Pub Date : 2024-08-05eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S473251
Yu-Qing Tan, Wang Zhang, Zi-Cong Xie, Jun Li, Heng-Wen Chen
Cardiovascular diseases (CVDs) tend to affect the young population and are associated with a significant economic burden and psychological distress to the society and families. The physiological and pathological processes underlying CVDs are complex. Ca2+/calmodulin-dependent kinase II (CaMK II), a protein kinase, has multiple biological functions. It participates in multiple pathological processes and plays a central role in the development of CVDs. Based on this, this paper analyzes the structural characteristics and distribution of CaMK II, the mechanism of action of CaMK II, and the relationship between CaMK II and CVDs, including ion channels, ischemia-reperfusion injury, arrhythmias, myocardial hypertrophy, cardiotoxicity, hypertension, and dilated cardiomyopathy. Given the different regulatory mechanisms of different isoforms of CaMK II, the clinical use of specific targeted inhibitors or novel compounds should be evaluated in future research to provide new directions.
心血管疾病（CVDs）多发于年轻人群，给社会和家庭带来沉重的经济负担和心理压力。心血管疾病的生理和病理过程十分复杂。Ca2+/钙调蛋白依赖性激酶 II（CaMK II）是一种蛋白激酶，具有多种生物学功能。它参与多种病理过程，在心血管疾病的发生发展中起着核心作用。基于此，本文分析了 CaMK II 的结构特点和分布、CaMK II 的作用机制，以及 CaMK II 与心血管疾病（包括离子通道、缺血再灌注损伤、心律失常、心肌肥厚、心脏毒性、高血压和扩张型心肌病）之间的关系。鉴于 CaMK II 不同异构体的调控机制不同，在未来的研究中应评估特定靶向抑制剂或新型化合物的临床应用，以提供新的研究方向。
{"title":"CaMK II in Cardiovascular Diseases, Especially CaMK II-δ: Friends or Enemies.","authors":"Yu-Qing Tan, Wang Zhang, Zi-Cong Xie, Jun Li, Heng-Wen Chen","doi":"10.2147/DDDT.S473251","DOIUrl":"10.2147/DDDT.S473251","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) tend to affect the young population and are associated with a significant economic burden and psychological distress to the society and families. The physiological and pathological processes underlying CVDs are complex. Ca<sup>2+</sup>/calmodulin-dependent kinase II (CaMK II), a protein kinase, has multiple biological functions. It participates in multiple pathological processes and plays a central role in the development of CVDs. Based on this, this paper analyzes the structural characteristics and distribution of CaMK II, the mechanism of action of CaMK II, and the relationship between CaMK II and CVDs, including ion channels, ischemia-reperfusion injury, arrhythmias, myocardial hypertrophy, cardiotoxicity, hypertension, and dilated cardiomyopathy. Given the different regulatory mechanisms of different isoforms of CaMK II, the clinical use of specific targeted inhibitors or novel compounds should be evaluated in future research to provide new directions.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11314529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916366","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}
Indah Purwaningsih, Iman Permana Maksum, Dadan Sumiarsa, Sriwidodo Sriwidodo
Purpose: This study aimed to isolate and characterize palmatine from Fibraurea tinctoria Lour stems, quantify its content, and determine its antioxidant and antidiabetic activities. Patients and Methods: Palmatine was isolated from the methanol extract of Fibraurea tinctoria Lour stems by silica gel column chromatography. Structural elucidation of the isolated compounds was performed using spectral data analysis and comparison with the literature. High-Performance Liquid Chromatography (HPLC) was used to quantitatively determine palmatine in the crude methanol extract and fractions. The DPPH and non-enzymatic SOD mimic methods were used to assess the antioxidant activity of the methanol extract, fractions, and isolated compounds. The antidiabetic activity was evaluated in silico by the molecular docking method of alpha-glucosidase and DPP-IV enzymes. Palmatine was used as a test ligand and was compared with berberine and its native ligand or standard compounds. Results: The isolated compound was identified as palmatine. Quantification of palmatine compound by HPLC showed that palmatine was found in the extract and all fractions. In the in vitro antioxidant activity test using the DPPH method, fraction 4 showed the highest activity, with an IC50 value of 91 ppm. In contrast, using the non-enzymatic SOD mimic method, the methanol extract, fraction 5, and isolated compound (palmatine) exhibited very strong antioxidant activity, with IC50 values of 18, 20, and 28 ppm, respectively. The in silico antidiabetic activity of palmatine is thought to have the potential to inhibit these two enzymes. Conclusion: These results showed that Fibraurea tinctoria Lour stems have potential as an antioxidant and antidiabetic agent. Further research on phytochemical and pharmacological is required to validate the use of this plant species for the treatment of various diseases, especially diabetes mellitus.
{"title":"Isolation and Quantification of Palmatine from Fibraurea tinctoria Lour: In Vitro Antioxidant Activity and In Silico Antidiabetic Activity Evaluation","authors":"Indah Purwaningsih, Iman Permana Maksum, Dadan Sumiarsa, Sriwidodo Sriwidodo","doi":"10.2147/dddt.s454091","DOIUrl":"https://doi.org/10.2147/dddt.s454091","url":null,"abstract":"<strong>Purpose:</strong> This study aimed to isolate and characterize palmatine from <em>Fibraurea tinctoria</em> Lour stems, quantify its content, and determine its antioxidant and antidiabetic activities.<br/><strong>Patients and Methods:</strong> Palmatine was isolated from the methanol extract of <em>Fibraurea tinctoria</em> Lour stems by silica gel column chromatography. Structural elucidation of the isolated compounds was performed using spectral data analysis and comparison with the literature. High-Performance Liquid Chromatography (HPLC) was used to quantitatively determine palmatine in the crude methanol extract and fractions. The DPPH and non-enzymatic SOD mimic methods were used to assess the antioxidant activity of the methanol extract, fractions, and isolated compounds. The antidiabetic activity was evaluated in silico by the molecular docking method of alpha-glucosidase and DPP-IV enzymes. Palmatine was used as a test ligand and was compared with berberine and its native ligand or standard compounds.<br/><strong>Results:</strong> The isolated compound was identified as palmatine. Quantification of palmatine compound by HPLC showed that palmatine was found in the extract and all fractions. In the in vitro antioxidant activity test using the DPPH method, fraction 4 showed the highest activity, with an IC<sub>50</sub> value of 91 ppm. In contrast, using the non-enzymatic SOD mimic method, the methanol extract, fraction 5, and isolated compound (palmatine) exhibited very strong antioxidant activity, with IC<sub>50</sub> values of 18, 20, and 28 ppm, respectively. The in silico antidiabetic activity of palmatine is thought to have the potential to inhibit these two enzymes.<br/><strong>Conclusion:</strong> These results showed that <em>Fibraurea tinctoria</em> Lour stems have potential as an antioxidant and antidiabetic agent. Further research on phytochemical and pharmacological is required to validate the use of this plant species for the treatment of various diseases, especially diabetes mellitus.<br/><br/><strong>Keywords:</strong> <em>Fibraurea tinctoria</em> Lour, berberine, palmatine, antioxidant, antidiabetic<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuqing Liang, Shuai Li, Zhao Zhong, Qichen Luo, Cai Nie, Donghua Hu, Yalan Li
Purpose: This study aimed to investigate patients’ expectative pain of spinal anesthesia puncture and anxiety pre-anesthesia, and to examine the effect of lidocaine-prilocaine cream and remimazolam prior to spinal anesthesia puncture on pain relief and anxiety release. Methods: Patients undergoing spinal anesthesia were divided into control, lidocaine-prilocaine cream, and lidocaine-prilocaine cream with remimazolam groups. A questionnaire consisting of The Amsterdam Preoperative Anxiety and Information Scale (APAIS) and patient’s concerns and Visual Analog Scale (VAS) was used to evaluate patient’s anxiety and pain. The primary outcomes were differences in VAS and anxiety scores. Patient’s spinal anesthesia-related concerns, advent events and hemodynamic index were also recorded. Results: The expected spinal anesthesia puncture pain was 5.34± 0.27 and anxiety scores before spinal anesthesia was 10.88 ± 0.64. A statistically significant positive correlation of 31.3% was detected between VAS and APAIS scores (r = 0.313; P=0.003). The VAS score at the time of puncture decreased by 29.7% (3.78± 0.40, P=0.001) in lidocaine-prilocaine cream group and 29.2% (3.75± 0.39, P=0.001) in lidocaine-prilocaine cream with remimazolam group compared with the expected VAS score. Lidocaine-prilocaine cream combined with or without remimazolam reduced the percentage of moderate pain (21.4% and 31.3% vs 50.0%, P=0.0001) and increased mild pain (60.7% vs 59.4% vs 22.7%, P=0.03). Anxiety score in lidocaine-prilocaine cream group was reduced by 2.84 (8.04± 0.76 vs 10.88 ± 0.46, P=0.05) when compared with pre-anesthesia. Concerns about postoperative pain (P=0.03) and fear of the needle or intervention (P=0.000) both decreased post-anesthesia among groups. Conclusion: Approximately half of the patients scheduled for spinal anesthesia experienced a moderate level of preoperative anxiety. The patient’s pain expectation from the spinal anesthesia puncture was moderate, which was higher than the actual pain. Lidocaine-prilocaine cream with or without remimazolam sedative before spinal anesthesia puncture reduced the patient’s pain and anxiety scores after surgery.
目的：本研究旨在调查患者对脊髓麻醉穿刺的预期疼痛和麻醉前焦虑，并探讨脊髓麻醉穿刺前使用利多卡因-阿鲁卡因乳膏和雷马唑仑对缓解疼痛和释放焦虑的影响：方法：将接受脊髓麻醉的患者分为对照组、利多卡因-阿鲁卡因乳膏组和利多卡因-阿鲁卡因乳膏加瑞马唑仑组。采用由阿姆斯特丹术前焦虑和信息量表（APAIS）、患者关注点和视觉模拟量表（VAS）组成的问卷来评估患者的焦虑和疼痛。主要结果是 VAS 和焦虑评分的差异。此外，还记录了患者与脊髓麻醉相关的担忧、突发事件和血液动力学指数：结果：预期脊髓麻醉穿刺疼痛为（5.34±0.27）分，脊髓麻醉前焦虑评分为（10.88±0.64）分。VAS评分和APAIS评分之间存在31.3%的统计学意义上的正相关（r=0.313；P=0.003）。与预期的 VAS 评分相比，利多卡因-阿鲁洛卡因乳膏组穿刺时的 VAS 评分下降了 29.7%（3.78± 0.40，P=0.001），利多卡因-阿鲁洛卡因乳膏加瑞咪唑仑组下降了 29.2%（3.75± 0.39，P=0.001）。利多卡因-普鲁卡因乳膏联合或不联合雷马唑仑可降低中度疼痛的比例（21.4% 和 31.3% vs 50.0%，P=0.0001），增加轻度疼痛的比例（60.7% vs 59.4% vs 22.7%，P=0.03）。与麻醉前相比，利多卡因-普鲁卡因乳膏组的焦虑评分降低了 2.84（8.04±0.76 vs 10.88±0.46，P=0.05）。对术后疼痛的担忧（P=0.03）和对针头或干预的恐惧（P=0.000）在麻醉后各组间均有所下降：结论：约有一半计划接受脊髓麻醉的患者在术前有中度焦虑。患者对脊髓麻醉穿刺疼痛的预期为中度，高于实际疼痛。在脊髓麻醉穿刺前使用利多卡因-阿鲁洛卡因乳膏或不使用雷马唑仑镇静剂可降低患者术后的疼痛和焦虑评分。 关键词：术前焦虑；APAIS；脊髓麻醉；利多卡因-阿鲁洛卡因；雷马唑仑
{"title":"The Effect of Lidocaine-Prilocaine Cream Combined with or Without Remimazolam on VAS and APAIS Anxiety Score in Patient Undergoing Spinal Anesthesia","authors":"Shuqing Liang, Shuai Li, Zhao Zhong, Qichen Luo, Cai Nie, Donghua Hu, Yalan Li","doi":"10.2147/dddt.s468486","DOIUrl":"https://doi.org/10.2147/dddt.s468486","url":null,"abstract":"<strong>Purpose:</strong> This study aimed to investigate patients’ expectative pain of spinal anesthesia puncture and anxiety pre-anesthesia, and to examine the effect of lidocaine-prilocaine cream and remimazolam prior to spinal anesthesia puncture on pain relief and anxiety release.<br/><strong>Methods:</strong> Patients undergoing spinal anesthesia were divided into control, lidocaine-prilocaine cream, and lidocaine-prilocaine cream with remimazolam groups. A questionnaire consisting of The Amsterdam Preoperative Anxiety and Information Scale (APAIS) and patient’s concerns and Visual Analog Scale (VAS) was used to evaluate patient’s anxiety and pain. The primary outcomes were differences in VAS and anxiety scores. Patient’s spinal anesthesia-related concerns, advent events and hemodynamic index were also recorded.<br/><strong>Results:</strong> The expected spinal anesthesia puncture pain was 5.34± 0.27 and anxiety scores before spinal anesthesia was 10.88 ± 0.64. A statistically significant positive correlation of 31.3% was detected between VAS and APAIS scores (r = 0.313; P=0.003). The VAS score at the time of puncture decreased by 29.7% (3.78± 0.40, P=0.001) in lidocaine-prilocaine cream group and 29.2% (3.75± 0.39, P=0.001) in lidocaine-prilocaine cream with remimazolam group compared with the expected VAS score. Lidocaine-prilocaine cream combined with or without remimazolam reduced the percentage of moderate pain (21.4% and 31.3% vs 50.0%, P=0.0001) and increased mild pain (60.7% vs 59.4% vs 22.7%, P=0.03). Anxiety score in lidocaine-prilocaine cream group was reduced by 2.84 (8.04± 0.76 vs 10.88 ± 0.46, P=0.05) when compared with pre-anesthesia. Concerns about postoperative pain (P=0.03) and fear of the needle or intervention (P=0.000) both decreased post-anesthesia among groups.<br/><strong>Conclusion:</strong> Approximately half of the patients scheduled for spinal anesthesia experienced a moderate level of preoperative anxiety. The patient’s pain expectation from the spinal anesthesia puncture was moderate, which was higher than the actual pain. Lidocaine-prilocaine cream with or without remimazolam sedative before spinal anesthesia puncture reduced the patient’s pain and anxiety scores after surgery.<br/><br/><strong>Keywords:</strong> preoperative anxiety, APAIS, spinal anesthesia, lidocaine-prilocaine, remimazolam<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141865038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonathan Barratt, Jens Kristensen, Christian Pedersen, Markus Jerling
Abstract: Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO®) and European Medicines Agency (EMA; KINPEYGO®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.
Keywords: drug delivery, biomarkers, pharmacokinetics, GALT
摘要：免疫球蛋白 A 肾病（IgAN）是一种免疫介导的慢性肾病，其特征是半乳糖缺陷免疫球蛋白 A1（Gd-IgA1）在肾脏沉积。IgAN患者体内过多的Gd-IgA1产生于粘膜相关淋巴组织，尤其是回肠远端固有层。Nefecon®是皮质类固醇布地奈德的靶向释放制剂，在III期NefIgArd试验的中期分析中显示蛋白尿临床显著减少，因此成为美国食品药品管理局（FDA；品牌名TARPEYO®）和欧洲药品管理局（EMA；KINPEYGO®）批准的首款治疗药物，用于治疗面临疾病快速进展风险的原发性IgAN患者。在该试验的两年期分析中，估计肾小球滤过率的下降明显减少，因此，FDA 批准 Nefecon 用于减少肾功能损失。Nefecon 专门设计用于将布地奈德输送到回肠远端，选择性地针对肠道相关淋巴组织中过量 Gd-IgA1 的产生。在本综述中，我们介绍了 Nefecon 的特性以及迄今为止证实其局部治疗效果的证据。我们还介绍了在健康参与者中调查奈非康的药代动力学和皮质醇抑制效果的 I 期试验中未发表的证据。这些研究表明，奈非康具有不同于其他布地奈德产品的药代动力学特征，可在回肠远端发挥有针对性的局部作用。现有证据表明，奈非康有选择性免疫调节作用机制，对IgAN患者有直接的疾病调节作用，同时全身暴露和不良反应较低。
{"title":"Insights on Nefecon®, a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy","authors":"Jonathan Barratt, Jens Kristensen, Christian Pedersen, Markus Jerling","doi":"10.2147/dddt.s383138","DOIUrl":"https://doi.org/10.2147/dddt.s383138","url":null,"abstract":"<strong>Abstract:</strong> Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon<sup>®</sup> is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO<sup>®</sup>) and European Medicines Agency (EMA; KINPEYGO<sup>®</sup>) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.<br/><br/><strong>Keywords:</strong> drug delivery, biomarkers, pharmacokinetics, GALT<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141865035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rani Yulifah Elkanawati, Sri Adi Sumiwi, Jutti Levita
Abstract: Insulin resistance (IR) is a complex pathological condition central to metabolic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease, and polycystic ovary syndrome (PCOS). This review evaluates the impact of lipids on insulin resistance (IR) by analyzing findings from human and animal studies. The articles were searched on the PubMed database using two keywords: (1) “Role of Lipids AND Insulin Resistance AND Humans” and (2) “Role of Lipids AND Insulin Resistance AND Animal Models”. Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity, and interventions like metformin and omega-3 fatty acids show potential benefits. In animal models, high-fat diets disrupt insulin signaling and increase inflammation, with lipid mediators such as diacylglycerol (DAG) and ceramides playing significant roles. DAG activates protein kinase C, which eventually impairs insulin signaling, while ceramides inhibit Akt/PKB, further contributing to IR. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies for IR-related diseases.
{"title":"Impact of Lipids on Insulin Resistance: Insights from Human and Animal Studies","authors":"Rani Yulifah Elkanawati, Sri Adi Sumiwi, Jutti Levita","doi":"10.2147/dddt.s468147","DOIUrl":"https://doi.org/10.2147/dddt.s468147","url":null,"abstract":"<strong>Abstract:</strong> Insulin resistance (IR) is a complex pathological condition central to metabolic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease, and polycystic ovary syndrome (PCOS). This review evaluates the impact of lipids on insulin resistance (IR) by analyzing findings from human and animal studies. The articles were searched on the PubMed database using two keywords: (1) “Role of Lipids AND Insulin Resistance AND Humans” and (2) “Role of Lipids AND Insulin Resistance AND Animal Models”. Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity, and interventions like metformin and omega-3 fatty acids show potential benefits. In animal models, high-fat diets disrupt insulin signaling and increase inflammation, with lipid mediators such as diacylglycerol (DAG) and ceramides playing significant roles. DAG activates protein kinase C, which eventually impairs insulin signaling, while ceramides inhibit Akt/PKB, further contributing to IR. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies for IR-related diseases.<br/><br/><strong>Keywords:</strong> high-fat diet, insulin resistance, lipid profile, type 2 diabetes mellitus<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141864744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maha Abdullah Alwaili, Abdallah H Elhoby, Norhan M El-Sayed, Islam Z Mahmoud, Afaf Alharthi, Mohammad El-Nablaway, Dina M Khodeer
Introduction: This comprehensive study investigated the therapeutic potential of α-asarone in mitigating myocardial oxidative damage, primarily induced by hexavalent chromium (Cr(VI)) exposure in mice. Methods: In this experiment, 24 mice were divided into four groups to assess the cardioprotective role of α-asarone. The study focused on two treatment groups, receiving 25 mg and 50 mg of α-asarone, respectively. These groups were compared against a control group subjected to Cr(VI) without α-asarone treatment, and a normal control negative group. The key biochemical parameters evaluated included serum levels of Creatine Kinase-MB (CK-MB) and Troponin I, markers indicative of myocardial damage. Additionally, the levels of Malondialdehyde (MDA) were measured to assess lipid peroxidation, alongside the evaluation of key inflammatory biomarkers in cardiac tissue homogenates, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). Results Remarkably, α-asarone treatment resulted in a significant reduction in these markers compared to the control group. The treatment also elevated the activity of cardinal antioxidant enzymes like catalase (CAT) and superoxide dismutase (SOD), and reduced the glutathione (GSH). Furthermore, a notable upregulation of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) in cardiac tissue homogenates was observed, highlighting a potential pathway through which α-asarone exerts its protective effects. Histopathological analysis of cardiac tissues revealed that α-asarone ameliorated the structural lesions induced by Cr(VI). The study thus provides substantial evidence that α-asarone ameliorates Cr(VI)-induced cardiotoxicity through a multifaceted approach. It enhances cardiac enzyme function, modulates free radical generation, improves antioxidant status, and mitigates histopathological damage in cardiac tissues. Given these findings, α-asarone emerges as a promising agent against Cr(VI)-induced myocardial injury. Purpose: This study paves the way for further research into the cardioprotective properties of α-asarone and its potential application in clinical settings by specifically exploring the protective efficacy of α-asarone against Cr(VI)-induced cardiotoxicity and delineating the underlying biochemical and molecular mechanisms involved.
{"title":"Cardioprotective Effects of α-Asarone Against Hexavalent Chromium-Induced Oxidative Damage in Mice","authors":"Maha Abdullah Alwaili, Abdallah H Elhoby, Norhan M El-Sayed, Islam Z Mahmoud, Afaf Alharthi, Mohammad El-Nablaway, Dina M Khodeer","doi":"10.2147/dddt.s464334","DOIUrl":"https://doi.org/10.2147/dddt.s464334","url":null,"abstract":"<strong>Introduction:</strong> This comprehensive study investigated the therapeutic potential of α-asarone in mitigating myocardial oxidative damage, primarily induced by hexavalent chromium (Cr(VI)) exposure in mice.<br/><strong>Methods:</strong> In this experiment, 24 mice were divided into four groups to assess the cardioprotective role of α-asarone. The study focused on two treatment groups, receiving 25 mg and 50 mg of α-asarone, respectively. These groups were compared against a control group subjected to Cr(VI) without α-asarone treatment, and a normal control negative group. The key biochemical parameters evaluated included serum levels of Creatine Kinase-MB (CK-MB) and Troponin I, markers indicative of myocardial damage. Additionally, the levels of Malondialdehyde (MDA) were measured to assess lipid peroxidation, alongside the evaluation of key inflammatory biomarkers in cardiac tissue homogenates, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). <strong>Results</strong> Remarkably, α-asarone treatment resulted in a significant reduction in these markers compared to the control group. The treatment also elevated the activity of cardinal antioxidant enzymes like catalase (CAT) and superoxide dismutase (SOD), and reduced the glutathione (GSH). Furthermore, a notable upregulation of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) in cardiac tissue homogenates was observed, highlighting a potential pathway through which α-asarone exerts its protective effects. Histopathological analysis of cardiac tissues revealed that α-asarone ameliorated the structural lesions induced by Cr(VI). The study thus provides substantial evidence that α-asarone ameliorates Cr(VI)-induced cardiotoxicity through a multifaceted approach. It enhances cardiac enzyme function, modulates free radical generation, improves antioxidant status, and mitigates histopathological damage in cardiac tissues. Given these findings, α-asarone emerges as a promising agent against Cr(VI)-induced myocardial injury.<br/><strong>Purpose:</strong> This study paves the way for further research into the cardioprotective properties of α-asarone and its potential application in clinical settings by specifically exploring the protective efficacy of α-asarone against Cr(VI)-induced cardiotoxicity and delineating the underlying biochemical and molecular mechanisms involved.<br/><br/><strong>Keywords:</strong> α-asarone, chromium, mice, cardiotoxicity, oxidative stress, histopathological studies<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141865040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose:Alisma orientale (AO, Alisma orientale (Sam). Juzep) has been widely employed for the treatment of macular edema (ME) in traditional Chinese medicine due to its renowned water-relief properties. Nonetheless, the comprehensive investigation of AO in alleviating ME remained unexplored. This study aims to identify the active components of AO that target the eye and investigate its pharmacological effects and mechanisms on ME. Methods: The study commenced with UPLC-Triple-TOF/MS analysis to identify the primary constituents of AO. Zebrafish eye tissues were then analyzed after a five-day administration of AO to detect absorbed components and metabolites. Subsequently, network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict the mechanisms of ME treatment via biological target pathways. In vivo experiments were conducted to corroborate the pharmacological actions and mechanisms. Results: A total of 7 compounds, consisting of 2 prototype ingredients and 5 metabolites (including isomers), were found to traverse the blood-eye barrier and localized within eye tissues. Network pharmacology results showed that AO played a role in the treatment of ME mainly by regulating the pathway network of PI3K-AKT and MAPK with TNF-α centered. Computational analyses suggested that 11-dehydro-16-oxo-24-deoxy-alisol A, a metabolite of alisol A, mitigates edema through TNF-α inhibition. Furthermore, zebrafish fundus confocal experiments and HE staining of eyes confirmed the attenuating effects of alisol A on fundus angiogenesis and ocular edema, representing the first report of AO’s ME-inhibitory effects. Conclusion: In this study, computational analyses with experimental validation were used to understand the biological activity and mechanism of alisol A in the treatment of ME. The findings shed light on the bioactive constituents and pharmacological actions of AO, offering valuable insights and a theoretical foundation for its clinical application in managing ME.
目的：东方泽泻（AO，Alisma orientale (Sam).Juzep）具有显著的利水作用，在传统中医中被广泛用于治疗黄斑水肿（ME）。然而，对东方鸢尾在缓解黄斑水肿方面作用的全面研究仍处于空白状态。本研究旨在确定 AO 中针对眼部的活性成分，并研究其对 ME 的药理作用和机制：研究首先通过UPLC-Triple-TOF/MS分析鉴定AO的主要成分。然后对斑马鱼眼组织进行为期五天的 AO 给药后分析，以检测吸收的成分和代谢物。随后，利用网络药理学、分子对接和分子动力学模拟来预测通过生物靶途径治疗 ME 的机制。为了证实药理作用和机制，还进行了体内实验：结果：共发现 7 种化合物（包括 2 种原型成分和 5 种代谢物（包括异构体））可穿过血眼屏障并在眼组织内定位。网络药理学结果表明，AO主要通过调节以TNF-α为中心的PI3K-AKT和MAPK通路网络在治疗ME中发挥作用。计算分析表明，秋水仙素A的代谢产物11-脱氢-16-氧代-24-脱氧-秋水仙素A可通过抑制TNF-α减轻水肿。此外，斑马鱼眼底共聚焦实验和眼球 HE 染色证实了泽泻醇 A 对眼底血管生成和眼部水肿的抑制作用，这是首次报道 AO 的 ME 抑制作用：本研究通过计算分析和实验验证，了解了泽泻醇 A 治疗 ME 的生物活性和机制。研究结果揭示了AO的生物活性成分和药理作用，为其临床应用于治疗ME提供了宝贵的见解和理论基础。关键词东方泽兰 黄斑水肿 网络药理学 斑马鱼 TNF-α
{"title":"Alisol A, the Eye-Entering Ingredient of Alisma orientale, Relieves Macular Edema Through TNF-α as Revealed by UPLC-Triple-TOF/MS, Network Pharmacology, and Zebrafish Verification","authors":"Rui Shen, Kebin Cheng, Guanyi Li, Zhendong Pan, Xijier Qiaolongbatu, Yuting Wang, Cui Ma, Xucong Huang, Li Wang, Wenjing Li, Yuanyuan Wang, Lili Jing, Guorong Fan, Zhenghua Wu","doi":"10.2147/dddt.s468119","DOIUrl":"https://doi.org/10.2147/dddt.s468119","url":null,"abstract":"<strong>Purpose:</strong> <em>Alisma orientale</em> (AO, <em>Alisma orientale</em> (Sam). Juzep) has been widely employed for the treatment of macular edema (ME) in traditional Chinese medicine due to its renowned water-relief properties. Nonetheless, the comprehensive investigation of AO in alleviating ME remained unexplored. This study aims to identify the active components of AO that target the eye and investigate its pharmacological effects and mechanisms on ME.<br/><strong>Methods:</strong> The study commenced with UPLC-Triple-TOF/MS analysis to identify the primary constituents of AO. Zebrafish eye tissues were then analyzed after a five-day administration of AO to detect absorbed components and metabolites. Subsequently, network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict the mechanisms of ME treatment via biological target pathways. In vivo experiments were conducted to corroborate the pharmacological actions and mechanisms.<br/><strong>Results:</strong> A total of 7 compounds, consisting of 2 prototype ingredients and 5 metabolites (including isomers), were found to traverse the blood-eye barrier and localized within eye tissues. Network pharmacology results showed that AO played a role in the treatment of ME mainly by regulating the pathway network of PI3K-AKT and MAPK with TNF-α centered. Computational analyses suggested that 11-dehydro-16-oxo-24-deoxy-alisol A, a metabolite of alisol A, mitigates edema through TNF-α inhibition. Furthermore, zebrafish fundus confocal experiments and HE staining of eyes confirmed the attenuating effects of alisol A on fundus angiogenesis and ocular edema, representing the first report of AO’s ME-inhibitory effects.<br/><strong>Conclusion:</strong> In this study, computational analyses with experimental validation were used to understand the biological activity and mechanism of alisol A in the treatment of ME. The findings shed light on the bioactive constituents and pharmacological actions of AO, offering valuable insights and a theoretical foundation for its clinical application in managing ME. <br/><br/><strong>Keywords:</strong> <em>Alisma orientale</em>, macular edema, network pharmacology, zebrafish, TNF-α<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141864868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children. Methods: This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics. Results: Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae, including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, P = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery (P = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection (P = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics. Conclusion: CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery.
{"title":"Ceftazidime-Avibactam as a Salvage Treatment for Severely Infected Immunosuppressed Children","authors":"Lvchang Zhu, Qiongyao Hu, Lijun Liu, Sheng Ye","doi":"10.2147/dddt.s467967","DOIUrl":"https://doi.org/10.2147/dddt.s467967","url":null,"abstract":"<strong>Background:</strong> Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children.<br/><strong>Methods:</strong> This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics.<br/><strong>Results:</strong> Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly <em>Pseudomonas aeruginosa</em> and <em>Klebsiella pneumoniae</em>, including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, <em>P</em> = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery (<em>P</em> = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection (<em>P</em> = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics.<br/><strong>Conclusion:</strong> CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery.<br/><br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141865039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: This study explored the effects of different doses of remimazolam tosilate (RT) and propofol combined with remifentanil anesthesia on hemodynamic and inflammatory responses in patients undergoing laparoscopic surgery. Subjects and Methods: Ninety patients with a BMI of less than 35 kg/m², classified as ASA II–III and scheduled for laparoscopic surgery, were enrolled in this study. Patients were divided into three groups: low-dose RT group (A), high-dose RT group (B), and propofol group (C). The changes in hemodynamic indices such as SBP, DBP, HR, MAP, and inflammatory response indices such as IL-6, SAA, CRP, and PCT, along with extubation time and doses of sufentanil, remifentanil, urapidil, and phenylephrine, were compared among the three groups. Results: There were no statistically significant differences in extubation time, doses of sufentanil and remifentanil, or the usage rates and average doses of urapidil and phenylephrine between the three groups. The average dose of phenylephrine in group A was lower than in group B and group C, with a statistically significant difference. There were no statistically significant differences among the groups in SBP, DBP, HR, and MAP from T0 to T2, nor in IL-6, SAA, CRP, or PCT levels. Conclusion: Using RT for induction and maintenance of anesthesia in laparoscopic surgery ensures stable hemodynamic and inflammatory responses in patients. Low-dose RT may reduce the usage rate and dose of vasopressors such as phenylephrine during surgery.
{"title":"Effects of Propofol, Low and High Doses of Remimazolam on Hemodynamic and Inflammatory Response in Laparoscopic Surgery","authors":"Wenguang Deng, Zhiming Zeng, Qingyan Liu, Jingjing Deng, Liyu Wang, Hui Li, Yuenong Zhang","doi":"10.2147/dddt.s459885","DOIUrl":"https://doi.org/10.2147/dddt.s459885","url":null,"abstract":"<strong>Background:</strong> This study explored the effects of different doses of remimazolam tosilate (RT) and propofol combined with remifentanil anesthesia on hemodynamic and inflammatory responses in patients undergoing laparoscopic surgery.<br/><strong>Subjects and Methods:</strong> Ninety patients with a BMI of less than 35 kg/m², classified as ASA II–III and scheduled for laparoscopic surgery, were enrolled in this study. Patients were divided into three groups: low-dose RT group (A), high-dose RT group (B), and propofol group (C). The changes in hemodynamic indices such as SBP, DBP, HR, MAP, and inflammatory response indices such as IL-6, SAA, CRP, and PCT, along with extubation time and doses of sufentanil, remifentanil, urapidil, and phenylephrine, were compared among the three groups.<br/><strong>Results:</strong> There were no statistically significant differences in extubation time, doses of sufentanil and remifentanil, or the usage rates and average doses of urapidil and phenylephrine between the three groups. The average dose of phenylephrine in group A was lower than in group B and group C, with a statistically significant difference. There were no statistically significant differences among the groups in SBP, DBP, HR, and MAP from T0 to T2, nor in IL-6, SAA, CRP, or PCT levels.<br/><strong>Conclusion:</strong> Using RT for induction and maintenance of anesthesia in laparoscopic surgery ensures stable hemodynamic and inflammatory responses in patients. Low-dose RT may reduce the usage rate and dose of vasopressors such as phenylephrine during surgery.<br/><br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Zhu, Meiling Chen, Chuangzan Yang, Geng Lu, Sa Huang, Meili Chen, Yufei Wang, Junfeng Ban
Purpose: Oral drug administration is the most common and convenient route, offering good patient compliance but drug solubility limits oral applications. Celecoxib, an insoluble drug, requires continuous high-dose oral administration, which may increase cardiovascular risk. The nanostructured lipid carriers prepared from drugs and lipid excipients can effectively improve drug bioavailability, reduce drug dosage, and lower the risk of adverse reactions. Methods: In this study, we prepared hyaluronic acid-modified celecoxib nanostructured lipid carriers (HA-NLCs) to improve the bioavailability of celecoxib and reduce or prevent adverse drug reactions. Meanwhile, we successfully constructed a set of FDA-compliant biological sample test methods to investigate the pharmacokinetics of HA-NLCs in rats. Results: The pharmacokinetic analysis confirmed that HA-NLCs significantly enhanced drug absorption, resulting in an AUC0-t 1.54 times higher than the reference formulation (Celebrex®). Moreover, compared with unmodified nanostructured lipid carriers (CXB-NLCs), HA-NLCs enhance the retention time and improve the drug’s half-life in vivo. Conclusion: HA-NLCs significantly increased the bioavailability of celecoxib. The addition of hyaluronic acid prolonged the drug’s in vivo duration of action and reduced the risk of cardiovascular adverse effects associated with the frequent administration of oral celecoxib.
{"title":"Revealing Changes in Celecoxib Nanostructured Lipid Carrier’s Bioavailability Using Hyaluronic Acid as an Enhancer by HPLC-MS/MS","authors":"Yi Zhu, Meiling Chen, Chuangzan Yang, Geng Lu, Sa Huang, Meili Chen, Yufei Wang, Junfeng Ban","doi":"10.2147/dddt.s461969","DOIUrl":"https://doi.org/10.2147/dddt.s461969","url":null,"abstract":"<strong>Purpose:</strong> Oral drug administration is the most common and convenient route, offering good patient compliance but drug solubility limits oral applications. Celecoxib, an insoluble drug, requires continuous high-dose oral administration, which may increase cardiovascular risk. The nanostructured lipid carriers prepared from drugs and lipid excipients can effectively improve drug bioavailability, reduce drug dosage, and lower the risk of adverse reactions.<br/><strong>Methods:</strong> In this study, we prepared hyaluronic acid-modified celecoxib nanostructured lipid carriers (HA-NLCs) to improve the bioavailability of celecoxib and reduce or prevent adverse drug reactions. Meanwhile, we successfully constructed a set of FDA-compliant biological sample test methods to investigate the pharmacokinetics of HA-NLCs in rats.<br/><strong>Results:</strong> The pharmacokinetic analysis confirmed that HA-NLCs significantly enhanced drug absorption, resulting in an <em>AUC<sub>0-t</sub></em> 1.54 times higher than the reference formulation (Celebrex<sup>®</sup>). Moreover, compared with unmodified nanostructured lipid carriers (CXB-NLCs), HA-NLCs enhance the retention time and improve the drug’s half-life in vivo.<br/><strong>Conclusion:</strong> HA-NLCs significantly increased the bioavailability of celecoxib. The addition of hyaluronic acid prolonged the drug’s in vivo duration of action and reduced the risk of cardiovascular adverse effects associated with the frequent administration of oral celecoxib. <br/><br/><strong>Keywords:</strong> nanostructured lipid carriers, celecoxib, HPLC-MS/MS, pharmacokinetics<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141864859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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