Pub Date : 2025-02-15eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S492691
Zilong Zhang, Xiaolin Yu, Jie Li, Xin Shen, Wenbo Fu, Yongguo Liu, Xiangyu Dong, Zhao Wang
Purpose: Doxorubicin (DOX), an anthracycline antibiotic, has limited clinical use due to its pronounced cardiotoxicity. Irisin, a myokine known for its metabolic regulation, has shown therapeutic effects on cardiovascular disease. This study investigates the potential cardioprotective function of irisin in reducing the cardiac injury induced by DOX.
Methods: In vitro, H9c2 cells were pretreated with irisin (20 nM) for 24 hours before exposure to DOX (1 μM). In vivo, C57BL/6 mice were administered DOX (5 mg/kg/week, i.p.) for 4 weeks, reaching a cumulative dose of 20 mg/kg. Irisin (1 mg/kg/ 3 days, i.p.) was administered to the mice both 7 days prior to and during DOX injection.Cardiac function was evaluated by echocardiography, and cardiac histology was assessed using HE, WGA, and Masson staining. Myocardial injury markers were quantified using ELISA, and apoptosis was analyzed via TUNEL staining. Oxidative stress was determined by measuring antioxidase activity, MDA and GSH levels, and DHE staining, while mitochondrial superoxide production was assessed using MitoSOX Red. Mitochondrial morphology and function evaluated using transmission electron microscopy and Seahorse analysis, respectively Inflammatory cytokines were quantified in serum and cell supernatants. The role of the PERK-eIF2α-ATF4 pathway mediated by irisin was investigated by Western blot. Using adeno-associated virus serotype-9 carrying mouse FNDC5 shRNA (AAV9-shFNDC5) further validated the protective role of irisin in DOX-induced myocardial injury.
Results: Irisin reduced DOX-induced cardiac dysfunction and fibrosis. Moreover, irisin mitigated oxidative stress and inflammation through inhibiting the PERK-eIF2α-ATF4 pathway activated by DOX, thus preserving mitochondrial function. While cardiac FNDC5 knockdown exacerbated DOX-induced heart injury and PERK-eIF2α-ATF4 activation, which was partially reversed by irisin.
Conclusion: Irisin mitigates oxidative stress and inflammation by modulating the PERK-eIF2α-ATF4 pathway, highlighting its potential as a prospective approach for combating DOX-induced cardiotoxicity.
{"title":"Irisin Mitigates Doxorubicin-Induced Cardiotoxicity by Reducing Oxidative Stress and Inflammation via Modulation of the PERK-eIF2α-ATF4 Pathway.","authors":"Zilong Zhang, Xiaolin Yu, Jie Li, Xin Shen, Wenbo Fu, Yongguo Liu, Xiangyu Dong, Zhao Wang","doi":"10.2147/DDDT.S492691","DOIUrl":"10.2147/DDDT.S492691","url":null,"abstract":"<p><strong>Purpose: </strong>Doxorubicin (DOX), an anthracycline antibiotic, has limited clinical use due to its pronounced cardiotoxicity. Irisin, a myokine known for its metabolic regulation, has shown therapeutic effects on cardiovascular disease. This study investigates the potential cardioprotective function of irisin in reducing the cardiac injury induced by DOX.</p><p><strong>Methods: </strong>In vitro, H9c2 cells were pretreated with irisin (20 nM) for 24 hours before exposure to DOX (1 μM). In vivo, C57BL/6 mice were administered DOX (5 mg/kg/week, i.p.) for 4 weeks, reaching a cumulative dose of 20 mg/kg. Irisin (1 mg/kg/ 3 days, i.p.) was administered to the mice both 7 days prior to and during DOX injection.Cardiac function was evaluated by echocardiography, and cardiac histology was assessed using HE, WGA, and Masson staining. Myocardial injury markers were quantified using ELISA, and apoptosis was analyzed via TUNEL staining. Oxidative stress was determined by measuring antioxidase activity, MDA and GSH levels, and DHE staining, while mitochondrial superoxide production was assessed using MitoSOX Red. Mitochondrial morphology and function evaluated using transmission electron microscopy and Seahorse analysis, respectively Inflammatory cytokines were quantified in serum and cell supernatants. The role of the PERK-eIF2α-ATF4 pathway mediated by irisin was investigated by Western blot. Using adeno-associated virus serotype-9 carrying mouse FNDC5 shRNA (AAV9-shFNDC5) further validated the protective role of irisin in DOX-induced myocardial injury.</p><p><strong>Results: </strong>Irisin reduced DOX-induced cardiac dysfunction and fibrosis. Moreover, irisin mitigated oxidative stress and inflammation through inhibiting the PERK-eIF2α-ATF4 pathway activated by DOX, thus preserving mitochondrial function. While cardiac FNDC5 knockdown exacerbated DOX-induced heart injury and PERK-eIF2α-ATF4 activation, which was partially reversed by irisin.</p><p><strong>Conclusion: </strong>Irisin mitigates oxidative stress and inflammation by modulating the PERK-eIF2α-ATF4 pathway, highlighting its potential as a prospective approach for combating DOX-induced cardiotoxicity.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1067-1081"},"PeriodicalIF":4.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456660","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}
Pub Date : 2025-02-15eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S497126
Dan Hou, Haobin Zhou, Yuting Tang, Ziyuan Liu, Lin Su, Junkai Guo, Janak Lal Pathak, Lihong Wu
Purpose: Cancer stands as a significant global public health concern, with traditional therapies potentially yielding severe side effects. Peptide-based cancer therapy is increasingly employed for diseases like cancer due to its advantages of excellent targeting, biocompatibility, and convenient synthesis. With advancements in computer technology and bioinformatics, rational design strategies based on computer technology have been employed to develop more cost-effective and potent anticancer peptides (ACPs). This study aims to explore the current status, hotspots, and future trends in the field of computer-aided design of peptides for cancer treatment through a bibliometric analysis.
Methods: A total of 1547 relevant publications published from 2006 to 2024 were collected from the Web of Science Core Collection. Bibliometric analysis was conducted using tools like CiteSpace, VOSviewer, Bibliometrix, Origin, and an online bibliometric platform.
Results: The research in this field has shown a steady growth trend, with the United States and China making the most significant contributions. Currently, ACP research mainly focuses on cell-penetrating peptides related to drug delivery, which are expected to become future research hotspots. Beyond that, peptide vaccines associated with immunotherapy are also worthy of attention. In addition, molecular dynamics simulation and molecular docking are currently popular research methods. At the same time, deep learning is the emerging keyword, indicating its potential for a more significant impact on future peptide design.
Conclusion: Deep learning technology represents emerging research hotspots with immense potential and promising prospects. As cutting-edge research directions, cellularly penetrating peptides and polypeptide immunotherapy are expected to achieve breakthroughs in cancer treatment. This study provides valuable insights into the computer-aided design of peptides in cancer therapy, contributing significantly to advancing the in-depth research and applications in this area.
{"title":"Dynamic Visualization of Computer-Aided Peptide Design for Cancer Therapeutics.","authors":"Dan Hou, Haobin Zhou, Yuting Tang, Ziyuan Liu, Lin Su, Junkai Guo, Janak Lal Pathak, Lihong Wu","doi":"10.2147/DDDT.S497126","DOIUrl":"10.2147/DDDT.S497126","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer stands as a significant global public health concern, with traditional therapies potentially yielding severe side effects. Peptide-based cancer therapy is increasingly employed for diseases like cancer due to its advantages of excellent targeting, biocompatibility, and convenient synthesis. With advancements in computer technology and bioinformatics, rational design strategies based on computer technology have been employed to develop more cost-effective and potent anticancer peptides (ACPs). This study aims to explore the current status, hotspots, and future trends in the field of computer-aided design of peptides for cancer treatment through a bibliometric analysis.</p><p><strong>Methods: </strong>A total of 1547 relevant publications published from 2006 to 2024 were collected from the Web of Science Core Collection. Bibliometric analysis was conducted using tools like CiteSpace, VOSviewer, Bibliometrix, Origin, and an online bibliometric platform.</p><p><strong>Results: </strong>The research in this field has shown a steady growth trend, with the United States and China making the most significant contributions. Currently, ACP research mainly focuses on cell-penetrating peptides related to drug delivery, which are expected to become future research hotspots. Beyond that, peptide vaccines associated with immunotherapy are also worthy of attention. In addition, molecular dynamics simulation and molecular docking are currently popular research methods. At the same time, deep learning is the emerging keyword, indicating its potential for a more significant impact on future peptide design.</p><p><strong>Conclusion: </strong>Deep learning technology represents emerging research hotspots with immense potential and promising prospects. As cutting-edge research directions, cellularly penetrating peptides and polypeptide immunotherapy are expected to achieve breakthroughs in cancer treatment. This study provides valuable insights into the computer-aided design of peptides in cancer therapy, contributing significantly to advancing the in-depth research and applications in this area.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1043-1065"},"PeriodicalIF":4.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457283","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}
Pub Date : 2025-02-14eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S507402
Hui-Yan Ding, Han Zhou, Yi Jiang, Si-Si Chen, Xiao-Xia Wu, Yang Li, Jun Luo, Peng-Fei Zhang, Yi-Nan Ding
Cancer remains a leading cause of mortality worldwide, accounting for approximately 10 million deaths annually. Standard treatments, including surgery, radiotherapy, and chemotherapy, often result in damage to healthy cells and severe toxic side effects. In recent years, antisense technology therapeutics, which interfere with RNA translation through complementary base pairing, have emerged as promising approaches for cancer treatment. Despite the availability of various antisense oligonucleotide (ASO) drugs on the market, challenges such as poor active targeting and susceptibility to clearance by circulating enzymes remain. Compared with other delivery systems, lipid nanovesicle (LNV) delivery systems offer a potential solution that uniquely enhances ASO targeting and stability. Studies have shown that LNVs can increase the accumulation of ASOs in tumor sites several-fold, significantly reducing systemic toxic reactions and demonstrating increased therapeutic efficiency in preclinical models. Additionally, LNVs can protect ASOs from enzymatic degradation within the body, extending their half-life and thus enhancing their therapeutic effects. This paper provides a comprehensive review of recent examples and applications of LNV delivery of ASOs in cancer treatment, highlighting their unique functions and outcomes. Furthermore, this paper discusses the key challenges and potential impacts of this innovative approach to cancer therapy.
{"title":"Lipid Nanovesicles in Cancer Treatment: Improving Targeting and Stability of Antisense Oligonucleotides.","authors":"Hui-Yan Ding, Han Zhou, Yi Jiang, Si-Si Chen, Xiao-Xia Wu, Yang Li, Jun Luo, Peng-Fei Zhang, Yi-Nan Ding","doi":"10.2147/DDDT.S507402","DOIUrl":"10.2147/DDDT.S507402","url":null,"abstract":"<p><p>Cancer remains a leading cause of mortality worldwide, accounting for approximately 10 million deaths annually. Standard treatments, including surgery, radiotherapy, and chemotherapy, often result in damage to healthy cells and severe toxic side effects. In recent years, antisense technology therapeutics, which interfere with RNA translation through complementary base pairing, have emerged as promising approaches for cancer treatment. Despite the availability of various antisense oligonucleotide (ASO) drugs on the market, challenges such as poor active targeting and susceptibility to clearance by circulating enzymes remain. Compared with other delivery systems, lipid nanovesicle (LNV) delivery systems offer a potential solution that uniquely enhances ASO targeting and stability. Studies have shown that LNVs can increase the accumulation of ASOs in tumor sites several-fold, significantly reducing systemic toxic reactions and demonstrating increased therapeutic efficiency in preclinical models. Additionally, LNVs can protect ASOs from enzymatic degradation within the body, extending their half-life and thus enhancing their therapeutic effects. This paper provides a comprehensive review of recent examples and applications of LNV delivery of ASOs in cancer treatment, highlighting their unique functions and outcomes. Furthermore, this paper discusses the key challenges and potential impacts of this innovative approach to cancer therapy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1001-1023"},"PeriodicalIF":4.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448515","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}
Background: Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.
Methods: The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.
Results: The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.
Conclusion: We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine's treatment of PND.
{"title":"Identification of Key Genes in Esketamine's Therapeutic Effects on Perioperative Neurocognitive Disorders via Transcriptome Sequencing.","authors":"Wen Hu, Jieqiong Luo, Hui Li, Yushan Luo, Xiaoyuan Zhang, Zhen Wu, Qian Yang, Sirun Zhao, Bailong Hu, Xiaohua Zou","doi":"10.2147/DDDT.S510752","DOIUrl":"10.2147/DDDT.S510752","url":null,"abstract":"<p><strong>Background: </strong>Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.</p><p><strong>Methods: </strong>The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.</p><p><strong>Results: </strong>The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.</p><p><strong>Conclusion: </strong>We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine's treatment of PND.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"981-1000"},"PeriodicalIF":4.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456659","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}
Pub Date : 2025-02-14eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S506537
Yuzi Jin, Joshua S Fleishman, Yudong Ma, Xiaoqing Jing, Qin Guo, Weiguang Shang, Hongquan Wang
Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.
{"title":"NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury.","authors":"Yuzi Jin, Joshua S Fleishman, Yudong Ma, Xiaoqing Jing, Qin Guo, Weiguang Shang, Hongquan Wang","doi":"10.2147/DDDT.S506537","DOIUrl":"10.2147/DDDT.S506537","url":null,"abstract":"<p><p>Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1025-1041"},"PeriodicalIF":4.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448517","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}
Pub Date : 2025-02-12eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S500189
Yuyan Nie, Xingfeng Sun, Rong Cao, Songjiang Tang, Qun Zhou, Min Zhou, Zuolei Chen, Shaoqiang Huang
Purpose: The effects of sufentanil-ropivacaine combination on the parturient women and the course of labor have been well documented. However, there is little information regarding the time-dependent pharmacokinetic characteristics of sufentanil after epidural administration in laboring women. We aimed to develop a population PK model for epidural sufentanil in laboring women to evaluate the sufentanil placental transfer quantitatively.
Patients and methods: Forty-one participants who underwent epidural labor analgesia were recruited into this study. Patients received a continuous epidural infusion of sufentanil 0.3 µg/mL with ropivacaine 0.1%. Maternal venous blood samples and umbilical venous blood samples were collected for population PK analysis. The trends of sufentanil blood concentrations in the mothers and umbilical cord were predicted by the model.
Results: Sufentanil disposition after continuous epidural administration in laboring women followed a two-compartment pharmacokinetic model. The estimated sufentanil central clearance (CL), central volume of distribution (V1), clearance between central compartment and umbilical cord compartment (CL2), and umbilical cord volume of distribution (V2) were 176 L/h, 519 L, 0.0134 L/h, and 0.187 L. The absolute level of sufentanil in placental circulation is low after epidural administration. A slow decline in placental sufentanil concentration was predicted by the final PK model after epidural infusion was discontinued.
Conclusion: A slow decline in placental sufentanil concentration is predicted by the final two-compartment PK model after epidural infusion was discontinued. This suggests that very large doses of epidural sufentanil should be avoided during labor analgesia.
{"title":"Population Pharmacokinetic of Epidural Sufentanil in Labouring Women: A Multicentric, Prospective, Observational Study.","authors":"Yuyan Nie, Xingfeng Sun, Rong Cao, Songjiang Tang, Qun Zhou, Min Zhou, Zuolei Chen, Shaoqiang Huang","doi":"10.2147/DDDT.S500189","DOIUrl":"10.2147/DDDT.S500189","url":null,"abstract":"<p><strong>Purpose: </strong>The effects of sufentanil-ropivacaine combination on the parturient women and the course of labor have been well documented. However, there is little information regarding the time-dependent pharmacokinetic characteristics of sufentanil after epidural administration in laboring women. We aimed to develop a population PK model for epidural sufentanil in laboring women to evaluate the sufentanil placental transfer quantitatively.</p><p><strong>Patients and methods: </strong>Forty-one participants who underwent epidural labor analgesia were recruited into this study. Patients received a continuous epidural infusion of sufentanil 0.3 µg/mL with ropivacaine 0.1%. Maternal venous blood samples and umbilical venous blood samples were collected for population PK analysis. The trends of sufentanil blood concentrations in the mothers and umbilical cord were predicted by the model.</p><p><strong>Results: </strong>Sufentanil disposition after continuous epidural administration in laboring women followed a two-compartment pharmacokinetic model. The estimated sufentanil central clearance (CL), central volume of distribution (V1), clearance between central compartment and umbilical cord compartment (CL2), and umbilical cord volume of distribution (V2) were 176 L/h, 519 L, 0.0134 L/h, and 0.187 L. The absolute level of sufentanil in placental circulation is low after epidural administration. A slow decline in placental sufentanil concentration was predicted by the final PK model after epidural infusion was discontinued.</p><p><strong>Conclusion: </strong>A slow decline in placental sufentanil concentration is predicted by the final two-compartment PK model after epidural infusion was discontinued. This suggests that very large doses of epidural sufentanil should be avoided during labor analgesia.</p><p><strong>Trial registration: </strong>https://www.chictr.org.cn, No: ChiCTR1800018810.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"971-980"},"PeriodicalIF":4.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440232","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}
Pub Date : 2025-02-11eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S493049
Mingyu Zhang, Suhong Xia, Lina Feng, Xu Han, Yu Zhang, Yujie Huang, Yiran Liu, Kai Zhao, Jialun Guan, Dean Tian, Jiazhi Liao, Yan Yu
Background: Aspirin is widely used to prevent and treat cardiovascular diseases. The most common side effect is gastrointestinal damage. In recent years, aspirin-associated enteropathy has received increasing attention. This study aimed to establish a chronic model of aspirin-associated enteropathy, investigate the effect of enteric-coated aspirin on the intestinal flora, and explore the specific molecular mechanism of small intestinal damage.
Methods: C57BL/6J mice were given aspirin for 45 days to induce chronic small intestinal injury. The intestinal mucosal injury was observed macroscopically and microscopically. Intestinal mucus levels were assessed by PAS staining. The intestinal permeability was measured by FD4. The oxidative stress levels of the small intestine were detected by immunofluorescence and immunohistochemistry. The mRNA and protein levels of inflammatory factors, tight junctions, and antioxidant defense-related genes were measured by qRT-PCR and Western Blot. The MPO activity, SOD activity and MDA content in serum were measured. The mitochondrial morphology and paracellular space were observed under transmission electron microscopy. The fecal samples were analyzed by high-throughput sequencing of 16S rRNA V3-V4 amplicons.
Results: Aspirin induced weight loss, reduced food intake and increased faecal occult blood in mice. Aspirin led to a shortened small intestine, macroscopic and microscopic damage to the intestinal mucosa, and local inflammation. Aspirin disrupted the intestinal barriers and increased the permeability of the small intestine. Aspirin destroyed mitochondrial structure and damaged antioxidant capacity, and aspirin may induce oxidative stress through Nrf2/Gpx4 signaling pathway. Intestinal flora analysis showed that aspirin could induce changes in the abundance of Akkermansia and Lactobacillus.
Conclusion: Long-term administration of enteric-coated aspirin successfully established a chronic small intestinal injury model in mice. It increased oxidative stress in the small intestine by disrupting mitochondrial structure and impairing antioxidant capacity. This damaged the intestinal mucosal barrier, increased intestinal permeability, and triggered gut microbial dysbiosis and inflammation.
{"title":"Enteric-Coated Aspirin Induces Small Intestinal Injury via the Nrf2/Gpx4 Pathway: A Promising Model for Chronic Enteropathy.","authors":"Mingyu Zhang, Suhong Xia, Lina Feng, Xu Han, Yu Zhang, Yujie Huang, Yiran Liu, Kai Zhao, Jialun Guan, Dean Tian, Jiazhi Liao, Yan Yu","doi":"10.2147/DDDT.S493049","DOIUrl":"10.2147/DDDT.S493049","url":null,"abstract":"<p><strong>Background: </strong>Aspirin is widely used to prevent and treat cardiovascular diseases. The most common side effect is gastrointestinal damage. In recent years, aspirin-associated enteropathy has received increasing attention. This study aimed to establish a chronic model of aspirin-associated enteropathy, investigate the effect of enteric-coated aspirin on the intestinal flora, and explore the specific molecular mechanism of small intestinal damage.</p><p><strong>Methods: </strong>C57BL/6J mice were given aspirin for 45 days to induce chronic small intestinal injury. The intestinal mucosal injury was observed macroscopically and microscopically. Intestinal mucus levels were assessed by PAS staining. The intestinal permeability was measured by FD4. The oxidative stress levels of the small intestine were detected by immunofluorescence and immunohistochemistry. The mRNA and protein levels of inflammatory factors, tight junctions, and antioxidant defense-related genes were measured by qRT-PCR and Western Blot. The MPO activity, SOD activity and MDA content in serum were measured. The mitochondrial morphology and paracellular space were observed under transmission electron microscopy. The fecal samples were analyzed by high-throughput sequencing of 16S rRNA V3-V4 amplicons.</p><p><strong>Results: </strong>Aspirin induced weight loss, reduced food intake and increased faecal occult blood in mice. Aspirin led to a shortened small intestine, macroscopic and microscopic damage to the intestinal mucosa, and local inflammation. Aspirin disrupted the intestinal barriers and increased the permeability of the small intestine. Aspirin destroyed mitochondrial structure and damaged antioxidant capacity, and aspirin may induce oxidative stress through Nrf2/Gpx4 signaling pathway. Intestinal flora analysis showed that aspirin could induce changes in the abundance of Akkermansia and Lactobacillus.</p><p><strong>Conclusion: </strong>Long-term administration of enteric-coated aspirin successfully established a chronic small intestinal injury model in mice. It increased oxidative stress in the small intestine by disrupting mitochondrial structure and impairing antioxidant capacity. This damaged the intestinal mucosal barrier, increased intestinal permeability, and triggered gut microbial dysbiosis and inflammation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"891-910"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432350","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}
Pub Date : 2025-02-11eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S497239
Xinlei Lu, Kaiyu Chen, Ye Xuan, Mengting Shen, Weiping Lei, Yaqin Huang, Jianliang Sun
Background: Perioperative shivering is a common adverse reaction to neuraxial anaesthesia. Intravenous oxycodone can be used to prevent shivering. However, few trials have been conducted on the use of oxycodone to prevent shivering, and the optimal dose is unknown. This study aimed to determine the optimal dose (90% minimum effective concentration [MEC90]) of intraoperative oxycodone to prevent shivering during caesarean section.
Methods: This study was designed by the biased-coin up-and-down method. We recruited pregnant women who underwent caesarean section under combined spinal-epidural anaesthesia. Oxycodone was administered intravenously after the delivery of the foetus. The initial dose was 80 µg/kg, and subsequent dose adjustments were determined by up-and-down sequential allocation using a biased-coin design based on the response of the previous patient. The primary outcome was the MEC90 for oxycodone injection based on the success or failure of the shivering-preventing dose.
Results: Fifty patients were enrolled in the study. The oxycodone dose ranged from 80 to 95 µg/kg. The estimated MEC90 (95% confidence interval [CI]) for preventing shivering was 88.1 µg/kg (81.5-92.5 µg/kg). The patient's postoperative temperature was 36.5 ± 0.2 °C. The incidence of intraoperative traction pain was 12%. The 5-min and 30-min Ramsay sedation scores were 3 (3-4) and 3 (3-3), respectively. The 2-h and 6-h postoperative VAS scores were 3 (2-3) and 4 (3-5), respectively. The patient's anaesthesia satisfaction score was 5 (4-5). The incidence of respiratory depression was 2%, and the incidence of nausea and vomiting was 16%.
Conclusion: The MEC90 of intraoperative intravenous oxycodone for the prevention of shivering in women undergoing caesarean section with neuraxial anaesthesia was 88.1 µg/kg (95% CI: 81.5-92.5 µg/kg).
{"title":"Determination of the MEC90 of Oxycodone for Preventing Perioperative Shivering in Pregnant Patients Undergoing Caesarean Delivery with Neuraxial Anaesthesia: A Biased-Coin up-and-Down Sequential Allocation Trial.","authors":"Xinlei Lu, Kaiyu Chen, Ye Xuan, Mengting Shen, Weiping Lei, Yaqin Huang, Jianliang Sun","doi":"10.2147/DDDT.S497239","DOIUrl":"10.2147/DDDT.S497239","url":null,"abstract":"<p><strong>Background: </strong>Perioperative shivering is a common adverse reaction to neuraxial anaesthesia. Intravenous oxycodone can be used to prevent shivering. However, few trials have been conducted on the use of oxycodone to prevent shivering, and the optimal dose is unknown. This study aimed to determine the optimal dose (90% minimum effective concentration [MEC90]) of intraoperative oxycodone to prevent shivering during caesarean section.</p><p><strong>Methods: </strong>This study was designed by the biased-coin up-and-down method. We recruited pregnant women who underwent caesarean section under combined spinal-epidural anaesthesia. Oxycodone was administered intravenously after the delivery of the foetus. The initial dose was 80 µg/kg, and subsequent dose adjustments were determined by up-and-down sequential allocation using a biased-coin design based on the response of the previous patient. The primary outcome was the MEC90 for oxycodone injection based on the success or failure of the shivering-preventing dose.</p><p><strong>Results: </strong>Fifty patients were enrolled in the study. The oxycodone dose ranged from 80 to 95 µg/kg. The estimated MEC90 (95% confidence interval [CI]) for preventing shivering was 88.1 µg/kg (81.5-92.5 µg/kg). The patient's postoperative temperature was 36.5 ± 0.2 °C. The incidence of intraoperative traction pain was 12%. The 5-min and 30-min Ramsay sedation scores were 3 (3-4) and 3 (3-3), respectively. The 2-h and 6-h postoperative VAS scores were 3 (2-3) and 4 (3-5), respectively. The patient's anaesthesia satisfaction score was 5 (4-5). The incidence of respiratory depression was 2%, and the incidence of nausea and vomiting was 16%.</p><p><strong>Conclusion: </strong>The MEC90 of intraoperative intravenous oxycodone for the prevention of shivering in women undergoing caesarean section with neuraxial anaesthesia was 88.1 µg/kg (95% CI: 81.5-92.5 µg/kg).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"945-954"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432348","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}
Pub Date : 2025-02-11eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S497554
Shuqi Shi, Jimin Wu, Yini Wu, Xin Han, Hong Dai, Xuedong Chen, Zhangnan Sun, Faxing Wang
Objective: This study compares postoperative recovery quality between Ciprofol and Propofol, providing a reference for the clinical application of anesthetics.
Methods: We randomized 112 patients undergoing ureteroscopic surgery into two groups: the Ciprofol group (Group C), with an induction dose of 0.4 mg/kg and a maintenance dose of 0.8-1.5 mg/(kg·h), and the Propofol group (Group P), with an induction dose of 2 mg/kg and a maintenance dose of 4-10 mg/(kg·h). Both groups received sevoflurane at a concentration of 1%. The Bispectral Index (BIS) was maintained between 40 and 60. The primary outcomes were the Quality of Recovery-15 (QoR-15) scores on postoperative day 1 (POD1). Secondary outcomes included hemodynamic parameters, vasopressor use, timing indicators, sedative consumption, BIS values, Riker Sedation-Agitation Scale (R-SAS) scores, urinary tract symptoms, patient satisfaction, and adverse events.
Results: No significant differences were observed in QoR-15 scores between the two groups. Although Group C had higher pain (P = 0.004) and comfort (P = 0.002) scores on POD1, these differences were not clinically significant. The incidence of hypotension and vasopressor use was lower in Group C, which had more stable hemodynamics. Additionally, the time from induction to BIS ≤ 60 was shorter in Group P (P = 0.001), while Group C had lower BIS values from drug discontinuation to full recovery of consciousness (P = 0.001). The incidence of urinary tract symptoms on POD1 was lower in Group C (P = 0.043). There were no significant differences in time to spontaneous breathing recovery, extubation, recovery room stay, time to first ambulation, hospital stay, patient satisfaction, or other adverse events.
Conclusion: Ciprofol provides comparable early postoperative recovery to Propofol during ureteroscopy and may be a preferable alternative for urological procedures, especially in patients with blood pressure concerns.
Trial registration: Chinese Clinical Trial Registry (ChiCTR2400082736).
{"title":"Effects of Ciprofol and Propofol General Anesthesia on Postoperative Recovery Quality in Patients Undergoing Ureteroscopy: A Randomized, Controlled, Double-Blind Clinical Trial.","authors":"Shuqi Shi, Jimin Wu, Yini Wu, Xin Han, Hong Dai, Xuedong Chen, Zhangnan Sun, Faxing Wang","doi":"10.2147/DDDT.S497554","DOIUrl":"10.2147/DDDT.S497554","url":null,"abstract":"<p><strong>Objective: </strong>This study compares postoperative recovery quality between Ciprofol and Propofol, providing a reference for the clinical application of anesthetics.</p><p><strong>Methods: </strong>We randomized 112 patients undergoing ureteroscopic surgery into two groups: the Ciprofol group (Group C), with an induction dose of 0.4 mg/kg and a maintenance dose of 0.8-1.5 mg/(kg·h), and the Propofol group (Group P), with an induction dose of 2 mg/kg and a maintenance dose of 4-10 mg/(kg·h). Both groups received sevoflurane at a concentration of 1%. The Bispectral Index (BIS) was maintained between 40 and 60. The primary outcomes were the Quality of Recovery-15 (QoR-15) scores on postoperative day 1 (POD1). Secondary outcomes included hemodynamic parameters, vasopressor use, timing indicators, sedative consumption, BIS values, Riker Sedation-Agitation Scale (R-SAS) scores, urinary tract symptoms, patient satisfaction, and adverse events.</p><p><strong>Results: </strong>No significant differences were observed in QoR-15 scores between the two groups. Although Group C had higher pain (P = 0.004) and comfort (P = 0.002) scores on POD1, these differences were not clinically significant. The incidence of hypotension and vasopressor use was lower in Group C, which had more stable hemodynamics. Additionally, the time from induction to BIS ≤ 60 was shorter in Group P (P = 0.001), while Group C had lower BIS values from drug discontinuation to full recovery of consciousness (P = 0.001). The incidence of urinary tract symptoms on POD1 was lower in Group C (P = 0.043). There were no significant differences in time to spontaneous breathing recovery, extubation, recovery room stay, time to first ambulation, hospital stay, patient satisfaction, or other adverse events.</p><p><strong>Conclusion: </strong>Ciprofol provides comparable early postoperative recovery to Propofol during ureteroscopy and may be a preferable alternative for urological procedures, especially in patients with blood pressure concerns.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry (ChiCTR2400082736).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"931-943"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432349","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}
Pub Date : 2025-02-11eCollection Date: 2025-01-01DOI: 10.2147/DDDT.S493911
Xiuqi Li, Shupeng Liu, Mengyang Yu, Wanlin Xi, Xiaofei Wu, Dan Liu, Aijing Liu, Hongyun Wang
Background: Proton pump inhibitors (PPIs) and potassium competitive acid blockers (P-CABs) are widely used to treat acid-related diseases (ARDs). Precisely quantifying their plasma levels is crucial for clinical pharmacokinetic assessments and therapeutic drug monitoring.
Aim: This study aimed to establish a generic and efficient ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the determination of five PPIs (esomeprazole, rabeprazole, ilaprazole, lansoprazole, and pantoprazole) and the P-CAB (vonoprazan) in human plasma.
Methods: The six analytes were extracted from human plasma via protein precipitation and a single dilution step. Detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization. Chromatographic separation was achieved on the ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) using gradient elution. The mobile elution was composed of 0.2% formic acid in acetonitrile (mobile phase A), 0.1% ammonium hydroxide and 10 mmol/L ammonium formate in deionized water (mobile phase B). The flow rate was 0.4 mL/min, the run time was 4.5 minutes, and the injection volume was 20 µL.
Results & conclusions: The method exhibited excellent linearity across the ranges of 0.2-200 ng/mL for PPIs and 0.5-500 ng/mL for the P-CAB. Both intra- and inter-day precision and accuracy were within the acceptance criteria, with precision ranging from 1.1% to 14.6% and accuracy ranging from 0.0% to 14.7%. Extraction recoveries were consistent, ranging from 88.1% to 96.7%, with no significant matrix effects observed. The stability of the six analytes under diverse storage and processing conditions was also confirmed, with both precision and accuracy falling within the acceptable range of 15%. The UPLC-MS/MS assay provided an efficient and reliable approach for the simultaneous determination of six acid-suppressing medications in a single analytical run. It has been successfully applied to the pharmacokinetic studies of PPIs and P-CABs, offering a valuable tool for clinical research and therapeutic drug monitoring.
{"title":"Simultaneous Determination of Multiple Acid-Suppressing Drugs by UPLC-MS/MS Method and Application for Pharmacokinetics Study.","authors":"Xiuqi Li, Shupeng Liu, Mengyang Yu, Wanlin Xi, Xiaofei Wu, Dan Liu, Aijing Liu, Hongyun Wang","doi":"10.2147/DDDT.S493911","DOIUrl":"10.2147/DDDT.S493911","url":null,"abstract":"<p><strong>Background: </strong>Proton pump inhibitors (PPIs) and potassium competitive acid blockers (P-CABs) are widely used to treat acid-related diseases (ARDs). Precisely quantifying their plasma levels is crucial for clinical pharmacokinetic assessments and therapeutic drug monitoring.</p><p><strong>Aim: </strong>This study aimed to establish a generic and efficient ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the determination of five PPIs (esomeprazole, rabeprazole, ilaprazole, lansoprazole, and pantoprazole) and the P-CAB (vonoprazan) in human plasma.</p><p><strong>Methods: </strong>The six analytes were extracted from human plasma via protein precipitation and a single dilution step. Detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization. Chromatographic separation was achieved on the ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) using gradient elution. The mobile elution was composed of 0.2% formic acid in acetonitrile (mobile phase A), 0.1% ammonium hydroxide and 10 mmol/L ammonium formate in deionized water (mobile phase B). The flow rate was 0.4 mL/min, the run time was 4.5 minutes, and the injection volume was 20 µL.</p><p><strong>Results & conclusions: </strong>The method exhibited excellent linearity across the ranges of 0.2-200 ng/mL for PPIs and 0.5-500 ng/mL for the P-CAB. Both intra- and inter-day precision and accuracy were within the acceptance criteria, with precision ranging from 1.1% to 14.6% and accuracy ranging from 0.0% to 14.7%. Extraction recoveries were consistent, ranging from 88.1% to 96.7%, with no significant matrix effects observed. The stability of the six analytes under diverse storage and processing conditions was also confirmed, with both precision and accuracy falling within the acceptable range of 15%. The UPLC-MS/MS assay provided an efficient and reliable approach for the simultaneous determination of six acid-suppressing medications in a single analytical run. It has been successfully applied to the pharmacokinetic studies of PPIs and P-CABs, offering a valuable tool for clinical research and therapeutic drug monitoring.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"955-969"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440234","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}