Drug Design, Development and Therapy最新文献

{"title":"A Novel Flavonoid Derivative of Icariside II (YS-10) Improves Erectile Dysfunction in a Diabetic Rat Model by Inhibiting Ferroptosis via Activation of the Nrf2/HO-1/GPX4 Pathway.","authors":"Yang Liu, Guan-Nan Liu, Ya-Rong Zha, Chen-Li Pan, Yong-de Xu, Hong-Wei Li, Yue-Yue Zang, Wan-Qi Wang, Jun-Jie Yao, Jun-Tao Sun, Yong Yang, Zhi-Tao Wei","doi":"10.2147/DDDT.S518992","DOIUrl":"https://doi.org/10.2147/DDDT.S518992","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to evaluate the therapeutic potential of YS-10, a novel flavonoid derivative of icariside II (ICA II), and to explore its mechanism of action in a diabetic rat model of erectile dysfunction (DMED).</p><p><strong>Methods: </strong>Twenty-four male Sprague-Dawley rats were divided into four groups: control, DMED, DMED + ICA II (2.5 mg/kg/day), and DMED + YS-10 (2.5 mg/kg/day). Treatments lasted for 4 weeks followed by a 3-day washout. Erectile function was assessed, and penile tissues were analyzed by histology, immunohistochemistry, ELISA, and Western blot. In vitro, primary corpus cavernosum endothelial cells (CCECs) were treated with advanced glycation end products (AGEs), YS-10, Fer-1 (ferroptosis inhibitor), or ML385 (Nrf2 inhibitor) to evaluate oxidative stress and ferroptosis.</p><p><strong>Results: </strong>In vivo, both YS-10 and ICA II (2.5 mg/kg/day) significantly improved erectile function in diabetic rats, increased smooth muscle content, reduced collagen deposition, and enhanced endothelial marker (CD31) expression in penile tissue (<i>p</i> < 0.01 vs DMED group). The maximum ICP/MAP ratio and oxidative stress markers were similarly restored in both treatment groups, with no significant difference between YS-10 and ICA II (<i>p</i> > 0.05). In vitro, YS-10 reversed AGEs-induced injury and ferroptosis in corpus cavernosum endothelial cells (CCECs), upregulated GPX4, downregulated ACSL4, and reduced ROS and lipid peroxidation, comparable to the effects of the ferroptosis inhibitor Fer-1. YS-10 also promoted Nrf2 nuclear translocation and elevated HO-1 expression. Molecular docking, immunofluorescence, and Western blotconfirmed the interaction between YS-10 and the Nrf2/HO-1/GPX4 signaling pathway.</p><p><strong>Conclusion: </strong>YS-10 improves erectile function in diabetic rats by reducing oxidative stress and inhibiting ferroptosis via activation of the Nrf2/HO-1/GPX4 pathway. At 2.5 mg/kg/day, YS-10 was effective, well-tolerated, and showed efficacy comparable to ICA II. These findings support its potential as a promising candidate for diabetes-related erectile dysfunction therapy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4481-4500"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198519","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":"Comparison of Esketamine/Propofol and Sufentanil/Propofol on Intraoperative Hypoxemia During Bronchoscopy: A Randomized Trial.","authors":"Xiao Huang, Xueyang Li, Yuan Sun, Anshi Wu, Pan Ai","doi":"10.2147/DDDT.S490423","DOIUrl":"https://doi.org/10.2147/DDDT.S490423","url":null,"abstract":"<p><strong>Purpose: </strong>Propofol and sufentanil are the most commonly used anesthetics during bronchoscopy. Esketamine is an s-enantiomer of ketamine racemate and has both sedative and analgesic effects, it does not inhibit respiration and maintains hemodynamic stability. We aimed to compare the intraoperative hypoxemia risk of esketamine/propofol with sufentanil/propofol for patients in bronchoscopy.</p><p><strong>Methods: </strong>This study was an investigator-initiated, single-center, randomized, double-blind clinical trial. Patients undergoing bronchoscopy were randomly assigned to receive either sufentanil group (n = 33; sufentanil: 0.2 μg/kg) or esketamine group (n = 33; esketamine: 0.2 mg/kg) for sedation and analgesia. Clinical data, anesthetics usage, incidence of intraoperative hypoxemia, total time of hypoxemia, recovery time, and adverse events were recorded.</p><p><strong>Main results: </strong>The incidence of intraoperative hypoxemia was significantly lower in the esketamine group than in the sufentanil group (27.2% vs 66.7%, <i>P</i>=0.001, OR=5.333, 95% CI=1.859-15.301). Propofol usage was significantly higher in the esketamine group than in the sufentanil group (t=2.952, <i>P</i>=0.004). The duration of hypoxia was significantly lower in the esketamine group than in the sufentanil group (Z=-3.445, <i>P</i><0.001), and the minimum oxygen saturation (SpO2) was significantly higher than in the sufentanil group (Z=-2.682, <i>P</i>=0.007). Recovery time from anesthesia was significantly lower in the esketamine group than in the sufentanil group (Z=-2.709, <i>P</i>=0.007). No difference was found in adverse reactions between the two groups.</p><p><strong>Conclusion: </strong>Esketamine combined with propofol reduced the incidence of intraoperative hypoxemia compared with sufentanil in bronchoscopy. Our results offer the possibility for a novel recommendation for the prevention of intraoperative hypoxemia during bronchoscopy. However, we mentioned the higher propofol use in the esketamine group. Additional clarification is necessary on the indications and the optimal dose of esketamine.</p><p><strong>Trial registration: </strong>Chinese clinical trial registry: ChiCTR2200058990.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4429-4436"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198520","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":"The Follicular Output Rate was Improved with 3-Day Letrozole Administration Compared with 5-Day Letrozole Administration Under Progestin-Primed Ovarian Stimulation.","authors":"Xiaoning Wang, Jiarong Tian, Liu Tian, Xin Chen, Zhenzhen Zhang, Honglu Diao, Ying Zhang","doi":"10.2147/DDDT.S521554","DOIUrl":"https://doi.org/10.2147/DDDT.S521554","url":null,"abstract":"<p><strong>Purpose: </strong>Progestin-primed ovarian stimulation (PPOS) has been widely employed in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. In recent years, letrozole (LE) combined with medroxyprogesterone acetate (MPA) has been used in this protocol to enhance ovarian response. This study compared the effects of a 5-day regimen with those of a 3-day regimen of letrozole within PPOS, focused on the follicular output rate (FORT) and blastocyst formation rates.</p><p><strong>Patients and methods: </strong>From January 2017 to January 2020, 1,754 infertility patients who received PPOS protocol were divided into two groups: 577 patients received 2.5 mg/day LE for 5 days (LE 5-day), and 1177 patients received the same dose of LE for 3 days (LE 3-day). Propensity score matching (1:1) balanced confounders, yielding 489 patients per group. The primary outcoms was the FORT. The rate of blastocyst formation was evaluated as the secondary outcome. A multivariable logistic regression analysis was performed to compare the disparity in the FORT between the two groups.</p><p><strong>Results: </strong>After matching, the number of oocytes retrieved, number of mature oocytes, number of blastocysts, blastocyst formation rates, FORT, and clinical pregnancy rates were more favourable in the LE 3-day group than in the LE 5-day group (P < 0.05). In the multivariable linear regression model, after making adjustments for factors such as age, anti-Müllerian hormone (AMH), antral follicle count (AFC), body mass index (BMI), infertility type, and basal P, patients in the LE 3-day group exhibited an increase in the FOTR (β = 0.08, 95% confidence interval [CI] 0.02 to 0.14, P = 0.0082) and blastocyst formation rate (β = 0.23, 95% CI 0.17 to 0.29, P < 0.0001) compared to those in the LE 5-day group.</p><p><strong>Conclusion: </strong>Compared with LE administration for 5 days, LE administration for 3 days may increase the FORT and the rate of blastocyst formation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4397-4406"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198527","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":"Research Trends and Developments in Nanomaterials for Rheumatoid Arthritis: A Comprehensive Bibliometric Analysis.","authors":"Xuezhao Jia, Lei He, Yonglong Chang, Jiajie Li, Jing Wang, Xiaojun Zhang, Jinchen Guo","doi":"10.2147/DDDT.S514898","DOIUrl":"https://doi.org/10.2147/DDDT.S514898","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is one of the common diseases associated with job loss and disability. However, the existing diagnosis and treatment methods are limited by factors such as misdiagnosis, missed diagnosis, and toxic side effects. In recent years, remarkable progress has been made in applying nanomedicine for RA treatment. However, previous studies lack a systematic and comprehensive analysis of the development trajectory of nanomaterials in the diagnosis and treatment of RA, the contributions of key researchers, and the evolution of research focuses. This study aims to fill this gap by providing a detailed bibliometric analysis of the global research landscape on nanomaterial applications in RA diagnosis and treatment, highlighting the significance of this field in advancing therapeutic interventions and identifying future research directions.</p><p><strong>Methods: </strong>Relevant literature on the application of nanomaterials in RA treatment was searched in the Web of Science Core Collection (WoSCC) database from January 1, 1985 to December 31, 2023. VOSviewer, CiteSpace, \"bibliometrix\" R-package, and Microsoft Office Excel 2021 were used for bibliometric analysis to evaluate the number of publications, research hotspots, main researchers, and institutions.</p><p><strong>Results: </strong>A total of 524 articles were included, involving 33 countries or regions, 784 institutions, and 2751 authors, covering 19 disciplines, including biochemistry and molecular biology, chemistry, engineering, immunology, and materials science. Countries with the highest publication output were China, India, and the United States, with China and the United States having the closest cooperation. The University of California at San Diego and CHEN X were the most influential institutions and authors. Journal of Controlled Release had the highest publication output and emerged as the most influential journal in the field. In recent years, research hotspots of nanomaterials in RA included \"dexamethasone\", \"micelle\", and \"diagnosis\".</p><p><strong>Conclusion: </strong>This study is the first comprehensive bibliometric analysis of nanotechnology in RA application. It highlights the importance of nanomaterials in advancing RA diagnosis and treatment and provides a valuable reference for future research. By identifying key research trends, influential contributors, and emerging hotspots, this analysis offers actionable insights for researchers to build upon, ultimately driving innovation and improving therapeutic outcomes in the field of nanomedicine for RA.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4355-4371"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198524","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":"Synthesis, Molecular Characterization, and Antimicrobial Evaluation of Hydrazones Derived from 2-Hydrazinobenzimidazole.","authors":"Muneera S M Al-Saleem, Mohamed S Mohamed Ahmed, Sayed M Riyadh, Awatif H Alruwaili, Magdi E A Zaki, Sobhi M Gomha","doi":"10.2147/DDDT.S521541","DOIUrl":"https://doi.org/10.2147/DDDT.S521541","url":null,"abstract":"<p><strong>Introduction: </strong>Hydrazones, due to the structural diversity of their nitrogen atoms, possess both electrophilic and nucleophilic properties, enabling strong hydrogen bonding interactions with enzymes and receptors. This study aimed to synthesize novel hydrazone derivatives and evaluate their antimicrobial potential.</p><p><strong>Methods: </strong>Hydrazones were synthesized via condensation of 2-hydrazinobenzimidazole with various aldehydes or ketones using citric acid as an eco-friendly catalyst. The (E)-configuration of the products was confirmed through frontier molecular orbital (FMO) calculations. Antimicrobial activities were assessed against selected Gram-positive and Gram-negative bacteria, and fungi. Molecular docking studies were conducted on the most active compounds (<b>3c</b> and <b>3o</b>) using bacterial and fungal protein targets (2IWC, 2NXW, 1EA1).</p><p><strong>Results: </strong>Compounds <b>3c</b> and <b>3o</b> showed strong antimicrobial activity. Docking studies revealed that both compounds interacted with 2IWC via one H-bond donor to THR531 (3.12 Å), mirroring ampicillin. Against 2NXW, they showed dual H-donor bonding to MET404 with binding energies of -5.96 and -5.72 kcal/mol, comparable to gentamicin. Both also bound ARG326 in 1EA1 with binding energies of -5.97 and -6.0 kcal/mol, similar to nystatin.</p><p><strong>Discussion: </strong>The comparable binding patterns and energies of compounds <b>3c</b> and <b>3o</b> to standard antimicrobial agents suggest that they are promising candidates for further development as broad-spectrum antimicrobial agents.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4437-4456"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198526","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":"<i>Anemarrhena asphodeloides</i> Bunge-<i>Fritillaria Cirrhosae</i> Bulbus Herb Pair Alleviates Ovalbumin-Induced Asthma by Regulating Arachidonic Acid Pathway.","authors":"Xi Tian, Qingfei Cui, Jinhuan Wei, Qian Zhang, Huiyi Zhang, Mengxin Yang, Yiqi Xing, Yukun Niu, Wenyu Li, Nan Wang, Yiran Jin, Yingfeng Du","doi":"10.2147/DDDT.S514891","DOIUrl":"https://doi.org/10.2147/DDDT.S514891","url":null,"abstract":"<p><strong>Background: </strong>In traditional Chinese Medicine (TCM), Zhimu (<i>Anemarrhena asphodeloides</i> Bunge, ZM) - Chuanbeimu (<i>Fritillaria Cirrhosae</i> Bulbus, CBM) (ZC) is one of the most classical herb pairs used in the treatment of lung diseases such as asthma. This study aimed to investigate how ZC affects asthma and its mechanism.</p><p><strong>Methods: </strong>Asthma model rats were sensitized by ovalbumin. The anti-asthma efficacy of ZM, CBM and ZC were evaluated through analysis of lung function, pathological sections and biochemical indices. Metabolomics based on UHPLC-QTOF-MS was conducted to determine the synergistic anti-asthma effect of combination therapy. Asthma targets and mechanism prediction were performed using network pharmacology. Then, the potential anti-asthma mechanism of ZC was explored using RT-qPCR.</p><p><strong>Results: </strong>According to the lung function test, Hematoxylin-Eosin Staining experiment, ZC herb pair had an obvious anti-asthma effect over either ZM or CBM alone. It has also been demonstrated that positive effect of ZC against Th1/Th2 immune imbalance. Both metabolomics and network pharmacology were highly enriched in the arachidonic acid metabolism pathway. The mRNA expression levels of ALOX5, PLA2G4A and CYP1A2, critical targets in arachidonic acid metabolism, were significantly down-regulated by RT-qPCR.</p><p><strong>Conclusion: </strong>By reducing the expression of cytokines and chemokines mediated by the arachidonic acid metabolism pathway, ZC could alleviate OVA-induced asthma in vivo. It was the first to demonstrate the complex mechanism of ZC for the treatment of asthma. Meanwhile, a new paradigm was established for evaluating the pharmacological effects of TCM drugs for asthma based on multiple mechanisms.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4407-4427"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198468","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":"Design and Synthesis of Novel 5,6,7,8-Tetrahydropyrido[2,3-<i>D</i>]pyrimidine Derivatives as VCP/p97 Inhibitors for the Treatment of Acute Myeloid Leukemia (AML).","authors":"Xueyuan Wang, Zebo Long, Tiantian Wen, Hang Miao, Xinran Ye, Meng Lei, Yongqiang Zhu","doi":"10.2147/DDDT.S509036","DOIUrl":"https://doi.org/10.2147/DDDT.S509036","url":null,"abstract":"<p><strong>Background: </strong>VCP/p97 plays an important role in endoplasmic reticulum related degradation pathways, and inhibition of p97 was shown to induce ER stress and subsequently cell death in a variety of solid tumors and hematoma. For acute myeloid leukemia (AML) cells, inhibition of p97 activity leads to the accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis.</p><p><strong>Methods: </strong>We have designed and synthesized a series of novel 5,6,7,8-tetrahydropyridine[2,3-d]pyrimidine derivatives. After synthesizing all the target compounds, the optimal lead compound was identified through screening for enzyme inhibitory activity and anti-tumor cell proliferation activity. Subsequently, the liver microsomal stability and pharmacokinetics of the lead compound was investigated. Finally, the in vivo antitumor efficacy of the lead compound was evaluated to assess its potential for the treatment of acute myeloid leukemia (AML).</p><p><strong>Results: </strong>Compound <b>V12</b> and metabolite <b>V13</b>, which was screened by enzyme inhibition activity, showed strong inhibitory activities against a variety of cell lines with IC₅₀ values less than 1 μM. In pharmacokinetic studies, after intragastric administration of <b>V12</b> (10 mg/kg) in SD rats, <b>V12</b> was rapidly metabolized to<b>V13</b>. The oral half-life of <b>V13</b> in plasma was 3.5 h, and the C_max and AUC_0-inf values of <b>V13</b> reached 1070 ng/mL and 1412 ng•h/mL, respectively, showing good pharmacokinetic properties. In addition, compound <b>V12</b> showed a strong anti-tumor therapeutic effect in vivo and lower toxic side effects in the human AML (Molm-13) mouse xenograft model.</p><p><strong>Conclusion: </strong>These results indicate that compound V12 is a potent p97 inhibitor with excellent in vitro and in vivo antitumor efficacy, which might provide a new therapeutic strategy for the treatment of AML.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4457-4479"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198522","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":"Comparison of the Dural Puncture Epidural and Conventional Epidural Analgesia Maintained Using Programmed Epidural Boluses for Labor Analgesia.","authors":"Xiaofei Mo, Jie Yu, Zhimin Qin, Junyi Ma, Yueyue Chen, Xi Chen","doi":"10.2147/DDDT.S521681","DOIUrl":"https://doi.org/10.2147/DDDT.S521681","url":null,"abstract":"<p><strong>Purpose: </strong>Research indicates that the dural puncture epidural (DPE) technique offers quicker analgesia onset compared to the conventional epidural (EP) technique. Programmed intermittent epidural bolus (PIEB) is superior to continuous epidural infusion (CEI) for maintaining labor analgesia, providing better pain relief and less motor block. Few studies have explored if combining DPE with the PIEB offers additional benefits in analgesia onset, maintenance, local anesthetic consumption, and side effects compared to DPE with EP. We hypothesized that DPE, when combined with PIEB, not only speeds up analgesia onset but also improves neuraxial analgesia maintenance over EP.</p><p><strong>Patients and methods: </strong>A total of 126 term nulliparous women with singleton pregnancies with a VAS pain score >50 mm and cervical dilation <5 cm were randomized to receive EP+PIEB or DPE+PIEB for labor analgesia, initiated with 15 mL of 0.0625% ropivacaine with 0.4 µg/mL of sufentanil using the EP or DPE technique (using 25-gauge Whitacre needle) technique and both maintained with the same solution for PIEB (fixed volume 10 mL, intervals 45 minutes, lockout interval 15 minutes) with labor analgesia. The primary outcome was time to achieving adequate analgesia, defined as a VAS pain score ≤30 mm. Secondary outcomes included pain scores, motor blockade, obstetric and neonatal outcomes, and satisfaction with analgesia.</p><p><strong>Results: </strong>Adequate analgesia was achieved faster in the DPE+PIEB group than in the EP+PIEB group (hazard ratio 2.409; 95% CI 1.670 to 3.474, <i>P</i><0.001). The median time (interquartile range) to VAS pain score ≤30 mm was 10 (7 to 13) minutes for the DPE+PIEB group and 15 (11 to 19) minutes for the EP+PIEB group (<i>P</i><0.001). No differences in any of the secondary outcomes between the two groups were observed.</p><p><strong>Conclusion: </strong>DPE with PIEB accelerated onset time but did not improve maintenance of neuraxial labor analgesia over DPE with EP.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4373-4382"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198521","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":"Simultaneous Determination of Unbound Plasma Concentration of Methotrexate and 7-Hydroxymethotrexate in Children Patients Receiving High-Dose Methotrexate Therapy.","authors":"Wei-Chong Dong, Shuai-Shuai Gao, Bo Shi, Hao-Ran Li, Ye Jiang, Jia-Liang Guo, Zhi-Qing Zhang, Ying-Ze Zhang","doi":"10.2147/DDDT.S516431","DOIUrl":"https://doi.org/10.2147/DDDT.S516431","url":null,"abstract":"<p><strong>Background: </strong>High-dose methotrexate (HD-MTX) is seen as an effective therapy for acute lymphoblastic leukemia (ALL); however, it is extremely toxic. Monitoring the plasma concentrations of methotrexate (MTX) and its important metabolite, 7-hydroxy-methotrexate (7-OH-MTX), on a routine basis aids in dose modification of rescue medications and in avoiding toxicity. The pharmacologically active and toxic effects of drugs are due to the unbound portion, as most drugs are bound to plasma proteins to some degree. However, the simultaneous measurement of unbound plasma concentrations of MTX and 7-OH-MTX has not been reported.</p><p><strong>Methods: </strong>We developed and validated a hollow fiber centrifugal ultrafiltration (HFCF-UF) technology to simultaneously analyze unbound MTX and 7-OH-MTX concentrations in human plasma. In total, 234 plasma samples from 58 children diagnosed with ALL who were administered HD-MTX were used in our study. We investigated the connection between unbound and total plasma concentrations of MTX and 7-OH-MTX, as well as how these concentrations relate to liver and renal function.</p><p><strong>Results: </strong>The method that was developed is both simple and accurate. A weak linear relationship was observed between the concentrations of unbound and total 7-OH-MTX (<i>r</i> ² = 0.732). The concentration of total MTX and unbound 7-OH-MTX were both positively correlated with creatinine (Cr) levels and negatively correlated with Creatinine clearance (CCr). There was a wide variation in the concentration ratios of 7-OH-MTX to MTX, both total and unbound, and these ratios were significantly lower in individuals with impaired liver function.</p><p><strong>Conclusion: </strong>The total concentration of 7-OH-MTX is an unreliable predictor of unbound concentration, necessitating the monitoring of unbound levels. The concentration ratios of 7-OH-MTX to MTX (both total and unbound) could be more accurate and sensitive biomarkers for predicting hepatotoxicity.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4383-4396"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198525","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":"Population Pharmacokinetics of Tranexamic Acid in Chinese Population Undergoing Cardiac Surgery with Cardiopulmonary Bypass.","authors":"Yue Liu, Chenghui Zhou, Hong Lv, Lei Tian, Juanjuan Jiang, Jia Shi","doi":"10.2147/DDDT.S493485","DOIUrl":"https://doi.org/10.2147/DDDT.S493485","url":null,"abstract":"<p><strong>Background: </strong>Population pharmacokinetics (PK) models could provide specific references for the formulation of personal drug delivery protocols, however, there is no population PK study of tranexamic acid (TXA) have been conducted in the Chinese population. The aim of this study was to establish a population PK model based on the data of perioperative plasma concentrations in Chinese participants, and to provide a reference for individualized administration of TXA.</p><p><strong>Methods: </strong>Participants undergoing cardiac surgery were randomly assigned to high-dose of TXA group (a 30-mg/kg bolus, a 16-mg/kg/h maintenance dose, and a 2-mg/kg prime, n = 7) and low-dose group of TXA (a 10-mg/kg bolus, a 2-mg/kg/h maintenance dose, and a 1-mg/kg prime, n = 9). Blood samples were collected at 14 time points and the concentration of TXA was determined by liquid chromatography-tandem mass spectrometry. Modelling was performed using Phoenix NLME 8.3 software.</p><p><strong>Results: </strong>The primary covariate identified was body weight, while no significant influence of cardiopulmonary bypass (CPB) on the PK was detected. The population estimates for clearance (CL₁), volume of the central compartment (V₁), diffusional clearance (CL₂), and volume of peripheral compartment (V₂) were 4.7 L/h, 4.9 L, 17.0 L/h, and 11.1 L, respectively, assuming a bodyweight of 70 kg.</p><p><strong>Conclusion: </strong>This study provides the first population PK model of TXA in the Chinese population undergoing cardiac surgery with CPB. The model could serve as a reference for the future development of individualized TXA administration strategies, with target-controlled infusion (TCI) emerging as a viable option.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"4343-4353"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198523","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}