Cts-Clinical and Translational Science最新文献

{"title":"Vitamin D Supplementation Improves Muscle Mass, Physical Function, and Quality of Life in Patients With Degenerative Lumbar Disease","authors":"Sinsuda Dechsupa,&nbsp;Wicharn Yingsakmongkol,&nbsp;Worawat Limthongkul,&nbsp;Weerasak Singhatanadgige,&nbsp;Suvichada Assawakosri,&nbsp;Sittisak Honsawek","doi":"10.1111/cts.70315","DOIUrl":"10.1111/cts.70315","url":null,"abstract":"<p>Degenerative lumbar disease is a significant contributor to acute or chronic musculoskeletal issues in the elderly, often associated with low serum 25-hydroxyvitamin D (25(OH)D) levels. The effect of vitamin D₂ supplementation on muscle mass, strength, and physical performance remains unclear. This study aimed to determine the effect of vitamin D₂ supplementation on these parameters in patients with degenerative lumbar disease and low vitamin D status. A total of 115 patients with serum 25(OH)D levels &lt; 30 ng/mL were administered 40,000 IU of vitamin D₂ (ergocalciferol) weekly for 6 months. Body composition, serum 25(OH)D, parathyroid hormone (PTH) levels, muscle strength, and physical performance were examined before and after 6 months of vitamin D₂ supplementation. Baseline median serum 25(OH)D was 24.9 ng/mL; 79.1% had vitamin D insufficiency, and 20.9% had vitamin D deficiency. After supplementation, median 25(OH)D increased to 43.1 ng/mL (<i>p</i> &lt; 0.001), with a significant reduction in PTH (<i>p</i> &lt; 0.001). Significant improvements were observed in muscle mass (<i>p</i> = 0.04), balance test (<i>p</i> = 0.01), gait speed (<i>p</i> = 0.009), chair stand test (<i>p</i> &lt; 0.001), short physical performance (<i>p</i> &lt; 0.001), Oswestry disability index (<i>p</i> &lt; 0.001), and visual analog scale (VAS) scores (<i>p</i> &lt; 0.001). Post-supplementation 25(OH)D levels correlated negatively with body mass index (<i>ρ</i> = −0.187, <i>p</i> = 0.045), fat mass (<i>ρ</i> = −0.219, <i>p</i> = 0.019), fat percentage (<i>ρ</i> = −0.199, <i>p</i> = 0.033), and VAS score (<i>ρ</i> = −0.313, <i>p</i> &lt; 0.001). Six months of vitamin D₂ supplementation significantly improved vitamin D status, muscle mass, physical performance, and quality of life in patients with degenerative lumbar disease.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE Genotype and Statin Response: Evidence From the UK Biobank and All of Us Program","authors":"Innocent G. Asiimwe,&nbsp;Andrea L. Jorgensen,&nbsp;Munir Pirmohamed,&nbsp;the Multimorbidity Mechanism and Therapeutic Research Collaborative (MMTRC)","doi":"10.1111/cts.70314","DOIUrl":"10.1111/cts.70314","url":null,"abstract":"<p><i>APOE</i> genotype may affect statin response. Using UK Biobank (UKB) and All of Us (AoU) data, we aimed to investigate associations between <i>APOE</i> genotype, statin use, and key health outcomes. Our analysis included UKB baseline data and linked mortality records (389,843–452,189 participants), and electronic health records (EHR) from 45,515 UKB and 35,562 AoU participants. Multivariable regression and Cox models assessed lipid biomarkers, all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). In UKB, <i>ε3ε4</i> (HR: 1.08, 95% CI: 1.01–1.15) and <i>ε4ε4</i> (HR: 1.54, 95% CI: 1.33–1.78) carriers had higher all-cause mortality risk. In AoU, only <i>ε4ε4</i> carriers showed increased risk (HR: 1.64, 95% CI: 1.08–2.49). Cardiovascular mortality was assessed only in UKB, where <i>ε4ε4</i> carriers had an increased risk (HR: 1.30, 95% CI: 1.01–1.68). Mortality associations in UKB EHR data were consistent with those from baseline data and linked mortality records (e.g., <i>ε4ε4</i> genotype: all-cause mortality HR: 1.51, 95% CI: 1.41–1.62; cardiovascular mortality HR: 1.54, 95% CI: 1.33–1.77). However, the statin:<i>APOE</i> interaction term included in the baseline analysis was not statistically significant. In AoU, changes in HDLC, LDLC, and triglycerides were associated with reduced all-cause mortality risk. No significant MACE associations were observed in either cohort. This study reaffirms that <i>APOE ε4</i> genotype increases mortality risk, including in statin-treated patients, and could therefore be used to inform enhanced monitoring or medication review in these patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Informed Paradigm in Drug Development—An End-To-End Case Study From Upadacitinib Development","authors":"Sumit Bhatnagar,&nbsp;Sven Stodtmann,&nbsp;Yuli Qian,&nbsp;Patrick Marroum,&nbsp;Wei Liu,&nbsp;Mohamed-Eslam F. Mohamed","doi":"10.1111/cts.70295","DOIUrl":"10.1111/cts.70295","url":null,"abstract":"<p>Model-informed drug development (MIDD) entails applying quantitative approaches to assist with decision-making during drug development and has been used for dose optimization, to inform clinical trial design, and to support clinical trial waivers. With increasing cost and competitiveness in drug development, the use of tools that improve efficiency, like MIDD, is increasingly crucial. A unique case for the successful application of MIDD approaches from early Phase 1 through postapproval for the upadacitinib development program is described herein. Upadacitinib is an orally administered selective Janus kinase inhibitor, which is approved for rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, axial spondylarthritis, nonradiographic axial spondyloarthritis, ulcerative colitis, and Crohn's disease for adults, in addition to recent approvals for polyarticular juvenile idiopathic arthritis and pediatric patients with psoriatic arthritis. Applications and impact of modeling and simulation approaches for informing key development decisions are presented to highlight the success of using MIDD for the clinical development of upadacitinib. The lessons learned can provide a framework for the clinical development of other drugs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrospective Analysis of Master Protocols in Tumor-Agnostic Drug Development: Evaluation of Application to Single-Agent Therapies With ORR as the Endpoint for Approval of Oncology Drugs","authors":"Keiko Yamamoto,&nbsp;Kentaro Takeda,&nbsp;Hideki Maeda","doi":"10.1111/cts.70313","DOIUrl":"10.1111/cts.70313","url":null,"abstract":"<p>The first global approval of a microsatellite instability-high solid tumors was a landmark in oncology, paving the way for targeted therapies approved globally. However, guidance remains limited regarding the biological and methodological conditions under which such designs, statistical borrowing, are most effective. We retrospectively evaluated the feasibility of tumor-agnostic development using Bayesian modeling based on the objective response rate (ORR) as the primary endpoint, focusing on single-agent molecular targeted therapy (MTT) in Japan. Using Pharmaceuticals and Medical Devices Agency (PMDA) approval documents, we identified MTTs approved for ≥ 3 cancer types in Japan between 2001 and 2023. We analyzed whether their ORR in treatment lines without standard therapy exceeded thresholds using the beta-binomial model (BBM) and hierarchical Bayesian model (HBM). Among 97 approved MTTs, 57 were for solid tumors or sarcomas, and 14 for ≥ 3 indications. Poly (ADP-ribose) polymerase (PARP) inhibitors and human epidermal growth factor receptor 2 antibody-drug conjugate (HER2 ADC) consistently exceeded thresholds in both models. In contrast, mechanistic target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) inhibitors showed generally consistent results across both models, although some exceeded the threshold while others did not, indicating considerable variability. This study evaluates single-agent therapies using ORR as the primary endpoint; therefore, the findings may not apply to combination therapies or endpoints such as progression-free survival or overall survival. Nevertheless, integrating Bayesian models and biological understanding can clarify when statistical borrowing is appropriate, particularly in biologically similar tumor types and improve interpretability and the strategic feasibility of basket trials in tumor-agnostic development.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Bocidelpar, ASP0367, in Renal and Hepatic Impairment: Results From Two Phase 1 Studies","authors":"Megumi Iwai,&nbsp;Nakyo Heo,&nbsp;Kentaro Hashimoto,&nbsp;Sayuri Guro,&nbsp;Selina Moy,&nbsp;Anna Spence,&nbsp;Tomasz Wojtkowski,&nbsp;Lauren Benner,&nbsp;Melanie Helmick,&nbsp;Tong Zhu,&nbsp;Brian C. Ferslew","doi":"10.1111/cts.70310","DOIUrl":"10.1111/cts.70310","url":null,"abstract":"<p>Bocidelpar is a peroxisome proliferator-activated receptor δ modulator designed to address mitochondrial impairment. Two open-label, single-dose phase 1 studies (NCT05117294/NCT04942964) investigated the effect of severe renal or mild/moderate hepatic impairment on bocidelpar pharmacokinetics and safety. Adult participants received 75 mg bocidelpar and underwent serial blood and urine sampling over 4 days to evaluate the pharmacokinetics of bocidelpar. Thirteen participants were included in the renal cohort (severe impairment, <i>n</i> = 7; healthy participants, <i>n</i> = 6). A minimal increase was observed in the maximum concentration (C_max) of the severe impairment group versus healthy participants (geometric least squares mean [GeoLSM] ratio [90% CI], 139.66% [86.33, 225.92]). No clear changes were observed in the area under the curve (AUC). Twenty-five participants were included in the hepatic cohort (mild impairment, <i>n</i> = 8; moderate impairment, <i>n</i> = 8; healthy participants, <i>n</i> = 9). Compared with matched controls, increased C_max was observed in the mild (GeoLSM ratio [90% CI], 181.37% [95.47, 344.56]) and moderate (GeoLSM ratio [90% CI], 298.78% [145.00, 615.65]) impairment groups. Mild impairment did not substantially affect the AUC_inf versus matched controls (GeoLSM ratio [90% CI], 110.73% [82.16, 149.24]); however, it was higher in the moderate impairment group versus matched controls (GeoLSM ratio [90% CI], 195.58% [115.26, 331.88]). Across both studies, five treatment-emergent adverse events were observed in five participants; all were considered mild in severity. Overall, bocidelpar was well tolerated and had an acceptable safety profile. Severe renal impairment had a minimal effect on bocidelpar pharmacokinetics, while moderate hepatic impairment resulted in increased bocidelpar concentration and exposure compared with matched controls.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasound Renal Denervation Attenuates Early Cardiac Remodeling After Acute Myocardial Infarction in a Swine Model of Hypertensions and Dyslipidemia: A Pilot Study","authors":"Thomas E. Sharp III,&nbsp;Amy L. Scarborough,&nbsp;Amelia G. Haydel,&nbsp;J. Stephen Jenkins,&nbsp;Marloe Prince,&nbsp;Aashish Gupta,&nbsp;Florian Rader,&nbsp;Zhen Li,&nbsp;David J. Lefer,&nbsp;Traci T. Goodchild","doi":"10.1111/cts.70289","DOIUrl":"10.1111/cts.70289","url":null,"abstract":"<p>Acute myocardial infarction (AMI) patients typically present with a constellation of one or more risk factors including hypertension, dyslipidemia, obesity, or diabetes. Neurohormonal modulation has been a mainstay pharmacotherapy in patients; however, patient compliance is a major obstacle towards clinical efficacy due to side effects and lifelong drug regimens. FDA approval of ultrasound renal denervation (uRDN) for the treatment of resistant hypertension raises the possibility of uRDN therapy for additional disease states involving sympathetic overactivity. In the current pilot study, we sought to explore if prior uRDN has cardioprotective effects against AMI in a comorbid-laden minipig model. Göttingen minipigs (female) were subject to mineralocorticoid excess and a Western high-fat, high-salt diet to induce hypertension, obesity, and hyperlipidemia. Minipigs were randomized to bilateral uRDN (<i>n</i> = 5) treatment or sham-RDN (<i>n</i> = 5) after 4 weeks. After 6 weeks of hypertension and Western high-fat, high-salt diet, animals were subjected to a 75-min left anterior descending coronary artery occlusion followed by 2 weeks of reperfusion. Markers of renal nerve viability, ischemic injury, and cardiac structure and function were assessed. In the uRDN treatment group, there was reduced renal norepinephrine content, improved survival, and reduced myocardial infarct area and calcification compared to sham-RDN treatment. Preservation of the myocardial performance Tei index indicated preserved systolic and diastolic function 2 weeks post AMI. The beneficial effects of uRDN were independent of any reductions in blood pressure. Our pilot study provides new preliminary evidence regarding the efficacy of uRDN in a preclinical large animal model of AMI that features clinically relevant comorbidities.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Esketamine Combined With Remimazolam Tosylate on Hemodynamics During Cardiovascular Anesthesia","authors":"Lei Xi,&nbsp;Hui Liu,&nbsp;XiaoJuan Tang,&nbsp;ZhenZhen Jiang","doi":"10.1111/cts.70232","DOIUrl":"10.1111/cts.70232","url":null,"abstract":"<p>This study aimed to evaluate the effects of esketamine combined with remimazolam tosylate on hemodynamic stability, cerebral oxygen metabolism, and cognitive outcomes in patients undergoing heart valve replacement. Seventy-eight patients were randomized to Group C (dexmedetomidine hydrochloride) or Group R (esketamine + remimazolam tosylate). The following parameters were measured: multiple time points, including mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), arterial-jugular vein oxygen content difference (Da-jvO₂), cerebral oxygen uptake rate (CERO₂), and biomarkers of myocardial injury (cTnI, CK-MB, FABP) at baseline (T0), incision (T1), sternotomy (T2), pre-cardiopulmonary bypass (T3), and post-surgery (T4). Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Confusion Assessment Method (CAM). Group R showed prolonged values of lower RR in T1 to T4 than Group C (<i>p</i> &lt; 0.05). The Da-jvO₂ and CERO₂ were found to be much higher in Group R in T2, T3, and T4 (<i>p</i> &lt; 0.05). This is an indication of improved cerebral oxygen metabolism. MMSE scores were elevated in Group R: the incidence of delirium and CAM Scores were lower compared with Group C (<i>p</i> &lt; 0.05). This indicates better cognitive outcomes. Also, cTnI, CK-MB, and FABP, myocardial injury markers, were significantly reduced in Group R at postoperative 24 and 72 h (<i>p</i> &lt; 0.05), indicating reduced myocardial injury. The combination of esketamine and remimazolam tosylate offers hemodynamic stability, enhances cerebral oxygen metabolism, improves cognitive function, and reduces myocardial injury in patients undergoing heart valve replacement surgery. This approach might provide significant benefits in cardiovascular anesthesia.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Risk of Major Bleeding With Concomitant Use of Oral Anticoagulants and Corticosteroid Bursts","authors":"Tsung-Chieh Yao,&nbsp;Sheng-Mao Chang,&nbsp;Yi-Fen Tsai,&nbsp;Shuo-Ju Chiang,&nbsp;Hui-Ju Tsai","doi":"10.1111/cts.70311","DOIUrl":"10.1111/cts.70311","url":null,"abstract":"<p>The choice of oral anticoagulants and oral corticosteroid (OCS) burst cotherapy may influence the risk of major bleeding; however, this risk remains poorly characterized. We aimed to quantify the comparative safety of non–vitamin K oral anticoagulants (NOACs) versus warfarin on major bleeding while receiving OCS burst cotherapy among patients with atrial fibrillation. A nationwide population-based cohort study was conducted using the National Health Insurance Research Database. We examined associations between NOACs (edoxaban, apixaban, dabigartran, or rivaroxaban) or warfarin with OCS burst cotherapy and major bleeding. We measured the risk by estimating incidence, incidence risk ratios (IRRs), and adjusted hazard ratios (AHRs) after adjusting for baseline differences using overlap weighting. In this study, among 239,693 patients receiving oral anticoagulants, 50,390 (21%) received at least one OCS burst, defined as OCS use for less than 30 days, were included. A lower risk of major bleeding related to OCS burst cotherapy with NOACs versus warfarin was noted (AHR = 0.57 [95% CI = 0.52–0.61]). The greatest incidence was observed in patients with warfarin and OCS burst cotherapy (67.30 per 1000 person-years). The incidence for patients prescribing OCS burst cotherapy with edoxaban (30.36 per 1000 person-years; IRR = 0.45 [95% CI = 0.38–0.53]), apixaban (34.93 per 1000 person-years; IRR = 0.52 [95% CI = 0.45–0.60]), dabigatran (42.47 per 1000 person-years; IRR = 0.63 [95% CI = 0.56–0.72]), and rivaroxaban (46.99 per 1000 person-years; IRR = 0.70 [95% CI = 0.63–0.77]), separately, was lower than that with warfarin. The results reveal that the incidence of major bleeding was lowest for edoxaban and highest for warfarin, with notable differences in incidence rates across NOACs among patients receiving oral anticoagulants and OCS burst cotherapy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proof of Pharmacology, Safety, and Pharmacokinetics of the Novel TRPA1 Antagonist BI 1839100: A Randomized, Placebo-Controlled, Parallel Group, First-In-Human Study in Healthy Male Participants","authors":"Marella C. E. van Ruissen,&nbsp;Sebastiaan J. W. van Kraaij,&nbsp;Jana Wolfova,&nbsp;Franziska E. Herrmann,&nbsp;Yanick Botilde,&nbsp;Lutz Wollin,&nbsp;Naomi B. Klarenbeek","doi":"10.1111/cts.70290","DOIUrl":"10.1111/cts.70290","url":null,"abstract":"<p>BI 1839100 is a selective antagonist of transient receptor potential ankyrin 1 (TRPA1). Topically applied TRPA1-agonistic allyl isothiocyanate (AITC), inducing non-invasively measurable increased dermal blood flow (DBF), is known as a skin challenge model to assess TRPA1-target engagement and pharmacodynamic (PD) activity of TRPA1 inhibitors. This study aims to support the pharmacological rationale of BI 1839100 based on preclinical evidence and to test its safety, pharmacokinetic (PK) profile, and PD effects using an AITC skin challenge in a phase I first-in-human clinical study. In vitro and in vivo experiments were conducted in human TRPA1-overexpressing human embryonal kidney (HEK)293 cells and mice, respectively. Exposure to BI 1839100 and AITC demonstrated a BI 1839100 exposure-related reduction of AITC-induced Ca²⁺ increase in HEK293 cells and skin edema in mice. Healthy male participants, aged 18–45 years, were randomized within 10 cohorts in the single-ascending dose part (<i>n</i> = 80) and two cohorts in the PD part (<i>n</i> = 32). All received single doses of BI 1839100/placebo followed by safety and PK measurements. In the PD part, participants underwent an AITC skin challenge twice; at baseline and at time to peak drug concentration after BI 1839100/placebo administration. No significant imbalance in occurrence of adverse events was detected between single doses of BI 1839100 up to 300 mg and placebo, and PK profiles were dose-proportional in the 40–300 mg range. BI 1839100 demonstrated a dose-dependent inhibitory effect on DBF after the AITC skin challenge, indicating TRPA1-targeted pharmacological activity and potentiating BI 1839100 for further clinical development for a broad range of TRPA1 antagonistic applications.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multicenter Randomized Controlled Study on Pharmacokinetic-Guided Vancomycin Use in Children With Severe Infections","authors":"Fuxiang He,&nbsp;Ya Yang,&nbsp;Bo Zhou,&nbsp;Chengcheng Li,&nbsp;Yu Feng,&nbsp;Xuexin Wang,&nbsp;Haifeng Liu,&nbsp;Yuhang Hu,&nbsp;Hongmin Fu,&nbsp;Yingbo Zou,&nbsp;Guoying Zhang,&nbsp;Jianli Chen,&nbsp;Yueqiang Fu,&nbsp;Shufang Xiao,&nbsp;Lan Hu,&nbsp;Chengjun Liu","doi":"10.1111/cts.70309","DOIUrl":"10.1111/cts.70309","url":null,"abstract":"<p>This study is a multicenter, randomized controlled prospective trial aimed at evaluating the effects of two vancomycin pharmacokinetics/pharmacodynamics (PK/PD) parameters on clinical outcomes in children with different severe infections: trough concentration (<i>C</i>_min) and the area under the curve (AUC_0-24/MIC). From January 2023 to December 2024, 472 pediatric patients from seven hospitals in Southwest China were included in the present study. These patients were randomly assigned to the AUC_0-24/MIC group or the <i>C</i>_min group. After excluding 75 patients with renal function impairment caused by the primary disease, three patients with incomplete data, and one patient who received vancomycin for less than 48 h, 393 patients were finally enrolled for the present study. Then, the vancomycin treatment for children was evaluated using two PK/PD parameters, to guide clinical efficacy and monitor the incidence of adverse reactions: AUC_0-24/MIC, with a target value of 400–600 mg·h/L; trough concentration (<i>C</i>_min), with a target value of 5–15 mg/L. The results indicated that there were no significant differences between the two groups in terms of daily dose, clinical efficacy, and adverse reactions. However, patients in the <i>C</i>_min group had significantly shorter pediatric intensive care unit (PICU) stays (<i>Z</i> = −2.05, <i>p</i> = 0.04), and patients in the 28-day to 1-year-old subgroup had shorter mechanical ventilation times (<i>Z</i> = −2.25, <i>p</i> = 0.024). Both <i>C</i>_min and AUC_0-24/MIC were effective in guiding the vancomycin treatment for children with severe infections. However, patients in the <i>C</i>_min group presented with advantages in PICU stay and ventilation duration.</p><p><b>Trial Registration:</b> China Clinical Trial Registry: ChiCTR2300067373</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}