Drug Design, Development and Therapy最新文献

{"title":"Interpreting Route, Dose, and Clinical Relevance in Perioperative Magnesium Sulfate After Total Knee Arthroplasty [Letter].","authors":"Simin Gu, Xinyi Chen","doi":"10.2147/DDDT.S648268","DOIUrl":"10.2147/DDDT.S648268","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"648268"},"PeriodicalIF":6.1,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135597","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 and Postoperative Delirium After Head and Neck Cancer Surgery with Free-Flap Reconstruction: A Secondary Analysis of a Randomized Placebo-Controlled Trial.","authors":"Shi-Jing Zhang, Qiumiao Chen, Liheng Li, Junli You, Yu-Bo Xie","doi":"10.2147/DDDT.S598574","DOIUrl":"10.2147/DDDT.S598574","url":null,"abstract":"<p><strong>Background: </strong>Postoperative delirium is common after major head and neck cancer surgery. We investigated whether intraoperative dexmedetomidine infusion was associated with a lower incidence of postoperative delirium in patients undergoing head and neck cancer surgery requiring free-flap reconstruction.</p><p><strong>Methods: </strong>This was a delirium-focused secondary analysis of a single-centre, randomized, double-blind, placebo-controlled trial. Adult patients with head and neck cancer scheduled for elective surgery requiring free-flap reconstruction under general anaesthesia were randomly assigned to receive intraoperative dexmedetomidine infusion at 0.3 μg kg^-1h^-1 until 1 h before the end of surgery; subjects in the placebo group were given comparable volumes of normal saline. The primary outcome was the incidence of delirium during the first 5 postoperative days, assessed once daily using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM).</p><p><strong>Results: </strong>There was less delirium during the initial 5 postoperative days in patients assigned to dexmedetomidine (14.9%, 7 of 47 patients) than in those given placebo (34.7%, 17 of 49 patients). Dexmedetomidine was associated with lower odds of postoperative delirium after adjustment for age, preoperative Mini-Mental State Examination score, and operative time (adjusted odds ratio 0.31, 95% confidence interval 0.10-0.92; <i>p</i> = 0.036). Postoperative pain and early sleep outcomes were improved by dexmedetomidine. Haemodynamic adverse events and postoperative complications did not differ significantly between groups.</p><p><strong>Conclusion: </strong>In patients undergoing head and neck cancer surgery with free-flap reconstruction, intraoperative dexmedetomidine infusion was associated with a lower incidence of postoperative delirium during the first 5 postoperative days, without an apparent increase in perioperative adverse events.</p><p><strong>Clinical trial registration: </strong>ChiCTR2300067376.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"598574"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105547","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":"Comparisons in Analgesic Effects Between Ultrasound-Guided Erector Spinae Plane Block and Ultrasound-Guided Modified Intercostal Nerve Block in Modified Radical Mastectomy: A Randomized Controlled Trial.","authors":"Xin Da, Zimeng Jin, Ziyi Zou, Wei Zhou, Sihui Zhu, Yulu Hu, Xinyue Wang, Qingmei Zhang, Guanghong Xu","doi":"10.2147/DDDT.S625940","DOIUrl":"10.2147/DDDT.S625940","url":null,"abstract":"<p><strong>Introduction: </strong>Postoperative acute pain is a common challenge after breast cancer surgery. This randomized controlled trial compared the analgesic effects of ultrasound-guided erector spinae plane block (ESPB) and modified intercostal nerve block (MINB) in patients undergoing unilateral modified radical mastectomy.</p><p><strong>Methods: </strong>Seventy patients were randomly allocated to ESPB or MINB group. The primary outcomes were the 6-hour postoperative resting and movement-evoked Visual Analogue Scale (VAS) scores. Secondary outcomes included resting and movement-evoked VAS scores at 0, 3, 12, and 24 hours, intraoperative opioid consumption, rescue analgesic use within 72 hours, Quality of Recovery-15 (QoR-15) score at 24 hours, and hospital stay.</p><p><strong>Results: </strong>At 6 hours postoperatively, both resting VAS (median 2 [0-2] vs 2 [2-3], P=0.005) and movement-evoked VAS (median 3 [2-4] vs 4 [3-4], P=0.015) were lower in the MINB group. Resting VAS scores at 0 and 3 hours were comparable between groups. Movement-evoked VAS scores were lower in the MINB group at all post-surgery time points (P<0.05 for all). Intraoperative remifentanil consumption was lower in the MINB group (P<0.001). Fewer patients required rescue analgesics in the MINB group (P=0.038). No significant difference was observed in QoR-15 scores between groups (P=0.055).</p><p><strong>Conclusion: </strong>Ultrasound-guided MINB was associated with lower 6-hour resting and movement-evoked pain scores and reduced intraoperative opioid consumption compared with ESPB, without compromising recovery quality in patients undergoing unilateral modified radical mastectomy.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry (ChiCTR2300077956; https://www.chictr.org.cn/showproj.aspx?proj=77956). Registered on November 24, 2023. Principal investigator: Guanghong Xu.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"625940"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105543","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":"Postoperative Analgesia and Recovery with Liposomal Bupivacaine TAP/RSB Block in Elderly Patients Undergoing Laparoscopic Inguinal Hernia Repair: A Randomized Controlled Trial [Response to Letter].","authors":"Jiahui Gu, Minli Sun, Peter Szmuk, Xuwen Yang, Zhaoyuan Chen, Chengyu Wang, Changhong Miao","doi":"10.2147/DDDT.S654534","DOIUrl":"10.2147/DDDT.S654534","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"654534"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105246","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":"Interpreting ED90 Estimates in a Sequential Labor Analgesia Study [Letter].","authors":"Lijun Qi, Bin Su","doi":"10.2147/DDDT.S659549","DOIUrl":"10.2147/DDDT.S659549","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"659549"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105558","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 Dual Role of Piezo1 in Cancer: Mechanotransduction, Microenvironment Remodelling, and Therapeutic Opportunities.","authors":"Haiyan Jiang, Ying Liu, Fei Xue, Hualin Sun, Yanan Ji, Lei Qi","doi":"10.2147/DDDT.S640902","DOIUrl":"https://doi.org/10.2147/DDDT.S640902","url":null,"abstract":"<p><p>The mechanosensitive ion channel Piezo1 translates physical cues from the tumor microenvironment-including extracellular matrix stiffness, fluid shear stress, and compressive forces-into intracellular calcium signals and downstream cascades, playing a pivotal role in cancer. Piezo1 exhibits pronounced tumor-type dependency: it acts as an oncogene in multiple solid tumor types (eg, glioma, pancreatic cancer, esophageal squamous cell carcinoma) but exerts tumor-suppressive effects in lung cancer and clear cell renal cell carcinoma. This context-dependent duality poses fundamental challenges for clinical translation. This review systematically dissects the molecular mechanisms by which Piezo1 regulates proliferation, migration, epithelial-mesenchymal transition, cancer stem cell maintenance, and Piezo1-mediated ferroptosis via the TfR1/DMT1/NCOA4/GPX4 axis, which couples iron overload and lipid peroxidation to mechanical cues, is also discussed as a novel therapeutic vulnerability. It further analyzes its role in tumor microenvironment remodelling, including extracellular matrix stiffening, cancer-associated fibroblast activation, angiogenesis, lymphangiogenesis, and metabolic reprogramming. Moreover, the bidirectional immunomodulatory functions of Piezo1 are highlighted: it enhances T cell and natural killer cell antitumor activity but may also promote immunosuppression through regulatory T cells, tumor-associated macrophages, and dendritic cells. Regarding Piezo1-targeted therapies, advances in small-molecule modulators, ultrasound-based physical modulation, nanotechnology, combination regimens, and antibody-drug conjugates are summarized. Five translational bottlenecks are critically appraised: tissue specificity, cancer type-dependent functional differences, limitations of pharmacological tools, clinical translation barriers of mechanical force stimulation and drug resistance and tumor heterogeneity. Finally, future directions are discussed, including structure-guided drug design, organ-on-a-chip screening, CRISPR-based editing, and emerging modalities. As a critical hub linking mechanical cues to tumor biology, precise Piezo1 modulation promises to establish a new \"mechanomedicine\" paradigm-an emerging field that leverages mechanical force-based diagnostics and therapeutics for disease management. Future efforts should focus on highly selective modulators, patient stratification based on Piezo1 expression and mechanical signatures, and spatiotemporally synergistic strategies combining Piezo1 targeting with chemotherapy, immunotherapy, and metabolic interventions.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"640902"},"PeriodicalIF":6.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105438","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":"Switching to Pegmolesatide in Maintenance Dialysis: Real-World Hemoglobin Response, Temporal Dynamics, and Modality-Specific Predictors.","authors":"Chunlei Luo, Sizeng Bao, Yuanyuan Ai, Lingling Bao, Ruijuan Wang, Jianwei Ma, Xueyan Bian","doi":"10.2147/DDDT.S632477","DOIUrl":"https://doi.org/10.2147/DDDT.S632477","url":null,"abstract":"<p><strong>Purpose: </strong>Pegmolesatide is a monthly subcutaneous erythropoietin mimetic peptide for renal anemia, but real-world data beyond randomized trials remain scarce. We evaluated its effectiveness, temporal response dynamics, and modality-specific response predictors in maintenance dialysis patients switched from prior anemia therapy.</p><p><strong>Patients and methods: </strong>In this single-center retrospective study, 192 maintenance dialysis patients (hemodialysis [HD], n = 90; peritoneal dialysis [PD], n = 102) receiving monthly subcutaneous pegmolesatide were analyzed; 52.6% had switched from erythropoiesis-stimulating agents and 47.4% from a hypoxia-inducible factor prolyl hydroxylase inhibitor, predominantly for suboptimal anemia control. The primary endpoint was hemoglobin (Hb) change at month 3. Secondary endpoints included iron dynamics, mixed-effects modeling of temporal patterns (1,423 observations), and predictors of poor response.</p><p><strong>Results: </strong>Mean Hb increased from 96.4 ± 15.9 to 110.0 ± 19.2 g/L at month 3 (model-estimated Δ = +13.0 g/L; 95% CI, 9.8 to 16.3; P<0.001) and remained stable through month 12. Target achievement (Hb ≥ 110 g/L) rose from 19.8% to 54.5%. The Hb trajectory was nonlinear, with a rapid first-month rise followed by deceleration; increments were attenuated at higher baseline Hb (ceiling effect), and higher serum albumin was associated with faster Hb improvement. Iron deficiency declined from 46.3% at baseline to a model-estimated 20.4% at month 12. Higher baseline Hb predicted a smaller increment; dialysis vintage of 12-36 months independently predicted attenuated response (pooled OR 5.17-8.68; P<0.001). Predictors differed by modality (body mass index in HD; diabetes in PD). Thromboembolic events (2.6%) were exclusively vascular access-related; mortality was 2.1%.</p><p><strong>Conclusion: </strong>Monthly pegmolesatide was associated with rapid and sustained Hb improvement and acceptable safety. Baseline Hb and dialysis vintage were the dominant response predictors, with distinct modality-specific profiles, supporting evaluation of individualized dosing strategies in randomized trials.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"632477"},"PeriodicalIF":6.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105488","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":"Emodin in Skeletal Muscle Ischemia-Reperfusion: Model Validity and Analytical Concerns [Letter].","authors":"Huayi Gao, Ruiyi Zhang, Mengzhou Xue","doi":"10.2147/DDDT.S657896","DOIUrl":"https://doi.org/10.2147/DDDT.S657896","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"657896"},"PeriodicalIF":6.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105524","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":"Optimal Dosing Strategies for Remimazolam Across Diverse Patient Populations: A Clinical Narrative Review.","authors":"Amina M Illias, Yung-Fong Tsai, Shao-Chun Wu","doi":"10.2147/DDDT.S644446","DOIUrl":"https://doi.org/10.2147/DDDT.S644446","url":null,"abstract":"<p><p>Remimazolam is an ultra-short-acting benzodiazepine that is hydrolyzed by carboxylesterase 1 (CES1) to the inactive metabolite CNS 7054. Since regulatory approval in 2020 it has been adopted globally for procedural sedation and general anesthesia, supported by an expanding evidence base of randomized trials, population pharmacokinetic/pharmacodynamic (PK/PD) modeling studies, dose-finding sequential-allocation analyses, and meta-analyses. Synthesizing 92 studies published between January 2020 and April 2026, this narrative review defines dose optimization across diverse populations. For adult procedural sedation, a fixed 5 mg initial bolus followed by 2.5 mg maintenance titrations achieves moderate sedation with a hemodynamic and respiratory profile that compares favorably with propofol, whereas general anesthesia requires an induction rate of 6 to 12 mg kg^-1 h^-1 followed by maintenance at 1.0-2.0 mg kg^-1 h^-1. Dosing demands a 25-30% reduction in the elderly (≥ 65 years), higher weight-adjusted requirements in pediatric patients (1-18 years), and lean or corrected body weight scalars in obesity, while severe hepatic impairment reduces clearance by approximately 38% and opioid co-administration yields a 15-63% synergistic reduction in effective concentrations. Several quantitative estimates, however, derive from single-center trials with fewer than 30 participants per arm that have not been externally validated. To help clinicians weigh these recommendations, each population-level dosing estimate is graded by the strength and external validity of its supporting evidence (A, B, or C); most special-population point estimates rest on single-center studies (grade C) and are best regarded as starting points rather than established standards. Crucially, the halted Japanese Phase II intensive care unit trial (ONO-2745-04) serves as a key safety counter-narrative: continuous infusions exceeding 24 hours in critically ill patients may be associated with drug accumulation and delayed emergence, suggesting that organ-independent clearance may not be guaranteed when CES1 activity is compromised. Major evidence gaps persist for infants under one year of age, long-duration anesthesia, CES1 polymorphisms, and non-East-Asian populations.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"644446"},"PeriodicalIF":6.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105710","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":"MAMs-Mediated Calcium Homeostasis in the Pathophysiology of Cardiovascular Diseases: A Mini-Review.","authors":"Maoxia Fan, Fang Liu, Yawen Wang, Weijuan Shi, Lijing Zhang","doi":"10.2147/DDDT.S641584","DOIUrl":"https://doi.org/10.2147/DDDT.S641584","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) remain a leading threat to human health, imposing substantial morbidity and a considerable clinical burden worldwide. Disrupted mitochondrial calcium ions (Ca²⁺) homeostasis is increasingly recognized as a shared pathophysiological feature of diverse CVDs. Mitochondria and the endoplasmic reticulum (ER) are key organelles involved in intracellular Ca²⁺ homeostasis and energy metabolism, and their physical and functional coupling occurs at mitochondria-associated ER membranes (MAMs). Through protein complexes such as IP3R-GRP75-VDAC1, VAPB-PTPIP51 and MFN1-MFN2, MAMs coordinate a finely tuned Ca²⁺-signalling network that is essential for maintaining mitochondrial Ca²⁺ homeostasis. This review provides a systematic overview of the structural organization of MAMs and the molecular mechanisms governing MAM-mediated Ca²⁺ transfer, with particular emphasis on how dysregulated Ca²⁺ signalling at MAMs contributes to myocardial ischaemia-reperfusion injury, atherosclerosis, heart failure (HF), pulmonary arterial hypertension and diabetic cardiomyopathy. Furthermore, on this basis, this review focuses on the IP3Rs‑GRP75‑VDAC1 complex, mitochondrial calcium uniporter (MCU)‑associated calcium‑transport pathways, the endoplasmic reticulum stress‑MAMs‑mitochondrial calcium overload axis, as well as MAMs‑mediated signaling cascades, and systematically elaborates the latest research advances of therapeutic interventions including small‑molecule inhibitors, targeted peptides, calcium chelators, chemical chaperones and natural products. At present, available therapeutic evidence is mostly obtained from cellular and animal models. The process of clinical translation is still constrained by suboptimal target selectivity, dilemmas in bidirectional calcium‑signal regulation, bottlenecks in tissue‑specific delivery and the lack of long‑term safety evaluation. This review is expected to provide theoretical foundations and cutting‑edge insights for novel cardiovascular drug discovery and translational research targeting MAMs‑related calcium homeostasis.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"641584"},"PeriodicalIF":6.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105681","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}