Drug Design, Development and Therapy最新文献

{"title":"Development of HPLC-MS/MS Method for Simultaneous Detection of Esketamine and Norketamine: Application to Pharmacokinetics Drug Interactions Affected by Dexmedetomidine.","authors":"Wei Zhou, Zhe Guo, Xianghan Zhang, Wenjiong Wang, Zhongfeng Zheng, Xaingjun Qiu","doi":"10.2147/DDDT.S553389","DOIUrl":"10.2147/DDDT.S553389","url":null,"abstract":"<p><strong>Purpose: </strong>Dexmedetomidine (DEX) and esketamine (ESK) are often used together during anesthesia. This study aimed to establish a sensitive and reliable HPLC-MS/MS method for simultaneous quantification of ESK and its active metabolite norketamine (NORK) in beagle dog plasma and to investigate the pharmacokinetic drug-drug interactions (DDIs) between DEX and ESK/NORK.</p><p><strong>Methods: </strong>A simple protein precipitation method using acetonitrile was applied for plasma sample preparation. After chromatographic separation, analytes were detected by HPLC-MS/MS in positive ion mode using multiple reaction monitoring (MRM). The mass transitions were m/z 238.10→125.10 for ESK, m/z 224.10→125.10 for NORK, and m/z 354.20→209.00 for the internal standard (proadifen). Six beagle dogs were intramuscularly administered 1 mg/kg ESK alone in the first period (ESK group). After a washout, the same dogs received intravenous DEX (2 µg/kg) for 7 consecutive days, followed by co-administration of ESK (DEX+ESK group). The pharmacokinetic parameters of ESK and NORK were calculated using DAS software. Independent-sample <i>t</i> test was used to compare the differences of pharmacokinetic parameters between ESK group and DEX+ESK group, and P < 0.05 indicated a statistically significant difference.</p><p><strong>Results: </strong>Both ESK and NORK exhibited good linearity within the concentration range of 1-400 ng/mL, and the methodological validation met the requirements. When ESK was used in combination with DEX, the main pharmacokinetic parameters of ESK and NORK changed, the C_max, AUC_(0-24) and AUC_(0-∞) of ESK increased, the C_max, of NORK decreased, and the AUC_(0-12) and AUC_(0-∞) of NORK increased too.</p><p><strong>Conclusion: </strong>A novel HPLC-MS/MS method was developed and validated and successfully applied to simultaneously quantify ESK and NORK in beagle dog plasma. The pharmacokinetic DDI results indicate that DEX could inhibit the metabolism of ESK, alter pharmacokinetic characteristics of ESK and its metabolite NORK, and significantly increase the systemic exposure of both ESK and NORK.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8589-8600"},"PeriodicalIF":5.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184956","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":"A Narrative Review of Phase II and III Clinical Trials for the Pharmacological Treatment of Fibrodysplasia Ossificans Progressiva (FOP): Efficacy, Safety, and Challenges in Treatment Strategies.","authors":"Mohammed S Alharthi","doi":"10.2147/DDDT.S537454","DOIUrl":"10.2147/DDDT.S537454","url":null,"abstract":"<p><strong>Background: </strong>Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder marked by progressive heterotopic ossification (HO), causing severe disability and reduced life expectancy. Despite advancements in understanding its pathophysiology, effective treatments remain limited. Promising pharmacological approaches include retinoic acid receptor γ (RARγ) agonists, such as palovarotene, and monoclonal antibodies targeting activin A, like garetosmab. However, the rarity of FOP complicates the generation of robust clinical evidence.</p><p><strong>Methods: </strong>This narrative review analysed data from Phase II and III clinical trials on ClinicalTrials.gov, including completed and terminated interventional studies evaluating pharmacological treatments for FOP. Key trial details were systematically extracted and reviewed, including design, interventions, outcomes, and adverse events.</p><p><strong>Results: </strong>Five trials met the inclusion criteria, focusing on palovarotene and garetosmab. Palovarotene significantly reduced HO progression, particularly during active disease phases or flare-ups. Garetosmab showed potential in preventing new HO lesions and reducing lesion activity. However, both treatments posed safety concerns, including premature epiphyseal fusion in younger patients (palovarotene) and systemic adverse events (garetosmab). Terminated trials revealed logistical and ethical challenges, such as recruitment difficulties, small sample sizes, and limitations of placebo-controlled designs.</p><p><strong>Conclusion: </strong>Pharmacological advances, including palovarotene and garetosmab, show promise in managing FOP. Nevertheless, safety concerns and the complexities of clinical trial implementation highlight the need for innovative approaches to ensure effective and equitable treatments. Future research should prioritise long-term safety, efficacy, and patient-centred outcomes to improve FOP management.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8581-8588"},"PeriodicalIF":5.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12474705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185016","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 Postoperative Analgesic Effects of Intravenous versus Perineural Dexamethasone Injection Combined with Ropivacaine in Thoracoscopy-Guided Thoracic Paravertebral Block for Thoracoscopic Radical Lung Cancer Resection: A Prospective Randomized Controlled Trial.","authors":"Ke-Wei Wu, Shu-Yu Deng, Xu-Feng Zhang, Da-Wei Zheng, Li-Hong Hu","doi":"10.2147/DDDT.S532934","DOIUrl":"10.2147/DDDT.S532934","url":null,"abstract":"<p><strong>Background: </strong>As an adjuvant, dexamethasone can enhance the analgesic intensity and prolong the duration of nerve blocks. However, to date, no studies have compared the effectiveness of different administration routes of dexamethasone for thoracoscopy-guided thoracic paravertebral block (TTPB). This prospective randomized controlled study evaluated the postoperative analgesic effects of dexamethasone administered intravenously or perineurally in combination with ropivacaine for TTPB in patients undergoing radical lung cancer resection.</p><p><strong>Methods: </strong>A total of 150 patients were randomly assigned to receive dexamethasone intravenously (Group I, n=75) or perineurally (Group D, n=75). Before wound closure, patients in Group I underwent TTPB with ropivacaine while receiving an intravenous dexamethasone injection, whereas patients in Group D received a perineural mixture of ropivacaine and dexamethasone. The primary outcome was the time to first postoperative rescue analgesia. Secondary outcomes included Visual Analogue Scale (VAS) scores, postoperative 48-hour sufentanil consumption in patient-controlled intravenous analgesia (PCIA), postoperative blood glucose levels, postoperative recovery parameters, and incidence of adverse events.</p><p><strong>Results: </strong>Compared with Group I, Group D showed a significantly longer time to first postoperative rescue analgesia, lower VAS scores at all assessed time points, and reduced postoperative 48-hour sufentanil consumption. Group D also showed a smaller increase in postoperative blood glucose levels, an earlier time to first ambulation and a shorter postoperative hospital stay (all <i>P</i> < 0.05). However, the incidence of postoperative nausea was higher in Group D than in Group I (<i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>In TTPB, perineural dexamethasone administration with ropivacaine provided superior and longer-lasting analgesia compared with intravenous administration. Additionally, it accelerated postoperative recovery and shortened hospital stay.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8601-8611"},"PeriodicalIF":5.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12474666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184949","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":"Integrative Metabolomics and Ionomics Identify Organ-Specific Responses Associated with Cisplatin Treatment in Mice.","authors":"Rong Sun, Qin Xiao, Houlong Long, Ruili Dang, Shiyuan Zhao, Jinxiu Guo, Xue Chu, Haosen Sun, Yazhou Zhang, Pei Jiang","doi":"10.2147/DDDT.S531720","DOIUrl":"10.2147/DDDT.S531720","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin is a widely used chemotherapeutic agent effective against various malignant tumors. However, its clinical application is limited by severe toxic side effects on multiple vital organs. Understanding the systemic metabolic and elemental alterations associated with cisplatin is essential for developing strategies to mitigate its toxicity.</p><p><strong>Methods: </strong>An integrative metabolomics and ionomics approach was employed to investigate organ-specific responses to cisplatin treatment in mice. Gas chromatography-mass spectrometry (GC-MS) and inductively coupled plasma-mass spectrometry (ICP-MS) were used to analyze metabolic and elemental changes in multiple organs, including the heart, liver, spleen, lungs, kidneys, cortex, hippocampus, brown adipose tissue, and blood. Histopathological evaluation was also performed to complement biochemical analyses.</p><p><strong>Results: </strong>Multivariate statistical analysis indicated that cisplatin was accompanied by significant changes in the levels of several key metabolites, including amino acids, fatty acids, and tricarboxylic acid cycle intermediates. A total of 9 metabolic pathways were implicated, particularly those involved in amino acid biosynthesis, energy metabolism, and redox regulation. In parallel, notable variations in metal ion concentrations, such as Ag, Na, Ca, Zn, Cu, Mg and Fe, were observed across organs. These changes may be linked to alterations in enzyme activity and antioxidant functions.</p><p><strong>Conclusion: </strong>This study provides a comprehensive overview of metabolic and elemental disturbances in vital organs correlated with cisplatin exposure. The findings suggest that modulation of specific metabolites and trace elements may help reduce cisplatin toxicity. The integrative omics approach offers novel insights into the pathways potentially underlying chemotherapy-induced side effects and highlights possible therapeutic targets.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8613-8639"},"PeriodicalIF":5.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12474739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184927","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":"Formulation Strategies for Ezetimibe and Its Combinations: Advancing Biopharmaceutical and Therapeutic Potential.","authors":"Sani Ega Priani, Anis Yohana Chaerunisaa, Gofarana Wilar, Iyan Sopyan","doi":"10.2147/DDDT.S550340","DOIUrl":"10.2147/DDDT.S550340","url":null,"abstract":"<p><p>Ezetimibe is a cholesterol absorption inhibitor widely used in the treatment of dyslipidemia. However, its clinical efficacy is limited by poor aqueous solubility and low oral bioavailability. Therapeutic guidelines on dyslipidemia recommend ezetimibe as an adjunct or alternative to statins, particularly in patients who are intolerant to high-dose statins or have inadequate LDL-C reduction. This review summarizes recent advances in ezetimibe formulations, including single-active and combination systems, and discusses their effects on solubility, pharmacokinetics, and therapeutic outcomes. The analysis is based on literature published within the last decade (2015-2025) from reputable scientific databases. Advanced strategies such as solid-state modification, particle size reduction, and lipid or surfactant-based delivery systems have significantly enhanced drug dissolution. In vivo studies report relative bioavailability improvements of approximately 120 to 800% compared to pure drug suspensions/marketed products, translating into favorable pharmacodynamic profiles. Beyond single-active systems, innovative co-delivery with statins such as simvastatin, atorvastatin, rosuvastatin, and lovastatin has demonstrated added pharmacological synergy and supports the development of fixed-dose combination products. Collectively, these advances provide strong evidence that optimized ezetimibe formulations in single-active or combination systems have strong potential to improve the biopharmaceutical profile and future therapeutic application in dyslipidemia management.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8555-8580"},"PeriodicalIF":5.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184988","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":"Lidocaine-Based vs Sufentanil-Based PCIA After Pulmonary Resection Surgery: A Randomized Controlled Trial.","authors":"Bin Tian, Yumin Wu, Wenjie Zhang, Ruijuan Liu, Song Qu, Zhenying Zhang, Wenjun Yan","doi":"10.2147/DDDT.S538226","DOIUrl":"10.2147/DDDT.S538226","url":null,"abstract":"<p><strong>Background: </strong>We investigated the efficacy and safety of lidocaine-based patient-controlled intravenous analgesia (PCIA), compared with sufentanil-based PCIA on postoperative pain and recovery quality in patients undergoing thoracoscopic lung surgery.</p><p><strong>Methods: </strong>We recruited 160 patients undergoing thoracoscopic lung surgery who were randomized to receive lidocaine-based PCIA (1.5 mg/kg/h) or sufentanil-based PCIA (2 μg/mL) within 48 hours postoperatively. The primary endpoint was visual analogue scores (VAS) pain scores at 6, 12, 24, and 48 hours postoperatively. Postoperative quality of recovery-15 (QoR-15) scores and other prespecified endpoints were also recorded.</p><p><strong>Results: </strong>VAS pain scores at rest and during coughing in the lidocaine group were significantly lower at 6, 12, and 24 hours postoperatively (<i>P</i><0.05), with no difference at 48 hours (<i>P></i>0.05). QoR-15 scores in the lidocaine group were higher on postoperative day (POD) 1 (<i>P</i><0.001) and POD2 (<i>P</i><0.001), with significant differences in the two dimensions of postoperative physical comfort and pain (<i>P</i><0.001). The lidocaine group also experienced a shorter time to first flatus, defecation, and ambulation (<i>P</i><0.05), with no difference in the length of postoperative hospitalization and thoracic drainage time (<i>P></i>0.05). The serum IL-6, TNF-α, IL-8, cortisol, and epinephrine concentrations were lower in the lidocaine group on POD1 and POD2 (<i>P</i><0.05). The incidence of postoperative nausea and vomiting in the lidocaine group was lower (<i>P</i><0.05), with no differences in other adverse events (<i>P</i>>0.05).</p><p><strong>Conclusion: </strong>Compared with sufentanil-based PCIA, lidocaine-based PCIA significantly relieved postoperative pain and improved recovery quality after thoracoscopic lung surgery with fewer postoperative adverse events, which is a considerable choice for postoperative analgesia.</p><p><strong>Trial registration: </strong>This study was retrospectively registered at the Chinese Clinical Trial Registry on March 1st, 2023 (number ChiCTR2300068840).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8541-8553"},"PeriodicalIF":5.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136890","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 Antimicrobial Peptides in Wound Dressings.","authors":"Aoxun Zhu, Baiqi Chen, Jing Ma, Jiajia Wang, Rongfang Tang, Liangeng Liu, Weixin Sun, Xingzhong Zheng, Guangtao Pan","doi":"10.2147/DDDT.S543233","DOIUrl":"10.2147/DDDT.S543233","url":null,"abstract":"<p><strong>Background: </strong>Growing antibiotic misuse and the rise of antimicrobial resistance have driven interest in antimicrobial peptides (AMPs) as therapeutic agents for wound dressings and clinical wound management. AMPs are short, cationic peptides with broad‑spectrum activity and diverse mechanisms of action that confer a low propensity for resistance development.</p><p><strong>Methods: </strong>We performed a focused literature synthesis to review AMP classification, structural features, antimicrobial mechanisms, and strategies for integrating AMPs into wound dressings. We emphasize materials and delivery approaches reported for hydrogels, electrospun fibers, films, scaffolds, and sponges, and we summarize advances in hybrid systems that combine AMPs with functional materials.</p><p><strong>Results: </strong>AMP‑loaded dressings promote infection control and tissue repair by maintaining a favorable wound microenvironment, enabling controlled peptide release, reducing biofilms, and stimulating cell proliferation and angiogenesis. Hybrid platforms-polysaccharide and stimuli‑responsive hydrogels, metal‑nanoparticle composites, exosome carriers, and cryogels-improve peptide stability and bioavailability while introducing functionalities such as real‑time bacterial sensing, antioxidant activity, and electrical conductivity for electrostimulation. In chronic wounds and burns, AMP‑based dressings show promise for anti‑biofilm activity, immunomodulation, enhanced re‑epithelialization, and reduced risk of resistance compared with conventional antibiotics.</p><p><strong>Conclusion: </strong>We identify key challenges and propose future directions: rational design of tailored AMPs, smart controlled‑release carriers, nanotechnology‑enabled formulations, and strategies to accelerate clinical translation. Advances in these areas are expected to expedite the clinical adoption of AMP‑based wound therapies, offering safer, more effective, and personalized treatment options.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8523-8539"},"PeriodicalIF":5.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148253","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 Cellular Senescence for Healthy Aging: Advances in Senolytics and Senomorphics.","authors":"Esther Ugo Alum, Sylvester Chibueze Izah, Daniel Ejim Uti, Okechukwu Paul-Chima Ugwu, Peter A Betiang, Mariam Basajja, Regina Idu Ejemot-Nwadiaro","doi":"10.2147/DDDT.S543211","DOIUrl":"10.2147/DDDT.S543211","url":null,"abstract":"<p><strong>Background: </strong>Cellular senescence is a fundamental characteristic of aging, marked by permanent cell cycle cessation and the release of pro-inflammatory mediators. Although senescence plays advantageous roles in tissue regeneration and tumor suppression, its accumulation leads to aging-related illnesses and functional deterioration.</p><p><strong>Objective: </strong>This review examines the processes of cellular senescence, its effects on aging and age-related disorders, and emerging therapeutic strategies to modulate senescence for promoting healthy aging.</p><p><strong>Methods: </strong>A thorough literature review was performed using peer-reviewed studies on cellular senescence, its molecular pathways, and therapeutic interventions. Emphasis was placed on senolytics, senomorphics, and lifestyle interventions that modulate senescence-associated pathways. Studies published in Scopus, Web of Science and PubMed between 2014-2025 were selected.</p><p><strong>Results: </strong>Recent discoveries underscore the dual function of cellular senescence in aging and pathology. The senescence-associated secretory phenotype (SASP) fosters chronic inflammation and tissue dysfunction, connecting senescence to age-related diseases including cardiovascular conditions, dementia, and metabolic disorders. Therapeutic strategies, including senolytics (drugs that specifically eradicate senescent cells) and senomorphics (compounds that suppress SASP without killing cells), show promise in preclinical and clinical studies. Notably, dosing interals (intermittent vs continuous) influence both therapeutic efficacy and adverse events such as thrombocytopenia. Additionally, the state and limitations of clinical validation of aging biomarkers (eg, p16^INK4a, β-galactosidase) remain major hurdles for translation. Lifestyle interventions such as calorie restriction and exercise have also been identified as natural modulators of senescence pathways.</p><p><strong>Conclusion: </strong>Targeting cellular senescence offers a promising avenue for promoting healthy aging and mitigating age-linked diseases. Continued research into senescence-modulating interventions may lead to novel therapeutics designed to prolong healthspan and lifespan.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8489-8522"},"PeriodicalIF":5.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136865","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":"Intraoperative Dexmedetomidine Enhances Postoperative Microcirculation and Reduces Acute Kidney Injury in Cardiac Surgery: A Double-Blind Randomized Trial.","authors":"Po-Yuan Shih, Tsung-Ta Wu, Kuang-Cheng Chan, Ron-Bin Hsu, Ching-Tao Chang, Wei-Han Chou, Chun-Yu Wu","doi":"10.2147/DDDT.S541433","DOIUrl":"10.2147/DDDT.S541433","url":null,"abstract":"<p><strong>Purpose: </strong>Dexmedetomidine, an alpha-2 adrenergic agonist, has shown potential benefits in various surgical settings, but its impact on microcirculation and renal function in cardiac surgery patients remains unclear.</p><p><strong>Patients and methods: </strong>This randomized, controlled, double-blind clinical trial was conducted at a single university hospital. Seventy patients undergoing non-emergency cardiac and aortic surgery requiring cardiopulmonary bypass were enrolled, and 68 patients were included in the final analysis. Patients were randomized to receive either dexmedetomidine (0.5 mcg/kg loading dose, followed by 0.5 mcg/kg/h) or saline. The infusion of dexmedetomidine or saline began at anesthesia induction and continued until the end of surgery. Key microcirculatory variables-total vessel density, proportion of perfused vessels, perfused vessel density, De Backer's score, microvascular flow index, and heterogeneity index-were measured at five time points: baseline, 1 hour after cardiopulmonary bypass, 1 hour after arrival in the intensive care unit, 24 hours after surgery, and 48 hours after surgery. Data were analyzed using a mixed-effects model with Tukey's Honestly Significant Difference correction. Intraoperative urine output, the incidence of postoperative acute kidney injury, and other postoperative complications were also compared.</p><p><strong>Results: </strong>Patients in the dexmedetomidine group maintained higher postoperative proportion of perfused vessels and perfused vessel density compared to the saline group, with a significant interaction effect for perfused vessel density. Baseline perfused vessel density was comparable between the two study groups (17.5 [15.9-18.6] vs 18.0 [16.1-19.8] mm/mm², p = 0.540). At 48 hours postoperatively, patients in the dexmedetomidine group had significantly higher PVD values than those in the saline group (17.0 [15.0-19.0] vs 15.6 [13.7-16.9] mm/mm²; P = 0.041). The dexmedetomidine group also had significantly higher intraoperative urine output (950 vs 605 mL, p = 0.002). Additionally, the incidence of postoperative acute kidney injury was significantly lower in the dexmedetomidine group (11.8% vs 50%, p = 0.001).</p><p><strong>Conclusion: </strong>Intraoperative dexmedetomidine infusion during cardiac surgery is associated with higher postoperative microcirculatory state and a reduced incidence of acute kidney injury.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8451-8462"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130291","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 and Covariate Analysis of Methotrexate in Pediatric Acute Lymphoblastic Leukemia.","authors":"Biao Yu, Ying Wan, Kangkang Mei, Didi Zhan, Qi Tang, Xiaowei Hu, Wenbo Ji, Heping Cai","doi":"10.2147/DDDT.S545368","DOIUrl":"10.2147/DDDT.S545368","url":null,"abstract":"<p><strong>Purpose: </strong>The current study was designed to develop and validate a population pharmacokinetic (PPK) model of methotrexate (MTX) in pediatric patients with acute lymphoblastic leukemia (ALL). We aimed to develop a PPK model to evaluate the effects of potential covariates and explore dosing regimen.</p><p><strong>Patients and methods: </strong>We retrospectively analyzed data from 214 pediatric patients with ALL who received high-dose methotrexate (HD-MTX) therapy, incorporating a total of 1672 plasma concentration measurements. Plasma samples were assayed using Enzyme-Multiplied Immunoassay Technique (EMIT). The PPK model was developed using a nonlinear mixed-effects model approach utilizing the NONMEM 7.4 software. Monte Carlo simulation was conducted to optimize the dosage regimen.</p><p><strong>Results: </strong>A two-compartment model with a 1-year age cutoff was found to adequately describe the PK disposition of MTX. The population typical values for clearance (CL) and volume of distribution (V) were 4.46 L/h and 15.9 L, respectively. Estimated glomerular filtration rate (eGFR) was identified as the most significant covariate, with body weight and blood urea nitrogen (BUN) also emerging as primary factors influencing CL. The model exhibited satisfactory predictive performance, with bootstrap analysis showing a 93.6% success rate. For external validation, the median prediction error (MPE) and median absolute prediction error (MAPE) were -3.99% and 22.4%, respectively. Additionally, 46.36% of prediction errors fell within ±20%, and 64.55% within ±30%, confirming the model's acceptable predictive performance. Monte Carlo simulations showed that optimized loading doses significantly improved steady-state MTX levels and reduced delayed elimination, especially in patients with renal impairment (eGFR < 100 mL/min/1.73m²).</p><p><strong>Conclusion: </strong>The PPK model established in this study can well predict the MTX exposure level in children with ALL, and it clearly identifies renal function status as a key basis for adjusting the loading dose. Combined with the results of Monte Carlo simulations, we propose that for patients with mild to moderate renal insufficiency, increasing the loading dose and prolonging the infusion time can improve the steady-state concentration compliance rate while reducing the risk of delayed excretion, providing a more targeted reference for clinical decision-making.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8475-8488"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130294","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}