Drug Design, Development and Therapy最新文献

{"title":"Prediction of High-Dose Methotrexate Blood Concentration in Osteosarcoma Patients Using Machine Learning.","authors":"Jin Zhao, Shuqi Dai, Jiali He, Na Liu, Baowanze Zhang, Su Li","doi":"10.2147/DDDT.S515535","DOIUrl":"https://doi.org/10.2147/DDDT.S515535","url":null,"abstract":"<p><strong>Introduction: </strong>High-dose methotrexate is a typical chemotherapy that is widely used in the treatment of osteosarcoma. However, the unique dose-response relationship of methotrexate makes its treatment window relatively narrow, and its clinical use is in a dilemma: either the drug concentration in the patient's body cannot reach the effective concentration level, or adverse reactions may occur due to drug overdose. For this circumstance, monitoring and predicting the drug concentration in the patient's body is well founded and necessary. While pharmacokinetic models exist, they often oversimplify patient-specific covariates. This study addresses the unmet need for early-exposure prediction through interpretable machine learning, enabling data-driven decisions before toxicity manifestation.</p><p><strong>Methods: </strong>In this article, 68 osteosarcoma patients' information including demography, administration and assay was gathered. We analyzed medical data and selected 10 important features using a random forest, including hydration status, red blood cell distribution width coefficient of variation, platelet distribution width, creatinine, γ-glutamyl transferase, large platelet ratio, serum potassium, lactate dehydrogenase, weight, and prealbumin. Then, cross-validation and SHAP has been conducted to confirm the robust and interpretation of the model.</p><p><strong>Results: </strong>On this basis, 7 machine learning regression models was built to predict the blood concentration of methotrexate. R², MSE, RMSE, MAE are the evaluation metrics. Finally, LightGBM was selected as the best prediction model with a performance of R²=0.87, MSE=0.020, RMSE=0.141, MAE=0.065.</p><p><strong>Discussion: </strong>This machine learning framework addresses a critical gap in high-dose methotrexate therapeutic monitoring by achieving early and personalized blood drug concentration prediction, allowing for personalized dosing of patients based on predicted concentrations. The interpretability of SHAP-derived feature importance enhances clinical utility, offering a paradigm shift from reactive toxicity management to proactive precision dosing in osteosarcoma therapy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3631-3643"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986570","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":"Hyodeoxycholic Acid Ameliorates Metabolic Syndrome Through Pathways of Primary Bile Acid Synthesis and Fatty Acid Degradation: Insights From a Rat Model.","authors":"Meimei Chen, Kaiyue Huang, Wenqian Luo, Fei Zhang, Huijuan Gan, Zhaoyang Yang","doi":"10.2147/DDDT.S514189","DOIUrl":"https://doi.org/10.2147/DDDT.S514189","url":null,"abstract":"<p><strong>Background: </strong>Bile acids (BAs) play a crucial role in metabolic regulation, but their specific functions in metabolic syndrome (MS) remain unclear. Hyodeoxycholic acid (HDCA) has shown potential effects in non-alcoholic fatty liver disease (NAFLD), yet its role in MS is unexplored.</p><p><strong>Aim: </strong>This study aims to assess whether HDCA is a characteristic BA of MS and to investigate its intervention effects and potential mechanisms.</p><p><strong>Methods: </strong>We employed 16S rDNA sequencing and UHPLC-MS/MS to investigate the dynamics of the gut microbiota and BA profiles in rats and conducted a correlation study between indices, identifying HDCA as the potential characteristic BA. We then examined its interventional effects in MS rats comparing efficacy with the positive drug of MS (metformin). Subsequently, liver RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), and Wes Automated Simple Western assays were employed to investigate mechanisms of HDCA ameliorating MS.</p><p><strong>Results: </strong> HDCA was identified as a characteristic BA for MS, exhibiting a significant positive correlation with beneficial gut bacteria and a negative correlation with harmful bacteria, and highly inversely related to various abnormal MS indexes. HDCA treatment led to significant improvements in metabolic abnormalities in MS rats, with a central role in altering serum BA profiles and profoundly modifying the gut microbiome composition. The results of RNA-seq and GSEA indicated that HDCA influenced the expression of genes related to primary bile acid synthesis and fatty acid degradation (p<0.05). Wes assays validated that FXR, CYP7A1, CYP7B1, PPARα, CPT1, CPT2, FABP1, HMGCS1 and HMGCS2 proteins in MS rats exhibited significant changes after HDCA treatment (<i>p</i><0.05), and this was more effective than metformin treatment.</p><p><strong>Conclusion: </strong>These study is the first to highlight HDCA as a therapeutic candidate for MS and provides new insights into the BA-MS axis, though further validation is needed.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3611-3630"},"PeriodicalIF":4.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967145","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 Median Effective Dose of Ciprofol Combined with Sufentanil for Inhibiting Responses to Gastroscope Insertion in Obese Patients: A Prospective, Single-Center Study.","authors":"Zhouya Xue, Xiang Liu, Weisheng Qian, Nan Yang, Yongyi Pan, Yong Zhou, Wei Jiang, Feng Li, Bin Qian","doi":"10.2147/DDDT.S494972","DOIUrl":"https://doi.org/10.2147/DDDT.S494972","url":null,"abstract":"<p><strong>Background: </strong>Ciprofol, a recently developed intravenous anesthetic, whereas sufentanil is a widely used adjuvant for gastroenteroscopy sedation. The recommended dosage of ciprofol for obese patients remains unclear. Our study aimed to determine the median effective dose (ED₅₀) of ciprofol in combination with sufentanil for obese patients undergoing gastroscopy sedation.</p><p><strong>Methods: </strong>A total of 70 patients undergoing painless gastroscopy from July 2024 to September 2024 were recruited. Patients were assigned to the obese group (body mass index [BMI]≥28 kg/m², n=34) and non-obese group (18.5 kg/m² ≤BMI<24 kg/m², n=36). All patients received 0.1 μg/kg of sufentanil, and the ciprofol dose was determined by the modified Dixon sequential method with an initial dose of 0.4 mg/kg and a dose gradient of 0.01 mg/kg. The dose of ciprofol administered to the subsequent patient was determined by the response of the preceding patient. The response referred to the patient's cough, swallowing, and body movement during gastroscope insertion. The primary outcome was the ED₅₀ of ciprofol in each group, while the secondary outcomes comprised the incidences of hypoxemia, hypotension, bradycardia, postoperative nausea and vomiting (PONV), and hemodynamic parameters.</p><p><strong>Results: </strong>The ED₅₀ of ciprofol was 0.278 mg/kg (95% confidence interval [CI]: 0.226-0.297 mg/kg) in the obese group and 0.347 mg/kg (95% CI: 0.329-0.360 mg/kg) in the non-obese group for gastroscopy sedation. The ED₅₀ of ciprofol in the obese group was significantly lower than that in the non-obese group (<i>P</i><0.05). The incidence of hypoxemia in the obese group was significantly higher than that in the non-obese group (<i>P</i><0.05).</p><p><strong>Conclusion: </strong>Obesity affected the ED₅₀ of ciprofol, suggesting that the ciprofol dosage should be adjusted in obese patients.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3577-3587"},"PeriodicalIF":4.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997110","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":"Optimized Sampling Strategies for Isoniazid in East Asian Pediatric Populations Using Population Pharmacokinetics-Informed Approaches.","authors":"Gehang Ju, Xin Liu, Yeheng Peng, Wenyu Yang, Nuo Xu, Qingfeng He, Chenchen Zhang, Lulu Chen, Nan Yang, Gufen Zhang, Chao Li, Pan Su, Xiao Zhu, Dongsheng Ouyang","doi":"10.2147/DDDT.S503987","DOIUrl":"10.2147/DDDT.S503987","url":null,"abstract":"<p><strong>Objective: </strong>Isoniazid exposure in vivo is significantly affected by NAT2 genotypes and has ethnic differences. To optimize the sampling strategy for isoniazid in East Asian pediatric populations. We employed a model-informed optimization approach based on INH population pharmacokinetic (PopPK) models.</p><p><strong>Methods: </strong>We selected PopPK models for children and East Asian adults and optimized the sampling strategy using PopED (Population Experimental Design), a method that helps identify the most efficient sampling points for maximizing parameter estimation accuracy. Virtual patients with varying NAT2 phenotypes were created, and real-world pediatric scenarios were evaluated using questionnaire data, sampling windows, and stochastic simulations.</p><p><strong>Results: </strong>From eight analyzed models (four for East Asian adults and four for non-East Asian pediatrics), we simplified two over-parameterized models using lumping without loss of performance. The optimized clinical sampling strategy involved collecting samples at 0.25 [0-0.5], 1.5 [1-2], 6 [3-8], 12 [9-14], and 24 [22-24] hours post-dose. Simulation verification showed that re-estimated major PK parameters had acceptable relative biases and relative standard error (<30%).</p><p><strong>Conclusion: </strong>Traditional adult sampling strategies are inadequate for East Asian pediatric populations. A tailored strategy involving up to five samples can accurately estimate INH PopPK parameters and should be considered for clinical implementation to optimize treatment and reduce patient sampling burden.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3555-3576"},"PeriodicalIF":4.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981565","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":"Procyanidin Improves Erectile Function in Rats by Inhibiting PDE5A Activity.","authors":"Yudong Su, Jinman Shui, Danshi Qi, Jie Bai, Xiaoxia Xu, Yongchun Huang, Ruilian Li, Qiong Wu, Haiyan Wang, Chengzhu Cao, Zhanhai Su, Shoude Zhang","doi":"10.2147/DDDT.S514209","DOIUrl":"https://doi.org/10.2147/DDDT.S514209","url":null,"abstract":"<p><strong>Purpose: </strong>Erectile dysfunction (ED), a prevalent form of male sexual dysfunction, is predominantly treated with Phosphodiesterase type 5 inhibitors (PDE5Is). Our previous research highlighted procyanidin, a natural compound, as a notably effective PDE5I. In the current study, we intend to further validate the inhibitory activity of procyanidin on PDE5A through in vitro and in vivo assessments. This study aims to validate the efficacy of procyanidin as a treatment for ED.</p><p><strong>Methods: </strong>The binding affinity of procyanidin for PDE5A was assessed by molecular docking, molecular dynamics (MD) simulations, and microscale thermophoresis (MST) assay. The toxicity of procyanidin on penile corpus cavernosum smooth muscle (CCSM) cells (n=5) was evaluated. Additionally, its effects on intracellular cyclic guanosine monophosphate (cGMP) levels in CCSM cells (n=5) were evaluated. The absorption of procyanidin was evaluated by measuring plasma levels at various times after oral gavage to Sprague-Dawley (SD) rats (n=6). Subsequently, the effects of procyanidin on intracavernous pressure (ICP) and cGMP levels in penile cavernous tissue were evaluated in SD rats (n=6).</p><p><strong>Results: </strong>Procyanidin forms three hydrogen bonds with PDE5A and stabilizes the complex structure, exhibiting equilibrium dissociation constants (K_D) value of 7.77 ± 2.39 µmol/L. Additionally, procyanidin exhibits minimal cytotoxicity toward CCSM cells and significantly elevates intracellular cGMP levels compared to the control group. In vivo studies demonstrate that procyanidin is rapidly absorbed, achieving peak blood concentrations within one hour. Simultaneously, procyanidin significantly increases ICP and cGMP levels in rats compared to the control group.</p><p><strong>Conclusion: </strong>These findings indicate that procyanidin sustains elevated cGMP levels within cells by targeting PDE5A, thereby exhibiting therapeutic efficacy in improving ICP. Procyanidin emerges as a promising PDE5I for treating ED and potentially other related conditions.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3351-3361"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988194","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":"Lean Six Sigma as a Management Tool Helps Standardize Antimicrobial Use in Hospital Settings.","authors":"Qian Wang, Xinru Han, Xiang Zhang, Lubo Guo","doi":"10.2147/DDDT.S510926","DOIUrl":"https://doi.org/10.2147/DDDT.S510926","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to standardize antimicrobial use in a hospital setting by implementing the Lean Six Sigma (LSS)-DMAIC model (Define, Measure, Analyze, Improve, Control), addressing the irrational use of antibacterial drugs.</p><p><strong>Methods: </strong>A retrospective analysis was conducted using data from a single hospital's information system in Shandong, China, covering antibacterial drug usage from January 2020 to December 2021. The LSS-DMAIC framework was applied, which involved defining problems, measuring key indicators, analyzing causes of irrational use, implementing improvement measures, and controlling outcomes. The project team comprised clinical pharmacists and healthcare professionals who evaluated antibiotic use and compliance with guidelines.</p><p><strong>Results: </strong>In the whole hospital, the management through LSS-DMAIC led to a significant reduction in the non-standard utilization rate of antibacterial drugs from 32.5% to 11.3% (P < 0.0001), achieving the set target. The intensity of antibacterial drug use decreased to 38.82 Defined Daily Doses (DDDs), meeting national standards. Additionally, the utilization rate of antibacterial drugs has dropped from 43.61% to 40.16% (P < 0.0001), and the average cost of antibacterial drugs per inpatient significantly dropped from 1909.59 RMB (known as Renminbi, which is the legal currency of China) to 1675.20 RMB (P < 0.0001), resulting in substantial annual savings.</p><p><strong>Conclusion: </strong>The application of the LSS-DMAIC model effectively improved the rational use of antibacterial drugs in the hospital, demonstrating its potential as a valuable management tool in healthcare settings. Continued efforts are necessary to sustain these improvements and further enhance clinician adherence to antimicrobial stewardship practices.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3539-3554"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972717","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":"Bibliometric Analysis of Non-Vitamin K Antagonist Oral Anticoagulants (NOACS) in the Prevention of Venous Thrombosis and Pulmonary Embolism.","authors":"Fangyi Zhou, Zicheng Pang, Zhuoming Chen, Kai Hu, Jian Luo, Sihui Huang, Qiang Qu","doi":"10.2147/DDDT.S505751","DOIUrl":"https://doi.org/10.2147/DDDT.S505751","url":null,"abstract":"<p><strong>Introduction: </strong>Venous thromboembolism (VTE) is a leading cause of cardiovascular-related deaths. Non-vitamin K antagonist oral anticoagulants (NOACs) offer effective therapy without injections or blood monitoring. This bibliometric analysis explores the research on NOACs for preventing VTE and pulmonary embolism.</p><p><strong>Methods: </strong>Literature up to July 20, 2024, was searched in Web of Science Core Collection. Citespace software was used for screening and analysis.</p><p><strong>Results: </strong>In this study, we analyzed 2124 articles and 767 reviews from 11,282 institutions across 528 countries and regions, encompassing 830 publications and 60 research directions. The USA led in publication count, followed by Germany and Canada. Cardiovascular System Cardiology, Hematology, and General Internal Medicine were the top research areas, while THROMBOSIS AND HAEMOSTASIS was the leading journal. From 2004 to 2024, we observed accelerated publication growth, particularly from 2008, highlighting the emergence of NOACs as a major research focus. Key contributors, including Bengt I. Eriksson, and major institutions like Harvard Medical School and University of Amsterdam, played pivotal roles in advancing anticoagulant research. Co-citation and keyword clustering analyses revealed research hotspots in NOACs, cancer-associated venous thromboembolism, stroke prevention, and COVID-19-related thrombotic events, reflecting a shift towards individualized anticoagulation therapy and the growing importance of NOACs in various clinical contexts.</p><p><strong>Conclusion: </strong>The development of NOACs has progressed rapidly, with an increasing number of publications, indicating the lead research in the United States and other Western nations. Comparative studies on the safety and efficacy of NOACs have become a significant focus, shifting from traditional anticoagulants. Pharmacogenetics-guided use of NOACS shows new hope of precision medicine.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3589-3610"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977635","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 Comprehensive Review on the Pharmacokinetics and Drug-Drug Interactions of Approved GLP-1 Receptor Agonists and a Dual GLP-1/GIP Receptor Agonist.","authors":"Jee Sun Min, Seong Jun Jo, Sangyoung Lee, Duk Yeon Kim, Da Hyun Kim, Chae Bin Lee, Soo Kyung Bae","doi":"10.2147/DDDT.S506957","DOIUrl":"https://doi.org/10.2147/DDDT.S506957","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3509-3537"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956866","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":"Preclinical Investigations of a Novel PEGylated Long-Acting Human Growth Hormone.","authors":"Jun Wang, He Wang, Rong Wang, Yu Zhuang, Chenyang Jiang, Baixue Zhao, Zhen Xu, Bruce Yong Ma","doi":"10.2147/DDDT.S517485","DOIUrl":"https://doi.org/10.2147/DDDT.S517485","url":null,"abstract":"<p><strong>Purpose: </strong>The daily administration of recombinant human growth hormone (rhGH) replacement therapies via subcutaneous (SC) injections can be burdensome for patients. Long-acting Growth hormone (GH) formulation could reduce injection frequency, and it will be expected to increase treatment adherence. ZHB111 is a PEGylated rhGH that requires sc injection every two weeks. This study aims to examine the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of multiple sc doses of ZHB111.</p><p><strong>Design and methods: </strong>In the PK study, naïve cynomolgus monkeys were divided into four groups with 3/sex/group. Each group received single subcutaneous administration at 0 (control article, Sodium chloride injection), 0.3, 1.0 and 3.0 mg/kg, respectively. To access safety and PD profile, cynomolgus monkeys were randomly assigned to 4 groups of 5/sex/group, and were dosed with ZHB111 once weekly for 4 times by subcutaneous injection at 0 (control article, Sodium chloride injection), 1, 5 or 20.6 mg/kg/dose. Tissue distribution was accessed by administering a single subcutaneous dose of ZHB111 to Sprague-Dawley Rats.</p><p><strong>Results: </strong>ZHB111 exhibits a significant difference in serum half-life (in monkeys) across varying dosages, with a trend of decreasing half-life as the dosage increases, ranging from 110-30 h. No significant differences were observed between different genders at the same dosage level. After subcutaneous administration of 0.3mg/kg of ZHB111, the mean values of IGF-1 in male animals ranged among 594.93~1294.98ng/mL at various time points, while those in female animals were within the range of 394.15~770.01ng/mL.</p><p><strong>Conclusion: </strong>The tolerability of ZHB111 was demonstrated in both rat and monkey models, with only minimal adverse effects observed. These findings support the continued clinical development of ZHB111 as a novel treatment for growth hormone deficiency (GHD) in both children and adult patients.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3497-3507"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962522","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":"Decoding TMAO in the Gut-Organ Axis: From Biomarkers and Cell Death Mechanisms to Therapeutic Horizons.","authors":"Jie Liu, Peng Ge, Yalan Luo, Zhenxuan Sun, Xinyu Luo, Huijuan Li, Boliang Pei, Lu Xun, Xuetao Zhang, Yunfei Jiang, Haiyun Wen, Jin Liu, Qi Yang, Shurong Ma, Hailong Chen","doi":"10.2147/DDDT.S512207","DOIUrl":"https://doi.org/10.2147/DDDT.S512207","url":null,"abstract":"<p><p>The gut microbiota and its metabolites are bi-directionally associated with various human illnesses, which has received extensive attention. Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite produced in the liver, which may serve the role of an \"axis\" connecting the gut and host organs. TMAO levels are significantly higher in the blood of individuals with cardiovascular, renal, neurological, and metabolic diseases. Endothelial cells are crucial for regulating microcirculation and maintaining tissue and organ barriers and are widely recognized as target cells for TMAO. TMAO not only induces endothelial dysfunction but also acts on various cell types, such as endothelial cells, epithelial cells, vascular smooth muscle cells, nerve cells, and pancreatic cells, triggering multiple cell death mechanisms, including necrosis and programmed cell death, thereby influencing host health. This paper thoroughly covers the origins, production, and metabolic pathways of TMAO, emphasizing its importance in the early detection and prognosis of human diseases in the \"Gut-Organ\" axis, as well as its mechanisms of influence on human diseases, particularly the cross-talk with cell death. Furthermore, we cover recent advances in treating human diseases by regulating gut microbiota structure and enzyme activity to influence TMAO metabolism and reduce TMAO levels, including the use of probiotics, prebiotics, antibiotics, anti-inflammatory drugs, antiplatelet drugs, hypoglycemic drugs, lipid-lowering drugs, and natural products.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3363-3393"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989886","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}