Drug Design, Development and Therapy最新文献

{"title":"Weight-Scaled Dose Optimization of Intravenous Anesthetics in Patients with Obesity: General Anesthesia and Procedural Sedation.","authors":"Han Gu, Haoran Qian, Kefan Chen, Juan Zhu, Peng Jiang, Longbin Zheng","doi":"10.2147/DDDT.S653515","DOIUrl":"10.2147/DDDT.S653515","url":null,"abstract":"<p><p>Obesity alters the pharmacokinetics and pharmacodynamics of intravenous anesthetics, complicating weight-based dose selection. This narrative review examines weight-scaling strategies and effective-dose estimates (ED50/ED95) for propofol, ciprofol, and remimazolam in patients with obesity undergoing general anesthesia or procedural sedation. Targeted searches of PubMed/MEDLINE were supplemented by DOI and title searches in Europe PMC and publisher records. Evidence was selected purposively according to clinical relevance, study design, population, dosing phase, and outcome, prioritizing obesity-specific studies. General pharmacological evidence was considered separately to contextualize findings and evidence gaps. The evidence supporting dose optimization is broader for propofol than for ciprofol or remimazolam. Propofol studies support weight-informed initial dosing followed by individualized adjustment, although no single weight scalar is appropriate across all settings. Obesity-specific induction and dose-finding studies of ciprofol and remimazolam provide preliminary information, but limited study numbers and population diversity restrict generalizability. Their maintenance dosing in patients with obesity remains insufficiently characterized. ED50/ED95 values reflect responses under specific study conditions and should not be interpreted as routine clinical dosing recommendations. For procedural sedation, dose selection requires consideration of the intended sedation depth, concomitant medications, and respiratory risk. Weight-based calculations provide initial dose estimates, while titration guided by clinical response and appropriate pharmacodynamic monitoring remains essential. The proposed dosing framework distinguishes approaches supported by broader clinical evidence from preliminary findings and suggestions based on pharmacological reasoning. The latter require further validation before routine adoption. Adequately powered, multicenter comparative trials should address maintenance dosing, extreme obesity, and clinically meaningful safety and recovery outcomes.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"653515"},"PeriodicalIF":6.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215388","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 Oliceridine on Early Postoperative Recovery in Children Undergoing Adenotonsillectomy: A Prospective, Double-Blind, Randomized Controlled Trial.","authors":"Yuan Wang, Zhichun Cui, Zhonggang Cheng, Yuping Qin, Hang Lu, Cuihua Chen, Zhouyan Wu, Wenbin Zhang, Xinnan Song, Yanzhuo Zhang","doi":"10.2147/DDDT.S634139","DOIUrl":"10.2147/DDDT.S634139","url":null,"abstract":"<p><strong>Background: </strong>Children undergoing adenotonsillectomy may be vulnerable to opioid-related adverse effects, creating a need for analgesic strategies that support rapid postoperative recovery. This study compared the perioperative effects of oliceridine and sufentanil in children undergoing adenotonsillectomy under general anesthesia.</p><p><strong>Methods: </strong>This single-center, double-blind, randomized controlled trial included 79 children aged 3-10 years with ASA physical status I-II undergoing elective adenotonsillectomy under general anesthesia with tracheal intubation. Participants were randomly assigned 1:1 to receive oliceridine 0.1 mg/kg (n = 39) or sufentanil 0.5 μg/kg (n = 40) during anesthesia induction. The co-primary endpoints were extubation time and PACU stay duration. Secondary endpoints included perioperative hemodynamics, Pediatric Anesthesia Emergence Delirium (PAED) score, Face, Legs, Activity, Cry, Consolability (FLACC) score, opioid exposure, rescue analgesic use, and postoperative adverse events.</p><p><strong>Results: </strong>Extubation time was shorter with oliceridine than with sufentanil (35.4 ± 8.5 vs 42.6 ± 14.9 min; mean difference, -7.16 min; 95% CI, -12.59 to -1.74; p = 0.010). PACU stay duration was also shorter with oliceridine (median, 55 [47.5, 65] vs 65 [53.8, 70] min; estimated location shift, -10.00 min; 95% CI, -15.00 to <0.00; p = 0.011). Both co-primary endpoint p-values remained below the post hoc Bonferroni threshold of 0.025. Exploratory age-stratified analyses showed no significant treatment-by-age interactions for either recovery outcome. PAED and FLACC scores and SpO₂ before PACU discharge did not differ significantly between groups. Postoperative adverse events were infrequent, and no participant required rescue analgesia.</p><p><strong>Conclusion: </strong>Compared with sufentanil, oliceridine was associated with shorter extubation time and PACU stay duration in children aged 3-10 years undergoing adenotonsillectomy under general anesthesia. These findings suggest that oliceridine may facilitate early postoperative recovery, although larger studies are needed to further characterize its comparative safety.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"634139"},"PeriodicalIF":6.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215423","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":"Construction and Validation of a Predictive Model for Voriconazole Treatment Efficacy in Influenza-Associated Pulmonary Aspergillosis Based on Machine Learning.","authors":"Xin Zhang, Qianqian Zhu, Sujuan Tang, Qingwen Wu, Juan Wang, Lanfang Li, Haining Huang","doi":"10.2147/DDDT.S641070","DOIUrl":"10.2147/DDDT.S641070","url":null,"abstract":"<p><strong>Purpose: </strong>To analyze risk factors affecting voriconazole efficacy in influenza-associated pulmonary aspergillosis (IAPA) and build interpretable machine learning (ML) predictive models.</p><p><strong>Patients and methods: </strong>This retrospective study enrolled voriconazole-treated IAPA patients into a primary retrospective set (Jan 1, 2020-Jul 31, 2025) and a separate temporal external validation set (Aug 1, 2025-Apr 30, 2026). To avoid data leakage, the primary set was stratified by treatment response and randomly split at a 7:3 ratio into training and internal validation set prior to feature screening. Forty-two baseline candidate variables were collected. Feature selection was performed exclusively within the training dataset via univariate screening, 10-fold cross-validated Least Absolute Shrinkage and Selection Operator (LASSO), and Variance Inflation Factor (VIF) collinearity filtering. Parallel multivariate logistic regression was performed to identify independent predictors without additional stepwise elimination. Validation sets were only used for model performance evaluation. Seven ML algorithms were constructed, and SHapley Additive exPlanations (SHAP) analysis was applied to interpret the best-performing model.</p><p><strong>Results: </strong>Patients in the internal set were categorized into voriconazole-responsive (VR, n=284) and non-responsive (VNR, n=56) groups based on clinical remission, radiological absorption, and reduction of inflammatory biomarkers. Multi-step variable screening retained 11 non-collinear candidate predictors. Multivariate logistic regression identified four independent predictors for poor therapeutic response: ICU admission, concomitant midazolam use, elevated baseline neutrophil percentage, and reduced baseline platelet count. The CatBoost model achieved the optimal discrimination, with internal-validation AUC = 0.88 (95% CI: 0.87-0.88) and temporal external-validation AUC = 0.83 (95% CI: 0.70-0.94). Decision Curve Analysis (DCA) demonstrated that all seven models yielded positive net clinical benefit across the threshold probability range of 0.00-0.90. SHAP analysis further illustrated the important contribution of ICU admission and midazolam to prediction outcomes, with partial discrepancy from multivariate logistic regression feature ranking.</p><p><strong>Conclusion: </strong>This study identified four independent predictors of voriconazole efficacy in IAPA patients. The established CatBoost model delivers stable, interpretable prediction to guide individualized voriconazole therapy for IAPA.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"641070"},"PeriodicalIF":6.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215400","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":"Nanozyme-Mediated Anesthetic Drug Delivery and Macrophage Immunomodulation: Emerging Concepts and Translational Challenges.","authors":"Ruifeng Li, Weifeng Gao, Yanfen Bing, Dongqing Ren","doi":"10.2147/DDDT.S646804","DOIUrl":"10.2147/DDDT.S646804","url":null,"abstract":"<p><p>Anesthetic agents can influence not only neuronal signaling but also oxidative stress, inflammasome activation, cellular metabolism, and perioperative immune responses. Macrophages are central regulators of tissue injury, inflammation resolution, neuroimmune interactions, and the tumor microenvironment, and therefore represent a plausible target for non-neuronal effects of anesthetic therapy. Nanozymes are nanomaterials with intrinsic enzyme-like catalytic activity; representative systems include cerium oxide and magnetite/iron-oxide nanoparticles with superoxide dismutase-, catalase-, peroxidase-, or related redox activities. Unlike conventional inert nanocarriers, nanozymes may combine drug loading with active remodeling of reactive oxygen species, hypoxia, and inflammatory microenvironments. However, direct studies that simultaneously demonstrate nanozyme-mediated anesthetic delivery, macrophage-dependent mechanisms, and therapeutic benefit remain scarce. Current evidence is therefore derived mainly from three adjacent areas: nanozyme regulation of macrophages, anesthetic modulation of macrophage function, and nanocarrier-mediated delivery of anesthetic agents. This review critically integrates these evidence streams, discusses redox regulation, inflammasome signaling, metabolic reprogramming, biological clearance, and context-dependent pro-oxidative versus antioxidant activity, and evaluates strategies for targeted and stimulus-responsive anesthetic delivery. We further compare nanozyme platforms with other advanced nanocarriers and highlight key translational barriers, including assay standardization, macrophage heterogeneity, long-term inorganic-material retention, and clinically meaningful pharmacodynamic evaluation. These emerging concepts provide a framework for testable perioperative drug-delivery and immunomodulation strategies rather than evidence of an already established clinical platform.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"646804"},"PeriodicalIF":6.1,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215447","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":"Managing Rebound Bone Loss After Denosumab Discontinuation: Mechanisms, Risk Stratification, and Sequential Therapy.","authors":"Ahmad, Yuting Liao, Mei Yu, Jiamei Xu, Yankui Zhai, Qixian Xiao, Guocai Wang, Zuocheng Qiu, Yanzhi Liu","doi":"10.2147/DDDT.S640547","DOIUrl":"10.2147/DDDT.S640547","url":null,"abstract":"<p><p>Denosumab is a fully human monoclonal antibody targets receptor activator of nuclear factor kappa-Β ligand (RANKL), potently suppresses bone resorption, increases bone mineral density (BMD), and reduces vertebral, hip, and non-vertebral fracture risk. However, its pharmacokinetic reversibility renders discontinuation clinically hazardous. This narrative review synthesizes current evidence on the mechanisms, clinical consequences, and risk determinants of rebound bone loss following denosumab discontinuation and critically evaluates available preventive strategies. Upon denosumab cessation, rapid restoration of RANKL bioavailability triggers a pathological osteoclast overshoot, driven by accumulated osteoclast precursors and unopposed RANK-RANKL signaling. The resulting rebound in bone turnover produces accelerated BMD loss and markedly elevated multiple vertebral fracture risk, with real-world cohorts documenting incidences of up to 10% within 12-18 months of unmanaged cessation, and hip and vertebral fractures in this setting have been associated with substantial excess mortality in observational studies. Sequential antiresorptive therapy, principally intravenous zoledronic acid or oral alendronate, is the most widely recommended approach; risedronate consistently fails to provide adequate skeletal protection. Treatment duration critically modulates rebound severity, with longer denosumab therapy, particularly beyond approximately three years is associated with greater post-discontinuation bone loss and reduced protection from a single bisphosphonate infusion, warranting intensified monitoring and management in this group. Anabolic agents, including teriparatide, are generally not recommended as primary sequential therapy, whereas romosozumab is promising only when initiated early in carefully selected patients. Serial serum C-terminal telopeptide (CTX) monitoring provides a practical framework for guiding therapeutic transitions and identifying inadequate bone turnover suppression. Safe denosumab management requires structured, individualized planning that integrates risk stratification, biochemical monitoring, and a pre-defined sequential therapy strategy established at the time of prescription, not at the point of cessation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"640547"},"PeriodicalIF":6.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13665659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192094","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":"Pharmacological and Safety Evaluation of the Small Molecule MP-004 Following Topical Ocular Administration for the Treatment of Inherited Retinal Dystrophies.","authors":"Araceli Lara-López, María Rodríguez-Hidalgo, Miren Sarasola-Gastesi, Klaudia González-Imaz, Julián Zayas-Arrabal, Maialen Sagartzazu-Aizpurua, Jose Ignacio Miranda, Ana Espinosa, Adolfo López de Munain, Jesús María Aizpurua, Francisco Javier Gil-Bea, Ainara Vallejo-Illarramendi, Javier Ruiz-Ederra","doi":"10.2147/DDDT.S611791","DOIUrl":"10.2147/DDDT.S611791","url":null,"abstract":"<p><strong>Purpose: </strong>MP-004 is a novel small molecule under development as a non-invasive therapeutic for inherited retinal dystrophies (IRDs), including retinitis pigmentosa. MP-004 halts photoreceptor degeneration by modulating calcium dysregulation and oxidative stress, two critical pathways involved in IRDs. Here, we evaluated its ocular concentration and safety profile following topical administration in three animal species (mouse, rabbit, and pig).</p><p><strong>Results: </strong>Formulation of MP-004 with 0.3% hyaluronic acid substantially enhanced retinal concentrations in mice compared to non-formulated compound (6.67 vs 1.27 µg/g at 4 h). MP-004 reached the retina in all species evaluated, with minimal systemic exposure. In mice, serum concentrations were below 5 ng/mL, while in rabbits, the compound was undetectable in blood and peripheral tissues 12 h post-dose. Interestingly, in rabbits the maximum serum concentration was 43.6 ng/mL with a half-life of 20 minutes, whereas the maximum retinal concentration was 387 ng/g and the half-life of 6.34 h. Seven-day repeated-dose toxicity studies in mice and rabbits showed no systemic or ocular toxicity. In rabbits, only transient ocular redness was observed following administration, with no evidence of corneal damage or systemic adverse effects. Hematological and biochemical parameters remained within normal limits in both species. Importantly, retinal and optic nerve concentrations remained detectable in rabbits 7 days after the final dose, while the compound had been systemically eliminated, supporting prolonged retention in target tissues.</p><p><strong>Conclusion: </strong>These findings demonstrate that MP-004 is well tolerated and achieves effective retinal concentrations via topical delivery, overcoming a major barrier in retinal drug development. The favorable pharmacokinetic and safety profile across species, including anatomically relevant models, supports the advancement of MP-004 toward regulatory preclinical studies and subsequently, its clinical translation as a non-invasive therapy for IRDs.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"611791"},"PeriodicalIF":6.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13665670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191945","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":"Proteomics in Antitumor Drug Target Discovery, Toxicity, Resistance, and Precision Oncology.","authors":"Qian Zhong, Xiuli Wu, Emilia Wiechec, Yulu Yang, Mingwan Liao, Hongqing Zhou, Shiqing Gao, Yangqiu Li, Shuhong Luo, Ling Xu","doi":"10.2147/DDDT.S629658","DOIUrl":"10.2147/DDDT.S629658","url":null,"abstract":"<p><p>Proteomics, the comprehensive study of protein expression, localization, and modifications, has evolved from a fundamental research tool into a key complementary layer to genomics in antitumor drug development and precision oncology. This review highlights its multi-dimensional applications, including differential, chemical, and post-translational modification proteomics, for drug-target discovery and mechanism-of-action elucidation. It further discusses proteomics strategies, such as mass spectrometry-based quantitative approaches, protein microarray and single-cell proteomics, which enable the profiling of adverse drug reactions, the dissection of resistance mechanisms, and the advancement of precision oncology. To date, the translational maturity of these applications is uneven: proteomic biomarkers have entered prospective trials and informed molecular tumor board recommendations in selected Clinical Laboratory Improvement Amendments (CLIA) certified settings, whereas de novo proteomics-derived drug targets remain largely at the preclinical stage. By bridging basic research and clinical practice, proteomics provides a scientific framework that facilitates drug development and informs clinical translation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"629658"},"PeriodicalIF":6.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13665675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191971","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":"Advances in Schaftoside Research: Pharmacological Mechanisms, Pharmacokinetics, and Therapeutic Perspectives.","authors":"Mengyue Wang, Shaoze Ren, Li Zhang, Yi Zheng, Junpeng Zhang, Meng Zhao, Shanshan Zhao, Qing Yu, Wenqing Wang, Rutao Bian, Xuegong Xu","doi":"10.2147/DDDT.S645951","DOIUrl":"https://doi.org/10.2147/DDDT.S645951","url":null,"abstract":"<p><p>Schaftoside is a flavonoid C-glycoside widely existing in medicinal plants and has been extensively reported due to its pharmacological activities, such as anti-inflammatory, hepatoprotective, antioxidant and neuroprotective activities. These pharmacological activities may be attributed to its effects on apoptosis, autophagy, ferroptosis, pyroptosis, oxidative stress and related signaling pathways. In this review, we summarize recent advances in pharmacological activities and pharmacomechanisms of schaftoside as well as its pharmacokinetic properties, formulation strategies, safety and therapeutic application. The biological effects of schaftoside have been demonstrated in various pathological models by relevant in vitro and in vivo experiments. However, its oral bioavailability is extremely low, which is a big challenge for its further development. Some formulation approaches, especially drug delivery systems, have shown preliminary prospects, but related reports are limited. Based on available toxicological findings, schaftoside is expected to have a relatively safe profile. However, the relationship between schaftoside and chemosensitivity as well as drug resistance needs to be further investigated. In conclusion, schaftoside is a promising bioactive compound; however, its pharmacokinetic properties and available clinical evidence need to be further investigated.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"645951"},"PeriodicalIF":6.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179913","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":"Oral Obesity Medicines in the Era of Cardiovascular-Kidney-Metabolic Syndrome (CKM): Beyond Weight Loss Toward Disease Modification.","authors":"Abdulhameed Alhazmi, Carel W Le Roux","doi":"10.2147/DDDT.S637685","DOIUrl":"https://doi.org/10.2147/DDDT.S637685","url":null,"abstract":"<p><p>Obesity is a major driver of Cardiovascular-Kidney-Metabolic (CKM) syndrome and contributes to the development of atherosclerotic cardiovascular disease, heart failure, atrial fibrillation, chronic kidney disease, and type 2 diabetes. Historically, oral obesity pharmacotherapy was evaluated primarily according to weight loss efficacy. However, the emergence of the CKM framework has shifted therapeutic priorities toward modifying obesity related complications and improving long term clinical outcomes. This review summarizes currently approved oral obesity medications, including first generation agents (orlistat, phentermine/topiramate, and naltrexone/bupropion) and second generation incretin-based therapies (oral semaglutide and orforglipron), within the context of CKM syndrome. First generation agents provide modest-to-moderate weight loss and variable metabolic benefits, but evidence supporting cardiovascular or kidney outcome improvement remains limited and largely observational. In contrast, oral incretin-based therapies demonstrate broader effects across the CKM spectrum, including substantial weight reduction, improved glycemic control, favorable effects on blood pressure and triglycerides, and emerging kidney benefits. Among currently available oral agents, oral semaglutide has the strongest evidence, with the SOUL trial demonstrating a reduction in major adverse cardiovascular events in high-risk individuals with type 2 diabetes. Signals suggesting benefits in heart failure and atrial fibrillation are encouraging but remain exploratory. Orforglipron represents the first non-peptide oral glucagon-like peptide-1 receptor agonist and offers simplified administration with promising metabolic efficacy; however, cardiovascular, kidney, heart failure, and arrhythmia outcome data are still awaited. Collectively, the role of oral obesity pharmacotherapy is evolving from weight management alone toward comprehensive CKM care.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"637685"},"PeriodicalIF":6.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179941","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":"Rebound Pain as a Treatment-Dependent Endpoint in the ITMB Non-Inferiority Trial [Letter].","authors":"Jianyi Xu, Haiwei Song, Jinzhong Wang","doi":"10.2147/DDDT.S658504","DOIUrl":"https://doi.org/10.2147/DDDT.S658504","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"658504"},"PeriodicalIF":6.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180010","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}