Drug Design, Development and Therapy最新文献

{"title":"UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research.","authors":"Ruanjuan Zhan, Yanan Liu, Jun Wu, Yuxin Shen, Xinhao Xu, Guanyang Lin, Xiaocheng Chen","doi":"10.2147/DDDT.S497308","DOIUrl":"10.2147/DDDT.S497308","url":null,"abstract":"<p><strong>Background: </strong>Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.</p><p><strong>Purpose: </strong>This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.</p><p><strong>Methods: </strong>Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows: <i>m/z</i> 422.01→186.11 for givinostat, and <i>m/z</i> 405.40→84.10 for IS, respectively.</p><p><strong>Results: </strong>In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (<i>r</i> ²=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t_1/2) value of 92.87 min.</p><p><strong>Conclusion: </strong>Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"219-228"},"PeriodicalIF":4.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intraoperative Administration of Esketamine is Associated with Reduced Opioid Consumption After Laparoscopic Gynecological Surgery: A Randomized Controlled Trial.","authors":"Chen Huan, Ting Zhang, Yiling Jiang, Shuangyu He, Juying Jin","doi":"10.2147/DDDT.S502938","DOIUrl":"https://doi.org/10.2147/DDDT.S502938","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the postoperative opioid-sparing effect and incidence of adverse events of different dosages of intraoperative esketamine administration in patients undergoing laparoscopic gynecological surgery.</p><p><strong>Patients and methods: </strong>Patients undergoing elective gynecological laparoscopic operation was enrolled and randomly allocated to lower-dose esketamine group, higher-dose esketamine group, or control group. Patients in the two intervention groups received esketamine doses of 0.25 mg/Kg and 0.50 mg/Kg before wound incision. Subsequently, maintenance doses of 0.20 mg/Kg/h and 0.40 mg/Kg/h were administered throughout the procedure, respectively. The control group was given an intravenous injection and a maintenance infusion of normal saline. A patient-controlled analgesia (PCA) intravenous pump containing sufentanil was connected to control postoperative pain. Rescue analgesia was provided with injection of tramadol 100 mg.</p><p><strong>Results: </strong>In total, 120 subjects were included in data analysis. The 24 hours and 48 hours PCA opioid consumption, 24 hours and 48 hours cumulative opioid in both lower-dose and higher-dose esketamine groups were lower than those in the control group. However, postoperative opioid consumption was comparable between the two intervention groups. No differences were found in extubation time, acute postoperative pain intensity, and incidence of adverse effects among the three groups.</p><p><strong>Conclusion: </strong>Intraoperative esketamine administration at both low and high doses reduces opioid consumption after gynecological laparoscopic surgery, without increasing the risk of adverse events.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"229-238"},"PeriodicalIF":4.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001960","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":"Phytosome-Enhanced Secondary Metabolites for Improved Anticancer Efficacy: Mechanisms and Bioavailability Review.","authors":"Lia Mardiana, Tiana Milanda, Yuni Elsa Hadisaputri, Anis Yohana Chaerunisaa","doi":"10.2147/DDDT.S483404","DOIUrl":"10.2147/DDDT.S483404","url":null,"abstract":"<p><strong>Purpose: </strong>Phytosome technology, an advanced lipid-based delivery system, offers a promising solution for enhancing the bioavailability and therapeutic efficacy of secondary metabolites, particularly in cancer treatment. These metabolites, such as flavonoids, terpenoids, and alkaloids, possess significant anticancer potential but are often limited by poor solubility and low absorption. This review aims to investigate how phytosome encapsulation improves the pharmacokinetic profiles and anticancer effectiveness of these bioactive compounds.</p><p><strong>Patients and methods: </strong>This comprehensive review is based on an analysis of recent literature retrieved from PubMed, Scopus, and ScienceDirect databases. It focuses on findings from preclinical and in vitro studies that examine the pharmacokinetic enhancements provided by phytosome technology when applied to secondary metabolites.</p><p><strong>Results: </strong>Phytosome-encapsulated secondary metabolites exhibit significantly improved solubility, absorption, distribution, and cellular uptake compared to non-encapsulated forms. This enhanced bioavailability facilitates more effective inhibition of cancer pathways, including NF-κB and PI3K/AKT, leading to increased anticancer efficacy in preclinical models.</p><p><strong>Conclusion: </strong>Phytosome technology has demonstrated its potential to overcome bioavailability challenges, resulting in safer and more effective therapeutic options for cancer treatment. This review highlights the potential of phytosome-based formulations as a novel approach to anticancer therapy, supporting further development in preclinical, in vitro, and potential clinical applications.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"201-218"},"PeriodicalIF":4.7,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001969","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":"Gonadotropin Releasing Hormone Agonists Combined with Hormone Replacement Therapy Significantly Improves Reproductive Outcomes for Patients with Thin Endometrium and Intramural Fibroids in Frozen Embryo Transfer Cycles.","authors":"Longlong Wei, Bing Tian, Shuna Wang, Siyue Xu, Cuilian Zhang","doi":"10.2147/DDDT.S501809","DOIUrl":"10.2147/DDDT.S501809","url":null,"abstract":"<p><strong>Background: </strong>Both intramural myomas and thin endometrium exert a detrimental influence on the outcomes of assisted reproductive technology (ART). The downregulation of gonadotropin releasing hormone agonists (GnRH-a) is regarded as an effective approach to reducing the size of intramural fibroids and enhancing endometrial receptivity. Consequently, we conducted this study to assess whether the GnRH-a combined with hormone replacement therapy (GnRH-a-HRT) can improve reproductive outcomes in frozen embryo transfer cycles for patients with a thin endometrium (≤7 mm) and intramural fibroids.</p><p><strong>Methods: </strong>This retrospective cohort study encompassed 360 patients who underwent frozen embryo transfer following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Patients were stratified into three groups based on the endometrial preparation protocol: the natural cycle (NC) group (n=96), the hormone replacement therapy (HRT) group (n=180), and the GnRH-a-HRT group (n=84). The live birth rate (LBR) was designated as the primary outcome, while clinical pregnancy rate (CPR), miscarriage rate, and ectopic pregnancy rate were classified as secondary outcomes.</p><p><strong>Results: </strong>The LBR and CPR in the GnRH-a-HRT group were significantly higher than those in both the HRT group and the NC group (both P < 0.0001). A logistic regression model indicated that the LBR was significantly higher in the GnRH-a-HRT group compared to both the HRT group (odds ratio, 0.269; 95% confidence interval, 0.114-0.637; P = 0.003) and the NC group (odds ratio, 0.524; 95% confidence interval, 0.457-0.956; P = 0.023). Subgroup analyses based on the number and dimension of fibroids demonstrate the positive efficacy of the GnRH-a-HRT regimen.</p><p><strong>Conclusion: </strong>Compared to NC and HRT protocol, improved reproductive outcomes were observed in the GnRH-a-HRT group. These findings provide valuable insights for exploration of the underlying mechanisms by which the GnRH-a-HRT protocol enhances reproductive outcomes in patients of thin endometrium with intramural fibroids.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"173-183"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983063","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":"Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis.","authors":"Zhida Long, Xiao Yu, Shijia Li, Nuo Cheng, Chenglong Huo, Xuewen Zhang, Shuai Wang","doi":"10.2147/DDDT.S497817","DOIUrl":"https://doi.org/10.2147/DDDT.S497817","url":null,"abstract":"<p><strong>Introduction: </strong>Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.</p><p><strong>Methods: </strong>Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.</p><p><strong>Results: </strong>Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.</p><p><strong>Conclusion: </strong>Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"159-171"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055871","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":"Novel Insight into the Modulatory Effect of Traditional Chinese Medicine on Cerebral Ischemia-Reperfusion Injury by Targeting Gut Microbiota: A Review.","authors":"Yisong Ren, Gang Chen, Ying Hong, Qianying Wang, Bo Lan, Zhaozhao Huang","doi":"10.2147/DDDT.S500505","DOIUrl":"10.2147/DDDT.S500505","url":null,"abstract":"<p><p>Cerebral ischemia-reperfusion injury (CIRI) is clinically characterized by high rates of morbidity, disability, mortality, and recurrence as well as high economic burden. The clinical manifestations of CIRI are often accompanied by gastrointestinal symptoms such as intestinal bacterial dysbiosis and gastrointestinal bleeding. Gut microbiota plays an important role in the pathogenesis of CIRI, and its potential biological effects have received extensive attention. The gut microbiota not only affects intestinal barrier function but also regulates gastrointestinal immunity and host homeostasis. Traditional Chinese medicine (TCM), a multi-component and multi-targeted drug, has shown remarkable effects and few adverse reactions in the prevention and treatment of CIRI. Notably, the effect of TCM on CIRI by regulating gut microbiota and maintaining gastrointestinal homeostasis has gradually become a hot topic. This review summarizes the functional role of the gut microbiota in the development and progression of CIRI and the therapeutic effects of TCM on CIRI by improving gut microbiota dysbiosis, affecting gut microbiota metabolism, and maintaining host immunity. The active ingredients of TCM used for the treatment of CIRI in relevant studies were saponins, triterpenoids, phenolics, and alkaloids. In addition, the clinical effects of TCM used to treat CIRI were briefly discussed. This review established the clinical significance and development prospects of TCM-based CIRI treatments and provided the necessary theoretical support for the further development of TCM resources for the treatment of CIRI.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"185-200"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983064","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":"Protective Effect of Rosmarinic Acid on Endotoxin-Induced Neuronal Damage Through Modulating GRP78/PERK/MANF Pathway.","authors":"Qian Li, Jing-Wen Zheng, Zi-Yao Wang, Shi-Ping Liao, Ling Zhu, Xia Wang, Li-Hong Wan","doi":"10.2147/DDDT.S481646","DOIUrl":"10.2147/DDDT.S481646","url":null,"abstract":"<p><strong>Objective: </strong>Neuronal damage is criminal to cognitive dysfunction, closely related to endoplasmic reticulum stress (ERS). However, due to the pathogenesis of endotoxin-induced long-term cognitive dysfunction is not fully clarified, there is still a lack of effective treatment. This study was conducted to explore the protective effects and mechanism of rosmarinic acid (RA) against ERS in endotoxin-induced cognitive dysfunction in mice and neuronal injury in cells.</p><p><strong>Methods: </strong>The efficacy of RA was evaluated using an endotoxin-induced cognitive dysfunction mice model and an in vitro neuronal injury model. Brain injury was assessed using behavioral tests and hematoxylin and eosin (HE) staining. Western blotting and Immunohistochemistry (IHC) were performed to determine NeuN, GRP78, PERK, ATF6, IRE1α, and MANF expression levels. Molecular docking was used to assess the associated mechanisms.</p><p><strong>Results: </strong>Behavioral tests indicated that 20 and 40 mg/kg RA significantly improve endotoxin-induced cognitive dysfunction without dose differences. Histological analysis revealed no significant alterations in the number, morphology, and arrangement of neurons in the hippocampus and amygdala. However, 40 mg/kg RA treatment significantly decreased the hippocampal level of PERK protein and increased MANF in CA1 and DG in mice. Furthermore, our data showed that 120 μM RA pretreatment significantly inhibited LPS-conditioned culture-induced GRP78, PERK, and MANF upregulation in vitro. Finally, molecular docking studies suggested that RA could directly interact with GRP78, PERK, and IRE1, but not with MANF.</p><p><strong>Conclusion: </strong>RA plays a protective role in improving cognitive function against endotoxemia-associated encephalopathy in mice via inhibiting the GRP78/PERK/MANF pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"39-50"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Dexmedetomidine on the ED₅₀ and ED₉₅ of Sufentanil in Patient-Controlled Intravenous Analgesia After Cesarean Section: A Randomized, Controlled, Double-Blind Trial.","authors":"Jiabei Li, Wuchang Fu, Na Wang, Sisi Zeng, Xuechao Li, Jixiang Wan, Fangjun Wang","doi":"10.2147/DDDT.S494162","DOIUrl":"10.2147/DDDT.S494162","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the effect of dexmedetomidine on the ED₅₀ and ED₉₅ of sufentanil in patient-controlled intravenous analgesia (PCIA) after cesarean section.</p><p><strong>Patients and methods: </strong>Parturients who underwent elective cesarean section (n = 80) were randomly assigned to either the sufentanil group (S group) or the dexmedetomidine-sufentanil combination group (DS group). Patients in the S group received a combination of sufentanil, 5 mg of tropisetron, and saline, whereas patients in the DS group were administered 1.5µg/kg of dexmedetomidine in addition to sufentanil, 5 mg of tropisetron, and saline. The ED₅₀ and ED₉₅ of sufentanil were determined by Dixon sequential method. We used probit regression to calculate the ED₅₀, ED₉₅, and 95% confidence intervals for sufentanil in each group.</p><p><strong>Results: </strong>The ED₅₀ and ED₉₅ for sufentanil in the S group were 1.634 (95% CI: 1.476-1.810)µg/kg and 2.035 (95% CI: 1.841-3.312)µg/kg, respectively. The ED₅₀ and ED₉₅ for sufentanil in the DS group were 1.275 (95% CI: 1.187-1.353)µg/kg and 1.503 (95% CI: 1.406-1.824)µg/kg. The VAS scores with rest at t₅ and with movement at t₄- t₅ were lower in the DS group (<i>P</i>< 0.05). The t₂-t₅ Ramsay scores in the DS group were higher than those in the S group (<i>P</i>< 0.05). The doses of sufentanil and tramadol were markedly reduced in the DS group, while the onset of first lactation occurred significantly earlier in the DS group (<i>P</i>< 0.05). Compared with the S group, the DS group had a lower incidence of nausea, vomiting, and skin itching (<i>P</i>< 0.05), and lower frequency of patient-controlled analgesia (PCA) episodes (<i>P</i>< 0.05), and better postoperative pain satisfaction (<i>P</i>< 0.05).</p><p><strong>Conclusion: </strong>The 1.5µg/kg dexmedetomidine can significantly decrease the ED₅₀ and ED₉₅ of sufentanil in patient-controlled intravenous analgesia after cesarean section, provide good postoperative analgesia and sedation, and promote the earlier occurrence of first lactation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"129-140"},"PeriodicalIF":4.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977978","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":"Identification of Lauric Acid as a Potent Sodium Channel Na_V1.5 Blocker from Compound Chinese Medicine Wenxin Keli.","authors":"Weiwei Xie, Jiaming Gao, Yingran Liang, Chenxing Huang, Boyong Zhang, Xiaonan Chen, Xi Yao, Guo Nan, Honghua Wu, Yuefei Wang, Lin Wu, Taiyi Wang, Yan Zhu","doi":"10.2147/DDDT.S485723","DOIUrl":"10.2147/DDDT.S485723","url":null,"abstract":"<p><strong>Purpose: </strong>The major cardiac voltage-gated sodium channel Na_V1.5 (I_Na) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of I_Na in WXKL and exploring their mode of action in electrophysiological conduction.</p><p><strong>Methods: </strong>A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the Na_V1.5 gene SCN5A. Candidate fractions with I_Na-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. Na_V1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches.</p><p><strong>Results: </strong>A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the Na_V1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for I_Na-inhibition with an IC₅₀ at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of I_Na to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel I_Na blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the Na_V1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na⁺. Mechanistically, lauric acid acts on the fast inactivation of Na_V1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL.</p><p><strong>Conclusion: </strong>Lauric acid is a potent blocker for sodium channel Na_V1.5 and alleviates arrhythmia via inhibiting I_Na.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"141-157"},"PeriodicalIF":4.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977984","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 Pharmacokinetic/Pharmacodynamic Study of Esomeprazole Comparing a Dual Delayed-Release Formulation (YYD601) to a Conventional Formulation Following Multiple Administrations in Healthy Adult Subjects.","authors":"Hae Won Lee, Woo Youl Kang, Ji Seo Park, Jae Hwa Lee, Jin Ju Park, Mi-Ri Gwon, Young-Ran Yoon, Sook Jin Seong","doi":"10.2147/DDDT.S500253","DOIUrl":"10.2147/DDDT.S500253","url":null,"abstract":"<p><strong>Background: </strong>YYD601 is a new dual delayed-release formulation of esomeprazole, developed to enhance plasma exposure and prolong the duration of acid suppression.</p><p><strong>Purpose: </strong>This study aimed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of YYD601 20 mg following single and multiple oral administrations in healthy, fasting adult Koreans, and to compare these outcomes to those of the conventional esomeprazole 20 mg capsule.</p><p><strong>Methods: </strong>A randomized, open-label, two-period crossover study was conducted in 28 participants, who were divided into two treatment groups: one group received YYD601 20 mg, and the other received conventional esomeprazole 20 mg, once daily for five consecutive days. Blood samples for PK analysis were collected pre-dose and up to 24 hours post-dose. The primary PK parameters (AUC_last and AUC_τ) were evaluated. PD endpoints included integrated gastric acidity, percentage of time with intragastric pH > 4 over 24-hour and nighttime intervals, and percent change in serum gastrin levels after multiple dosing.</p><p><strong>Results: </strong>A total of 22 participants completed the study. YYD601 displayed more prolonged plasma concentration-time profiles than the conventional formulation, although the extent of the systemic exposure (AUC values) showed no statistically significant difference between the two formulations. With regard to the 24-hour gastric acid inhibition, YYD601 was comparable to the conventional formulation. The YYD601 showed a greater tendency for acid inhibition at night, as indicated by the percentage change of time with nocturnal acid breakthrough and other PD parameters. Both treatments were well tolerated, with no serious adverse events reported.</p><p><strong>Conclusion: </strong>Through extended systemic exposure of esomeprazole, YYD601 produces gastric acid suppression that is comparable to that of the conventional esomeprazole formulation, with a greater tendency to suppress acid at night. YYD601 20 mg was safe and well tolerated following single and multiple oral administrations, supporting its use as an effective alternative to conventional esomeprazole therapy.</p><p><strong>Clinical trial registry: </strong>http://clinicaltrials.gov, NCT03985319 (Date of registration: May 29, 2019; Study period: between July 2019 and March 2020).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"97-110"},"PeriodicalIF":4.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969995","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}