authors":"He Wang, Qindong Liu, Peng Gao, Jia Liu, Yu Jin, Tianyu Gao, Wenting Wang, Dabuxilite Bayartaikishigtai, Yang Zhang, Jinping Liu","doi":"10.2147/DDDT.S634756","DOIUrl":"https://doi.org/10.2147/DDDT.S634756","url":null,"abstract":"<p><strong>Purpose: </strong>Neonatal hemostatic immaturity complicates anticoagulation during cardiopulmonary bypass (CPB). Current practice largely follows the strategy of 400 U/kg from adult protocols, as neonatal-specific guidelines and high-quality evidence remain lacking, which frequently fails to achieve adequate anticoagulation. This single-center randomized controlled trial evaluated the initial heparin dose of 600 U/kg to refine neonatal CPB anticoagulation.</p><p><strong>Patients and methods: </strong>In this prospective, randomized, controlled, single-blind trial, 76 neonates undergoing CPB were assigned to receive an initial heparin dose of either 600 U/kg (n = 38) or 400 U/kg (n = 38). The primary endpoint was the pre- to post-CPB change in prothrombin fragment 1+2 (ΔF1+2). Secondary endpoints included the proportion of neonates achieving the ACT threshold after the initial heparin bolus, perioperative coagulation measures, postoperative blood loss, transfusion requirements, and adverse clinical outcomes.</p><p><strong>Results: </strong>Mean ΔF1+2 was 0.70 vs 4.08 nmol/L in the 600 and 400 U/kg groups, respectively (treatment-minus-control mean difference, -3.38 nmol/L; 95% confidence interval, -4.58 to -2.18; <i>P</i> <0.001). ACT target achievement rate after the initial dose was higher in the 600 U/kg group (84.2% vs 44.7%, <i>P</i> < 0.001). Surgical preparation time was shorter (median 31.50 vs 36.50 mins, <i>P</i> = 0.028), and supplemental heparin use was lower, while total heparin dose did not differ significantly. Secondary endpoints showed lower 72-hour chest drainage and albumin use and shorter mechanical ventilation duration (<i>P</i> = 0.036, 0.028, and 0.031, respectively). Red-cell, plasma, and platelet transfusion requirements and most other clinical outcomes did not differ significantly. One in-hospital death occurred with 600 U/kg and none with 400 U/kg. Complete-case sensitivity analysis supported the primary finding.</p><p><strong>Conclusion: </strong>An initial heparin dose of 600 U/kg in neonatal CPB was associated with a smaller F1+2 increase and greater initial ACT response. Larger studies are needed to establish clinical benefit and safety.</p><p><strong>Clinical trial registry number: </strong>ChiCTR2300069157.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"634756"},"PeriodicalIF":6.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Clobazam as Adjunctive Therapy for Pediatric Patients with Refractory Epilepsy in Xinjiang, China: A Multicenter Real-World Study.","authors":"Ting Zhao, Hong-Jian Li, Hui-Lan Zhang, Lu-Hai Yu, Jing Yu, Yan Sun, Lu-Feng Cheng","doi":"10.2147/DDDT.S652340","DOIUrl":"https://doi.org/10.2147/DDDT.S652340","url":null,"abstract":"<p><strong>Objective: </strong>This real-world retrospective observational study evaluated the efficacy and safety of clobazam as adjunctive therapy in pediatric patients with refractory epilepsy (RE) in Xinjiang to provide evidence for its rational clinical application.</p><p><strong>Methods: </strong>Treatment efficacy was assessed according to the four-level efficacy criteria established by the First National Epilepsy Academic Conference of the Chinese Medical Association using seizure frequency recorded at the final follow-up. Changes in seizure frequency from baseline were evaluated at 3, 6, and 12 months after treatment initiation. All adverse drug reactions occurring during follow-up were recorded.</p><p><strong>Results: </strong>The response rates to clobazam therapy were 50.7%, 50.7%, 53.8%, and 56.7% at 1, 3, 6, and 12 months, respectively. The effective group received a significantly higher daily clobazam dose than the ineffective group (<i>P</i> < 0.05). The proportion of pediatric patients with no reduction in seizure frequency decreased significantly from 14.7% at 1 month to 1.7% at ≥12 months (<i>P</i> < 0.05), while the proportion of pediatric patients with a <50% reduction in seizure frequency gradually increased over time. The highest efficacy was observed in patients with a disease duration of 3-6 years (62.5%, 10/16), while those with a duration of <1 year showed relatively lower efficacy (30.8%, 4/13). Sex and comorbidities were significant predictors of clobazam controlling seizures (<i>P</i> = 0.039 and <i>P</i> = 0.030, respectively). During the clobazam treatment period, 31 pediatric patients (41.33%) experienced at least one adverse drug reaction.</p><p><strong>Conclusion: </strong>Clobazam demonstrated favorable efficacy, safety, and tolerability as adjunctive therapy in pediatric patients with RE. These real-world findings provide clinical evidence supporting the rational use of clobazam in pediatric RE.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"652340"},"PeriodicalIF":6.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogel Microneedles for Perioperative Applications: Drug Delivery, Biosensing, and Theranostic Translation.","authors":"Yue Qi, Cong Wang, Jinyue Chen, Dalong Wu","doi":"10.2147/DDDT.S648986","DOIUrl":"10.2147/DDDT.S648986","url":null,"abstract":"<p><p>Hydrogel microneedles provide access across the skin barrier for drug delivery and interstitial-fluid sampling. Their perioperative use depends on whether that access remains reliable during skin preparation, surgical positioning, and changes in tissue perfusion. This narrative review examines how material design affects delivered dose, measurement accuracy, and clinical feasibility. Human sampling studies establish feasibility for selected measurements; most therapeutic and integrated sensing applications remain at the preclinical stage or have been investigated in other clinical settings. The review distinguishes these findings from evidence in surgical patients. Particular attention is given to insertion and adhesion on disinfected or compromised skin, the relationship between interstitial and plasma measurements, and drug exposure after delivery is interrupted. Short-duration superficial procedures and observational drug or wound-adjacent monitoring offer focused questions for initial studies with standard care maintained. Progress toward treatment requires validation of the complete product, including sterilization, batch consistency, shelf life, and safeguards against uncontrolled release. Clinical studies should report failed applications and adverse events alongside patient outcomes. Autonomous anesthetic administration remains a development goal whose safety cannot be inferred from separate demonstrations of sensing and drug release.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"648986"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statistical and Rehabilitation Outcome Considerations in a Non-Inferiority Study of Parasacral Ischial Plane Block After Total Knee Arthroplasty [Letter].","authors":"Guoli Yao, Gang Zhao, Jinxian Shi, Xuede Duan","doi":"10.2147/DDDT.S658959","DOIUrl":"10.2147/DDDT.S658959","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"658959"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Machine Learning Models to Predict Tigecycline Exposure in Critically Ill Patients Using Different Limited Sampling Strategies.","authors":"Anran Dai, Hao Liu, Bo Yang, Feiyue Zheng, Yan Guan, Jieqiong Liu, Jianping Zhu, Gang Liang, Yi Yang, Lingyan Yu, Yuhua Zhao, Zhenwei Yu","doi":"10.2147/DDDT.S630414","DOIUrl":"10.2147/DDDT.S630414","url":null,"abstract":"<p><strong>Background: </strong>The high variability in the pharmacokinetics of tigecycline may impact therapeutic efficacy, particularly in critically ill patients. This study introduces machine learning (ML) methods, aiming to clarify their effectiveness in individualized drug exposure prediction and determine the optimal modeling strategy.</p><p><strong>Methods: </strong>The least absolute shrinkage and selection operator (LASSO) method was used to screen the covariates. Four ML models, random forest, extreme gradient boosting, multilayer perceptron, and long short-term memory network (LSTM), were trained and tested using 751 concentrations from 98 patients in the pharmacokinetic dataset to predict the area under the steady-state plasma concentration-time curve within 24 hours (AUC_0-24h) of tigecycline. Furthermore, on the internal test set, we evaluated the accuracy of the published tigecycline Population Pharmacokinetics (PopPK) models.</p><p><strong>Results: </strong>Seven covariates were screened out by LASSO method, including total bilirubin, creatinine clearance, Sequential Organ Failure Assessment (SOFA) score, body mass index, serum creatinine, age, and prothrombin time. Internal validation showed that, among the four ML models, the LSTM model performed the best, with the combination of covariates and the plasma concentration feature \"C₀ + C_0.5 + C₆\" exhibited the optimal predictive performance (R²: 0.887, RMSE: 2.496 mg·h/L, F₂₀: 75%). In comparison, the model combining covariates with C₀ was the most concise and better suited to practical computational conditions; its LSTM model was comparable to some PopPK models in terms of overall trend fitting and systematic bias control (R²: 0.818, RMSE: 3.164 mg·h/L, F₂₀ = 60%).</p><p><strong>Conclusion: </strong>The LSTM model established in this study enables an accurate estimate of tigecycline AUC_0-24h. Three-point sampling provided the lowest prediction error, whereas C₀ alone reduced the sampling burden. These findings provide an effective modeling reference for tigecycline therapeutic drug monitoring.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"630414"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Internal Validation of a Nomogram for Subtherapeutic Total Aripiprazole Concentrations: A Retrospective Real-World Study.","authors":"Jiao He, Yuanyuan Zhai, Yang Chen, Yang Zhang, Dehua Shen, Ying Lei, Ying Chen, Jing Ding","doi":"10.2147/DDDT.S642609","DOIUrl":"10.2147/DDDT.S642609","url":null,"abstract":"<p><strong>Background: </strong>A straightforward and user-friendly tool for predicting whether the total aripiprazole concentration in a patient falls below 150 ng/mL is currently unavailable. In this study, we identified independent risk factors that influence the subtherapeutic total aripiprazole concentration and developed a nomogram prediction model, thereby providing a reference for individualized dosing.</p><p><strong>Methods: </strong>This was a retrospective cohort study that included 409 therapeutic drug monitoring samples. According to established guidelines, the recommended plasma total concentration range for aripiprazole and its active metabolite, dehydroaripiprazole, is between 150 and 500 ng/mL. Therefore, samples with concentrations below 150 ng/mL are classified as belonging to the subtherapeutic concentration group, whereas those within the 150-500 ng/mL range are categorized as the therapeutic concentration group. A multivariate logistic regression analysis was performed to identify independent factors that affect the subtherapeutic total aripiprazole concentration and a nomogram prediction model was developed. The Net Reclassification Improvement (NRI) and the Integrated Discrimination Improvement (IDI) were employed to assess whether the nomogram model provides statistically significant incremental value over the daily dose-only model.</p><p><strong>Results: </strong>Among the 409 samples, 94 (22.98%) had concentrations below 150 ng/mL. Multivariate logistic regression analysis revealed that the male (OR = 3.922, 95% CI: 1.732-9.169, <i>P</i> = 0.0012), lower daily dose (OR = 0.525, 95% CI: 0.444-0.608, <i>P</i> < 0.001) and the use of combined valproate (OR = 4.360, 95% CI: 2.013-9.883, <i>P</i> < 0.001) were independent factors affecting the total aripiprazole concentration less than 150 ng/mL. Based on the results, a risk nomogram model was developed to predict the subtherapeutic total aripiprazole concentration. The nomogram showed robust predictive performance, achieving an area under the curve (AUC) of 0.916. The concordance index (C-index) was found to be 0.924 based on 1,000 bootstrap resamples. Additionally, the model showed good internal calibration (calibration intercept = 0.00, slope = 1.00, Brier score = 0.088), decision curve analysis indicated favorable clinical utility, with a wide range of threshold probabilities (5-95%). Compared with the daily dose-only model, the full nomogram achieved a NRI of 0.631 (95% CI: 0.305-0.930; <i>P</i> < 0.001) and an IDI of 0.0472 (95% CI: 0.0188-0.0963; <i>P</i> < 0.001).</p><p><strong>Conclusion: </strong>This study established, for the first time, a visualized nomogram model designed to preliminarily predict total aripiprazole plasma concentrations that are below 150 ng/mL. In the future, we will conduct external validation to further evaluate the predictive performance of the model.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"642609"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacteriophage Therapy in Cystic Fibrosis: Emerging Strategies for Managing Chronic <i>Pseudomonas aeruginosa</i> Infections.","authors":"Ayona Puthenpurayil, Lauren Gordon, Joanne L Fothergill","doi":"10.2147/DDDT.S612130","DOIUrl":"https://doi.org/10.2147/DDDT.S612130","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is the leading cause of chronic respiratory infection in people with cystic fibrosis (pwCF) and remains a major driver of morbidity and premature mortality. The unique environment of the CF lung promotes persistent colonisation, biofilm formation, and the emergence of multidrug-resistant (MDR) phenotypes, severely limiting the effectiveness of conventional antibiotic therapies. Despite aggressive and prolonged antibiotic regimens, eradication of chronic <i>P. aeruginosa</i> infection is rarely achieved, and repeated exposure accelerates resistance development. Consequently, there is an urgent need for alternative or adjunctive therapeutic strategies. Bacteriophage (phage) therapy has re-emerged as a promising approach for treating MDR <i>P. aeruginosa</i> infections due to its strain specificity, self-amplifying activity, and capacity to disrupt biofilms. Importantly, phage-driven selection pressure can impose fitness costs on bacteria, including reduced virulence and increased susceptibility to antibiotics, providing a potential route to antimicrobial resensitisation. However, translating phage therapy into routine clinical practice faces challenges, particularly in the context of CF lung disease, where heterogeneous bacterial populations, thick mucus, biofilms, and host immune responses complicate treatment efficacy. This scoping review synthesises current understanding of <i>P. aeruginosa</i> pathogenesis in CF, focusing on antibiotic resistance mechanisms, virulence factors that function as phage receptors, and the evolutionary trade-offs exploited by phage therapy, including the role of phage-encoded depolymerases that degrade protective biofilms and bacterial defence mechanisms that drive phage resistance. We critically evaluate clinical evidence supporting phage use in pwCF, highlighting key limitations in existing studies, and priorities for future research required to establish phage therapy as a viable, regulated treatment option.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"612130"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Regulatory Networks in Cardiac Fibrosis: Therapeutic Targets, Crosstalk, and Future Directions.","authors":"Yansheng Yao, Chongyu Shao, Haitong Wan","doi":"10.2147/DDDT.S631934","DOIUrl":"https://doi.org/10.2147/DDDT.S631934","url":null,"abstract":"<p><p>Cardiac fibrosis is a central driver of pathological cardiac remodeling and a critical risk factor for the progression to heart failure. Cardiac fibrosis may induce myocardial ischemia and hypoxia, impaired cardiac function, and arrhythmias, and is thereby intimately linked to escalating cardiac mortality. Epigenetic mechanisms serve as core drivers in both the initiation and malignant evolution of cardiac fibrosis. Currently, the epigenetic regulatory network primarily covers five cutting-edge domains: (1) dynamic DNA methylation modifications, (2) the histone post-translational modifications, (3) emerging RNA epitranscriptomic modifications, (4) the non-coding RNA regulatory network, and (5) ATP-dependent chromatin remodeling. This review moves beyond conventional pathological frameworks to examine the multi-layered synergistic actions of epigenetic regulation in cardiac fibrosis. By deconstructing the specific spatiotemporal expression profiles of these dynamic modification mechanisms, we systematically evaluate their translational potential as reversible interventional targets, offering a critical synthesis of these epigenetic mechanisms and pointing to plausible research directions for overcoming fibrotic progression toward heart failure.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"631934"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of a Subanesthetic Dose of Esketamine on Postoperative Sleep Disturbance After Oocyte Retrieval Under Intravenous Anesthesia: A Randomized Controlled Trial.","authors":"Qiaoling Ma, Huixin Li, Xulin Wang, Jiaqi Chen, Ping Zhang, Na Xing, Dan Cheng","doi":"10.2147/DDDT.S630545","DOIUrl":"10.2147/DDDT.S630545","url":null,"abstract":"<p><strong>Purpose: </strong>Postoperative sleep disturbance (PSD) is a common complication after oocyte retrieval under intravenous anesthesia. This study aimed to evaluate whether a subanesthetic dose of esketamine reduces the incidence of PSD.</p><p><strong>Patients and methods: </strong>This randomized, double-blind, placebo-controlled trial included 196 women undergoing oocyte retrieval under intravenous anesthesia. Participants were randomly assigned to the esketamine or control group. During anesthesia induction, the esketamine group received an intravenous bolus of esketamine 0.2 mg/kg, whereas the control group received an equivalent volume of normal saline. The primary analysis was conducted according to the intention-to-treat principle, with missing outcome data handled using multiple imputation; 189 participants (95 in the control group and 94 in the esketamine group) were included in the per-protocol sensitivity analysis. The primary outcome was the incidence of PSD on postoperative day (POD) 3, defined using a composite criterion of an Athens Insomnia Scale (AIS) score ≥6 or a numerical rating scale (NRS) score ≥6. Secondary outcomes included the incidence of PSD on POD 1, postoperative pain scores, postoperative anxiety and depression scores, and patient satisfaction with the anesthetic technique.</p><p><strong>Results: </strong>In the intention-to-treat analysis with multiple imputation, the estimated incidence of PSD on POD 3 was lower in the esketamine group than in the control group (13.06% vs 24.90%; risk difference, -11.84 percentage points [95% CI, -22.98 to -0.69]; relative risk [RR], 0.52 [95% CI, 0.28-0.99]; <i>P</i> = 0.047). The per-protocol (PP) sensitivity analysis yielded similar results (12.8% vs 24.2%; RR, 0.53 [95% CI, 0.28-0.99]; <i>P</i> = 0.043). PSD on POD 1 did not differ between the groups. No between-group differences in postoperative anxiety or depression scores were noted. Postoperative pain scores at 30 minutes were significantly lower in the esketamine group (<i>P</i> < 0.001). Dreaming was more frequent in the esketamine group (21.4% vs 11.2%; <i>P</i> = 0.048), and the time to full alertness (12 [10-14] vs 11 [9-13] minutes; <i>P</i> = 0.002) and postanesthesia care unit (PACU) stay (34 [30-37] vs 31 [29-34] minutes; <i>P</i> = 0.005) were modestly longer.</p><p><strong>Conclusion: </strong>A single subanesthetic dose of esketamine was associated with a lower incidence of short-term PSD on POD 3 in women undergoing oocyte retrieval under intravenous anesthesia. Larger multicenter studies are warranted to confirm these findings.</p><p><strong>Trial registration: </strong>China Clinical Trial Registry Identifier: ChiCTR2500105998.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"630545"},"PeriodicalIF":6.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Cancer-Associated Fibroblasts with Small-Molecule Inhibitors: Molecular Mechanisms and Therapeutic Potential.","authors":"Qinghao Liu, Zhikui Huo, Meng Zhou, Yu Zhang, Zehua Yin, Yifan Zhang","doi":"10.2147/DDDT.S649473","DOIUrl":"10.2147/DDDT.S649473","url":null,"abstract":"<p><p>The multifaceted role of cancer-associated fibroblasts (CAFs) in orchestrating extracellular matrix remodeling, immune evasion, and therapeutic resistance positions these stromal cells as critical yet underexploited nodes in the tumor microenvironment (TME). While small-molecule agents offer practical advantages over biologics for stromal modulation, a systematic understanding of their mechanistic diversity and translational barriers remains incomplete. To address this gap, this review consolidates current knowledge on the principal signaling axes-TGF-β/STAT3, NF-κB, Notch, Hedgehog, PI3K/AKT, and CXCL12/CXCR4-that sustain CAF activation and pathogenic functions. Distinct from prior CAF reviews, particular emphasis is placed on the structure-activity refinement (SAR) of fibroblast activation protein (FAP)-targeted small-molecule ligands and on pharmacokinetic optimization via fatty acid conjugation and porphyrin integration that substantially improve tumor retention. Representative pharmacological inhibitors-including nicotinamide N-methyltransferase (NNMT), phosphodiesterase 5A (PDE5A), and NADPH oxidase 4 (NOX4) inhibitors-are evaluated for their capacities to remodel immunosuppressive networks, with attention to their synergism when combined with chemotherapeutic agents, immune checkpoint blockers, or antibody-drug conjugates. Emerging evidence indicates that CAF heterogeneity and plasticity pose fundamental obstacles to monotherapy efficacy, whereas rationally designed combination regimens produce superior antitumor outcomes in preclinical models. We further identify key knowledge gaps-including the lack of CAF-subset-selective drugs, unresolved pharmacotoxicology of pan-FAP inhibition, and limited biomarker-guided patient stratification-and discuss translational and regulatory barriers that must be overcome before widespread clinical adoption. Collectively, this review argues that the future of CAF-directed pharmacotherapy lies not in indiscriminate depletion but in subset-selective reprogramming, and that clinical success will increasingly depend on biomarker-guided patient stratification and mechanistically anchored multidrug scheduling rather than on isolated target inhibition.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"649473"},"PeriodicalIF":6.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}