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Ground Salicornia herbacea Powder Suppresses AOM/DSS-induced Colon Cancer by Inhibiting Wnt/β-catenin Signaling and Nrf2. 研磨的沙棘草粉通过抑制 Wnt/β-catenin 信号转导和 Nrf2 抑制 AOM/DSS 诱导的结肠癌
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 Epub Date: 2024-10-21 DOI: 10.1007/s11095-024-03784-1
Yeonoh Cho, Ji Hyeon Cha, Yujin Hwang, Hee-Taik Kang, Jong Hun Lee

Purpose: This study aims to evaluate the effects of prebiotics and probiotics on colorectal cancer (CRC) progression in an AOM/DSS-induced mouse model.

Methods: In AOM/DSS-induced mouse model, treatment groups received either S. herbacea as a prebiotic (PRE) or in combination with Lactobacillus plantarum as a probiotic (PRO). PCNA, Ki-67, β-catenin, c-Myc, and Nrf2 were evaluated using immunohistochemistry (IHC). The impact on polyp formation and progression was assessed by categorizing polyps according to their size.

Results: Both PRE and PRO treatments resulted in a significant reduction in large polyp formation when compared to AOM/DSS induced control group. IHC analyses demonstrated reduced biomarker expression for cell proliferation in PRE and PRO groups, specifically showing decreased staining for PCNA, Ki-67, β-catenin, and c-Myc, indicating downregulation of Wnt signaling and suppressed cell proliferation. Reduced Nrf2 expression highlights the impact of treatments interfering with cancer cell defenses. Notably, there were no significant differences in the outcomes between PRE and PRO groups, suggesting that prebiotics show anticancer effects.

Conclusion: The study suggests that S. herbacea, a prebiotic, effectively suppresses CRC progression, with limited additional benefits from combining with probiotics. These findings underscore the therapeutic potential of prebiotics in CRC.

目的:本研究旨在评估益生元和益生菌对AOM/DSS诱导的小鼠模型中结直肠癌(CRC)进展的影响:方法:在AOM/DSS诱导的小鼠模型中,治疗组接受草本酵母作为益生菌(PRE)或与植物乳杆菌联合作为益生菌(PRO)。采用免疫组织化学(IHC)方法对 PCNA、Ki-67、β-catenin、c-Myc 和 Nrf2 进行了评估。根据息肉的大小进行分类,评估其对息肉形成和发展的影响:结果:与AOM/DSS诱导的对照组相比,PRE和PRO治疗均显著减少了大息肉的形成。IHC分析表明,PRE和PRO组细胞增殖的生物标志物表达减少,特别是PCNA、Ki-67、β-catenin和c-Myc的染色减少,表明Wnt信号下调,细胞增殖受到抑制。Nrf2 表达的减少凸显了干扰癌细胞防御功能的治疗所产生的影响。值得注意的是,PRE 组和 PRO 组的结果没有明显差异,这表明益生元具有抗癌作用:研究表明,益生菌 S. herbacea 能有效抑制 CRC 的进展,与益生菌结合使用能带来的额外益处有限。这些发现强调了益生元对 CRC 的治疗潜力。
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引用次数: 0
Chemical Distribution Uniformity Assessment of "Intra-Tablet" by Hyperspectral Raman Imaging Analysis. 通过高光谱拉曼成像分析评估 "药片内 "的化学分布均匀性
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 Epub Date: 2024-11-06 DOI: 10.1007/s11095-024-03778-z
Ningyun Sun, Jing Zhang, Mingtao Guo, Yibin Mao, Wei Wu, Yi Lu

Purpose: This study aimed to develop a new index, Distribution Uniformity Index (DUI), to assess the "intra-tablet" homogeneity.

Methods: High-resolution hyperspectral Raman imaging was adopted to scan a tablet to get the components' distribution. The heuristic algorithm was applied to generate a Raman heatmap with RGB colors quantitatively correlated with the concentrations of each component. DUI is defined as the ratio of the area under the uniformity curve of the sample image to that of the randomized image. The accuracy and applicability of DUI were verified by constructing model images with controlled uniformity and random regions. The effects of "intra-tablet" homogeneity on the disintegration and dissolution of spironolactone tablets were investigated.

Results: DUI value was directly obtained from heuristic visual analysis of macro-pixel from hyperspectral Raman images. A good linear relationship and good repeatability were confirmed between DUI and the uniformity of model images. The size of CaSO4·2H2O affected the "intra-tablet" homogeneity of spironolactone tablets, which was detected by the DUI value. The better "intra-tablet" homogeneity led to a higher disintegration and dissolution of spironolactone tablets.

Conclusions: DUI represents a novel index to evaluate the "intra-tablet" homogeneity and is beneficial for formulation research and development.

目的:本研究旨在开发一种新的指数--分布均匀性指数(DUI),以评估 "片剂内部 "的均匀性。方法:采用高分辨率高光谱拉曼成像技术扫描片剂,以获得各成分的分布情况。采用启发式算法生成拉曼热图,其 RGB 颜色与各成分的浓度定量相关。DUI 的定义是样品图像均匀性曲线下的面积与随机图像均匀性曲线下的面积之比。通过构建具有受控均匀性和随机区域的模型图像,验证了 DUI 的准确性和适用性。研究了 "片内 "均匀性对螺内酯片崩解和溶出的影响:通过对高光谱拉曼图像中的宏观像素进行启发式视觉分析,直接获得了 DUI 值。结果表明,DUI 值与模型图像的均匀性之间具有良好的线性关系和可重复性。CaSO4-2H2O 的大小会影响螺内酯片剂的 "片内 "均匀性,这一点可通过 DUI 值检测出来。片内 "均匀性越好,螺内酯片的崩解和溶解度就越高:结论:DUI 是评价 "片内 "均一性的新指标,有利于制剂的研究和开发。
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引用次数: 0
Pharmacological Innovations in Space: Challenges and Future Perspectives. 太空药理学创新:挑战与未来展望》。
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 Epub Date: 2024-11-12 DOI: 10.1007/s11095-024-03788-x
Zinnet Şevval Aksoyalp, Aybala Temel, Merve Karpuz

Purpose: Since the first human experience in space, the interest in space research and medicine to explore universe is growing day by day. The extreme space conditions mainly radiation and microgravity effects on human physiology, antimicrobial susceptibility, and efficacy, safety, and stability of drugs. Therefore, the aim of this review is to address the impact of extreme space conditions, mainly microgravity and radiation, on human physiology and highlights the need for future approaches by evaluating the effectiveness of strategies to prevent or mitigate health problems.

Methods: Published papers and NASA technical documents were searched in Pubmed and Google Scholar databases using the keywords ''antimicrobial susceptibility or drug resistance or drug stability or innovations or pharmacokinetic or pharmacodynamics'' and ''radiation or microgravity or space environments or space medicine or space pharmacy'' to prepare this review.

Results: In this review, the challenges regarding physiological effects and drug-related problems are examined through the evaluation of extreme conditions in space. Medications used in spaceflight are summarized, and the role of pharmacists specializing in space medicine is briefly explained. Last but not least, to overcome the aforementioned issues, novel approaches have been addressed, such as personalised treatments, development of space-resistant formulations and various microbial applications.

Conclusions: Further research in the space medicine is required to facilitate the safe and healthy travel of humans to the Moon, Mars and other extraterrestrial destinations. One bear in mind that space research will contribute not only to the exploration of the universe, but also to the advancement of health and technological discoveries on Earth.

目的:自人类首次进入太空以来,人们对太空研究和探索宇宙的医学兴趣与日俱增。以辐射和微重力为主的极端空间条件对人体生理、抗菌药敏感性以及药物的有效性、安全性和稳定性都有影响。因此,本综述旨在探讨极端太空条件(主要是微重力和辐射)对人体生理的影响,并通过评估预防或减轻健康问题的策略的有效性,强调未来方法的必要性:方法:在 Pubmed 和 Google Scholar 数据库中使用关键词"'抗菌素敏感性或耐药性或药物稳定性或创新或药代动力学或药效学'"和"'辐射或微重力或太空环境或太空医学或太空药学'"检索已发表的论文和 NASA 技术文档,以编写本综述:在这篇综述中,通过对太空极端条件的评估,研究了有关生理效应和药物相关问题的挑战。总结了太空飞行中使用的药物,并简要说明了太空医学专业药剂师的作用。最后但并非最不重要的一点是,为了克服上述问题,还探讨了一些新方法,如个性化治疗、开发抗太空制剂和各种微生物应用:为促进人类安全健康地前往月球、火星和其他地外目的地,需要进一步开展太空医学研究。要知道,太空研究不仅有助于探索宇宙,还有助于促进地球上的健康和技术发现。
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引用次数: 0
The Current State of Biotransformation Science - Industry Survey of In Vitro and In Vivo Practices, Clinical Translation, and Future Trends. 生物转化科学的现状--体外和体内实践、临床转化和未来趋势的行业调查。
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 Epub Date: 2024-11-04 DOI: 10.1007/s11095-024-03787-y
John P Savaryn, Kevin Coe, Matthew A Cerny, Kevin Colizza, Patricia Moliner, Lloyd King, Bin Ma, Jim Atherton, Adam Auclair, Mark T Cancilla, Marsha Eno, Ulrik Jurva, Qin Yue, Sean Xiaochun Zhu, Elyse Freiberger, Guo Zhong, Ben Barlock, Jonny Nachtigall, Laurent Laboureur, Sandeepraj Pusalkar, Runcong Guo, Michael Niehues, Simon Hauri, Ester Tor Carreras, Christine Maurer, Chandra Prakash, Gary J Jenkins

Embedded within the field of drug metabolism and pharmacokinetics (DMPK), biotransformation is a discipline that studies the origins, disposition, and structural identity of metabolites to provide a comprehensive safety assessment, including the assessment of exposure coverage in toxicological species. Spanning discovery and development, metabolite identification (metID) scientists employ various strategies and tools to address stage-specific questions aimed at guiding the maturation of early chemical matter into drug candidates. During this process, the identity of major (and minor) circulating human metabolites is ascertained to comply with the regulatory requirements such as the Metabolites in Safety Testing (MIST) guidance. Through the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the "Translatability of MetID In Vitro Systems Working Group" was created within the Translational and ADME Sciences Leadership Group. The remit of this group was to objectively determine how accurate commonly employed in vitro systems have been with respect to prediction of circulating human metabolites, both qualitatively and quantitatively. A survey composed of 34 questions was conducted across 26 pharmaceutical companies to obtain a foundational understanding of current metID practices, preclinically and clinically, as well as to provide perspective on how successful these practices have been at predicting circulating human metabolites. The results of this survey are presented as an initial snapshot of current industry-based metID practices, including our perspective on how a harmonized framework for the conduct of in vitro metID studies could be established. Future perspectives from current practices to emerging advances with greater translational capability are also provided.

生物转化是药物代谢和药代动力学(DMPK)领域的一门学科,它研究代谢物的来源、处置和结构特性,以提供全面的安全性评估,包括评估毒理学物种的暴露范围。代谢物鉴定(metID)科学家横跨发现和开发两个阶段,采用各种策略和工具来解决特定阶段的问题,旨在指导早期化学物质成熟为候选药物。在此过程中,要确定主要(和次要)循环人体代谢物的身份,以符合法规要求,如安全测试中的代谢物(MIST)指南。通过国际药品开发创新和质量联合会(IQ),在转化和 ADME 科学领导小组内成立了 "MetID 体外系统可转化性工作组"。该工作组的任务是客观确定常用体外系统在定性和定量预测人体循环代谢物方面的准确性。该小组对 26 家制药公司进行了一项包含 34 个问题的调查,以获得对当前临床前和临床中的代谢物检测方法的基本了解,并透视这些方法在预测人体循环代谢物方面的成功程度。本次调查的结果是对当前基于行业的 metID 实践的初步概括,包括我们对如何建立体外 metID 研究统一框架的看法。此外还提供了从当前实践到具有更大转化能力的新兴进展的未来展望。
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引用次数: 0
Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer. 开发用于脉冲式释放多肽和渗透促进剂的三维打印两室囊式装置
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 DOI: 10.1007/s11095-024-03785-0
Pengchong Xu, Hanh Thuy Nguyen, Siyuan Huang, Huyen Tran

Objective: The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10).

Methods: 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS.

Results: A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5 mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices.

Conclusion: These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

目的:多肽的口服吸收是由胃肠道中高浓度的渗透促进剂(PE)驱动的。我们假设,从固体制剂中控制 PE 和肽的释放,使 PE 和肽保持有效的共定位浓度,可以促进口服肽的吸收。本研究旨在开发一种三维打印的两室胶囊装置,可控制肽和癸酸钠(C10)的脉动释放。方法:采用熔融沉积建模方法制造了三维打印双室囊式装置,然后在该装置中填充 LY 肽和 C10。通过改变胶囊装置的厚度和聚合物类型来调节释放曲线。USP 仪器 II 溶解试验用于评估装置厚度和聚合物选择对体外释放曲线的影响。然后用 HPMCAS 对最佳装置进行肠溶包衣:结果:观察到胶囊装置的厚度与释放开始时间的延迟之间存在很强的线性关系。装置厚度增加或使用聚乳酸会降低释放率。第 1 区、第 2 区和栅栏厚度分别为 0.4、0.95 和 0.5 毫米的胶囊装置以及 PVA 的使用都能达到理想的多肽和 C10 脉动释放曲线。此外,使用 HPMCAS 的肠溶胶囊装置与非肠溶胶囊装置相比,具有相似的脉动释放曲线:这些研究结果表明,三维打印技术在复杂改性药物释放产品的配方开发中具有潜在的应用价值。
{"title":"Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.","authors":"Pengchong Xu, Hanh Thuy Nguyen, Siyuan Huang, Huyen Tran","doi":"10.1007/s11095-024-03785-0","DOIUrl":"10.1007/s11095-024-03785-0","url":null,"abstract":"<p><strong>Objective: </strong>The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10).</p><p><strong>Methods: </strong>3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS.</p><p><strong>Results: </strong>A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5 mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices.</p><p><strong>Conclusion: </strong>These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2259-2270"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An Update on Recent Drug Delivery Systems Targeting Brain Diseases via the Transnasal Pathway. 经鼻途径治疗脑部疾病的最新药物输送系统。
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-11-01 Epub Date: 2024-10-30 DOI: 10.1007/s11095-024-03790-3
Huiying Zeng, Huangjie Lu, Jie Yang, Ping Hu

Objective: To explore the potential of transnasal drug delivery systems (DDS) as an effective means of bypassing the bloodbrain barrier (BBB) for enhanced central nervous system (CNS) targeting, aiming to improve therapeutic outcomes for CNS disorders while reducing systemic side effects.

Methods: A review of current and emerging DDS technologies, including polymer nanoparticles, liposomes, and micelles, was conducted to assess their suitability for precision-targeted delivery to the brain through the transnasal route.

Results: The investigated DDS demonstrate promising capabilities for CNS targeting via the nasal pathway, effectively preserving both the nasal mucosa and CNS integrity. These systems enhance drug precision within neural tissues, potentially improving therapeutic outcomes without harming adjacent tissues.

Conclusions: Transnasal DDS offer a promising alternative to traditional delivery methods, with significant potential to advance the treatment of cerebrovascular diseases, neurodegenerative disorders, brain tumors, and psychiatric conditions. This approach represents an evolving frontier in neurotherapeutics, with the potential to transform CNS drug delivery practices.

目的探索经鼻给药系统(DDS)作为绕过血脑屏障(BBB)增强中枢神经系统(CNS)靶向性的有效手段的潜力,旨在改善中枢神经系统疾病的治疗效果,同时减少全身副作用:方法:对当前和新兴的 DDS 技术(包括聚合物纳米颗粒、脂质体和胶束)进行了综述,以评估它们是否适合通过经鼻途径向大脑进行精确靶向递送:结果:所研究的 DDS 展示了通过鼻腔途径靶向中枢神经系统的良好能力,有效地保护了鼻粘膜和中枢神经系统的完整性。这些系统提高了神经组织内的药物精确度,有可能在不损害邻近组织的情况下改善治疗效果:经鼻 DDS 为传统给药方法提供了一种前景广阔的替代方法,在推动脑血管疾病、神经退行性疾病、脑肿瘤和精神疾病的治疗方面潜力巨大。这种方法代表了神经治疗学不断发展的前沿,有可能改变中枢神经系统给药方法。
{"title":"An Update on Recent Drug Delivery Systems Targeting Brain Diseases via the Transnasal Pathway.","authors":"Huiying Zeng, Huangjie Lu, Jie Yang, Ping Hu","doi":"10.1007/s11095-024-03790-3","DOIUrl":"10.1007/s11095-024-03790-3","url":null,"abstract":"<p><strong>Objective: </strong>To explore the potential of transnasal drug delivery systems (DDS) as an effective means of bypassing the bloodbrain barrier (BBB) for enhanced central nervous system (CNS) targeting, aiming to improve therapeutic outcomes for CNS disorders while reducing systemic side effects.</p><p><strong>Methods: </strong>A review of current and emerging DDS technologies, including polymer nanoparticles, liposomes, and micelles, was conducted to assess their suitability for precision-targeted delivery to the brain through the transnasal route.</p><p><strong>Results: </strong>The investigated DDS demonstrate promising capabilities for CNS targeting via the nasal pathway, effectively preserving both the nasal mucosa and CNS integrity. These systems enhance drug precision within neural tissues, potentially improving therapeutic outcomes without harming adjacent tissues.</p><p><strong>Conclusions: </strong>Transnasal DDS offer a promising alternative to traditional delivery methods, with significant potential to advance the treatment of cerebrovascular diseases, neurodegenerative disorders, brain tumors, and psychiatric conditions. This approach represents an evolving frontier in neurotherapeutics, with the potential to transform CNS drug delivery practices.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2121-2141"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacokinetic Study of Fingolimod Nasal Films Administered via Nose-to-Brain Route in C57BL/6 J Mice as Potential Treatment for Multiple Sclerosis. 芬戈莫德鼻膜经鼻入脑途径给药 C57BL/6 J 小鼠作为多发性硬化症潜在治疗方法的药代动力学研究
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-10-01 Epub Date: 2024-10-29 DOI: 10.1007/s11095-024-03745-8
Paraskevi Papakyriakopoulou, Evangelos Balafas, Nikolaos Kostomitsopoulos, Dimitrios M Rekkas, Kumlesh K Dev, Georgia Valsami

Background: Fingolimod hydrochloride (FH) has emerged as a vital medication for managing Multiple Sclerosis (MS). Despite its high oral bioavailability of 93%, it is plagued by slow oral absorption (Tmax = 8-12 h) and extensive hepatic metabolism. Intranasal administration has emerged as an alternative to address these limitations, ensuring efficient central nervous system delivery and minimizing peripheral exposure and first-pass metabolism.

Objective: This study aims to develop and evaluate FH nasal films for enhanced drug delivery.

Methods: A Design of Experiments approach was employed to formulate FH nasal films, utilizing HPMC E50 as a film-forming polymer, PEG 400 as a plasticizer, and Me-β-CD as a permeation enhancer. Two formulations with superior in vitro and ex vivo performance were selected for in vivo evaluation. A comparative pharmacokinetic study was conducted in C57BL/6 J mice in the brain and serum after administration of nasal films and oral FH solution, respectively. Sparse sampling and non-compartmental analysis were used.

Results: FH nasal films efficiently delivered the drug to both serum (Cmax(F3) = 0.35 ± 0.021, Cmax(F4) = 0.38 ± 0.029 μg/mL) and brain (Cmax(F3) = 0.39 ± 0.05, Cmax(F4) = 0.44 ± 0.048 μg/mL), achieving higher levels than oral delivery. Brain relative bioavailability (% Frel (0-6 h)) was 519% and 534%, while serum % Frel (0-6 h) was 295% and 343%.

Conclusions: The rapid nose-to-brain delivery within 30 min, in contrast to 10-h Tmax of the oral solution, indicates the potential of a combined IN and oral treatment regimen. This approach could expedite the attainment of steady-state concentrations, offering a promising method for managing multiple sclerosis (MS).

背景:盐酸芬戈莫德(FH盐酸芬戈莫德(FH)已成为治疗多发性硬化症(MS)的重要药物。尽管盐酸芬戈莫德的口服生物利用度高达 93%,但其口服吸收缓慢(Tmax = 8-12 小时),且存在广泛的肝脏代谢。鼻内给药已成为解决这些局限性的一种替代方法,可确保高效的中枢神经系统给药,并最大限度地减少外周暴露和首过代谢:本研究旨在开发和评估用于增强给药效果的 FH 鼻膜:方法:采用实验设计法配制 FH 鼻膜,使用 HPMC E50 作为成膜聚合物,PEG 400 作为增塑剂,Me-β-CD 作为渗透促进剂。选择了两种体外和体内性能优越的制剂进行体内评估。在 C57BL/6 J 小鼠体内进行了一项药代动力学比较研究,研究对象分别是鼻膜和口服 FH 溶液后大脑和血清中的药代动力学。研究采用了稀疏取样和非室分析方法:结果:FH鼻膜可将药物有效地输送到血清(Cmax(F3) = 0.35 ± 0.021,Cmax(F4) = 0.38 ± 0.029 μg/mL)和大脑(Cmax(F3) = 0.39 ± 0.05,Cmax(F4) = 0.44 ± 0.048 μg/mL),达到比口服给药更高的水平。脑相对生物利用度(Frel%(0-6 h))分别为519%和534%,而血清Frel%(0-6 h)分别为295%和343%:与口服溶液 10 小时的 Tmax 相比,30 分钟内从鼻腔到大脑的快速给药显示了 IN 和口服联合治疗方案的潜力。这种方法可以加快达到稳态浓度,为治疗多发性硬化症(MS)提供了一种前景广阔的方法。
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引用次数: 0
Molecular Dynamic Simulations Reveal that Water-Soluble QTY-Variants of Glutamate Transporters EAA1, EAA2 and EAA3 Retain the Conformational Characteristics of Native Transporters. 分子动力学模拟揭示了谷氨酸转运体 EAA1、EAA2 和 EAA3 的水溶性 QTY 变体保留了原生转运体的构象特征。
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-10-01 Epub Date: 2024-09-25 DOI: 10.1007/s11095-024-03769-0
Alper Karagöl, Taner Karagöl, Shuguang Zhang

Objective: Glutamate transporters play a crucial role in neurotransmitter homeostasis, but studying their structure and function is challenging due to their membrane-bound nature. This study aims to investigate whether water-soluble QTY-variants of glutamate transporters EAA1, EAA2 and EAA3 retain the conformational characteristics and dynamics of native membrane-bound transporters.

Methods: Molecular dynamics simulations and comparative genomics were used to analyze the structural dynamics of both native transporters and their QTY-variants. Native transporters were simulated in lipid bilayers, while QTY-variants were simulated in aqueous solution. Lipid distortions, relative solvent accessibilities, and conformational changes were examined. Evolutionary conservation profiles were correlated with structural dynamics. Statistical analyses included multivariate analysis to account for confounding variables.

Results: QTY-variants exhibited similar residue-wise conformational dynamics to their native counterparts, with correlation coefficients of 0.73 and 0.56 for EAA1 and EAA3, respectively (p < 0.001). Hydrophobic interactions of native helices correlated with water interactions of QTY- helices (rs = 0.4753, p < 0.001 for EAA1). QTY-variants underwent conformational changes resembling the outward-to-inward transition of native transporters.

Conclusions: Water-soluble QTY-variants retain key structural properties of native glutamate transporters and mimic aspects of native lipid interactions, including conformational flexibility. This research provides valuable insights into the conformational changes and molecular mechanisms of glutamate transport, potentially offering a new approach for studying membrane protein dynamics and drug interactions.

目的:谷氨酸转运体在神经递质平衡中发挥着至关重要的作用,但由于其具有膜结合特性,研究其结构和功能具有挑战性。本研究旨在探讨谷氨酸转运体 EAA1、EAA2 和 EAA3 的水溶性 QTY 变体是否保留了原生膜结合转运体的构象特征和动力学特性:分子动力学模拟和比较基因组学用于分析原生转运体及其 QTY-变体的结构动态。原生转运体在脂质双层中模拟,而 QTY-变体在水溶液中模拟。对脂质变形、相对溶剂可及性和构象变化进行了研究。进化保护概况与结构动力学相关联。统计分析包括多变量分析,以考虑混杂变量:结果:QTY 变体在残基构象动态方面与原生变体相似,EAA1 和 EAA3 的相关系数分别为 0.73 和 0.56(p 结论:水溶性 QTY 变体与原生变体的相关系数分别为 0.73 和 0.56(p 结论:水溶性 QTY 变体与原生变体的相关系数分别为 0.73 和 0.56):水溶性 QTY 变体保留了原生谷氨酸转运体的关键结构特性,并模拟了原生脂质相互作用的各个方面,包括构象灵活性。这项研究为谷氨酸转运的构象变化和分子机制提供了宝贵的见解,有可能为研究膜蛋白动力学和药物相互作用提供一种新方法。
{"title":"Molecular Dynamic Simulations Reveal that Water-Soluble QTY-Variants of Glutamate Transporters EAA1, EAA2 and EAA3 Retain the Conformational Characteristics of Native Transporters.","authors":"Alper Karagöl, Taner Karagöl, Shuguang Zhang","doi":"10.1007/s11095-024-03769-0","DOIUrl":"10.1007/s11095-024-03769-0","url":null,"abstract":"<p><strong>Objective: </strong>Glutamate transporters play a crucial role in neurotransmitter homeostasis, but studying their structure and function is challenging due to their membrane-bound nature. This study aims to investigate whether water-soluble QTY-variants of glutamate transporters EAA1, EAA2 and EAA3 retain the conformational characteristics and dynamics of native membrane-bound transporters.</p><p><strong>Methods: </strong>Molecular dynamics simulations and comparative genomics were used to analyze the structural dynamics of both native transporters and their QTY-variants. Native transporters were simulated in lipid bilayers, while QTY-variants were simulated in aqueous solution. Lipid distortions, relative solvent accessibilities, and conformational changes were examined. Evolutionary conservation profiles were correlated with structural dynamics. Statistical analyses included multivariate analysis to account for confounding variables.</p><p><strong>Results: </strong>QTY-variants exhibited similar residue-wise conformational dynamics to their native counterparts, with correlation coefficients of 0.73 and 0.56 for EAA1 and EAA3, respectively (p < 0.001). Hydrophobic interactions of native helices correlated with water interactions of QTY- helices (rs = 0.4753, p < 0.001 for EAA1). QTY-variants underwent conformational changes resembling the outward-to-inward transition of native transporters.</p><p><strong>Conclusions: </strong>Water-soluble QTY-variants retain key structural properties of native glutamate transporters and mimic aspects of native lipid interactions, including conformational flexibility. This research provides valuable insights into the conformational changes and molecular mechanisms of glutamate transport, potentially offering a new approach for studying membrane protein dynamics and drug interactions.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1965-1977"},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Role of MicroRNA-124-3p in Breast Cancer Stem Cell Inhibition by Benzyl Isothiocyanate. 微RNA-124-3p在异硫氰酸苄酯抑制乳腺癌干细胞中的作用
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-10-01 Epub Date: 2024-10-07 DOI: 10.1007/s11095-024-03775-2
Su-Hyeong Kim, Shivendra V Singh

Purpose: We have shown previously that benzyl isothiocyanate (BITC) derived from cruciferous vegetables inhibits self-renewal of breast cancer stem-like cells (bCSC). The current study provides insights into the mechanism of bCSC inhibition by BITC.

Methods: Quantitative real time-polymerase chain reaction and western blot analysis were performed to detect microRNAs (miRNAs) and Forkhead box Q1 (FoxQ1) protein expression, respectively. The bCSC were characterized by aldehyde dehydrogenase 1 activity and flow cytometric analysis of CD49f high/CD133high fraction.

Results: BITC treatment resulted in induction of miR-124-3p expression in MDA-MB-231 and MCF-7 cells. miR-124-3p did not affect BITC-mediated inhibition of cell migration or cell proliferation but it significantly regulated bCSC in response to BITC. We also found that miR-124-3p directly targets the 3'untranslated regions (UTR) of FoxQ1 and negatively regulates its expression. The BITC-mediated inhibition of bCSC was partially attenuated by miR-124-3p inhibitor.

Conclusions: These findings indicate that miR-124-3p plays an important role in BITC-mediated inhibition of bCSC.

目的:我们以前研究发现,从十字花科蔬菜中提取的异硫氰酸苄酯(BITC)可抑制乳腺癌干样细胞(bCSC)的自我更新。本研究深入探讨了BITC抑制乳腺癌干细胞的机制:方法:采用定量实时聚合酶链反应和Western印迹分析分别检测微RNA(miRNA)和叉头盒Q1(FoxQ1)蛋白的表达。通过醛脱氢酶1活性和流式细胞分析CD49f高/CD133高部分对bCSC进行定性:miR-124-3p并不影响BITC介导的细胞迁移或细胞增殖抑制作用,但它能显著调控BITC作用下的bCSC。我们还发现,miR-124-3p 直接靶向 FoxQ1 的 3'非翻译区(UTR),并负向调控其表达。miR-124-3p抑制剂部分减弱了BITC介导的对bCSC的抑制作用:这些研究结果表明,miR-124-3p 在 BITC 介导的 bCSC 抑制过程中发挥了重要作用。
{"title":"The Role of MicroRNA-124-3p in Breast Cancer Stem Cell Inhibition by Benzyl Isothiocyanate.","authors":"Su-Hyeong Kim, Shivendra V Singh","doi":"10.1007/s11095-024-03775-2","DOIUrl":"10.1007/s11095-024-03775-2","url":null,"abstract":"<p><strong>Purpose: </strong>We have shown previously that benzyl isothiocyanate (BITC) derived from cruciferous vegetables inhibits self-renewal of breast cancer stem-like cells (bCSC). The current study provides insights into the mechanism of bCSC inhibition by BITC.</p><p><strong>Methods: </strong>Quantitative real time-polymerase chain reaction and western blot analysis were performed to detect microRNAs (miRNAs) and Forkhead box Q1 (FoxQ1) protein expression, respectively. The bCSC were characterized by aldehyde dehydrogenase 1 activity and flow cytometric analysis of CD49f <sup>high</sup>/CD133<sup>high</sup> fraction.</p><p><strong>Results: </strong>BITC treatment resulted in induction of miR-124-3p expression in MDA-MB-231 and MCF-7 cells. miR-124-3p did not affect BITC-mediated inhibition of cell migration or cell proliferation but it significantly regulated bCSC in response to BITC. We also found that miR-124-3p directly targets the 3'untranslated regions (UTR) of FoxQ1 and negatively regulates its expression. The BITC-mediated inhibition of bCSC was partially attenuated by miR-124-3p inhibitor.</p><p><strong>Conclusions: </strong>These findings indicate that miR-124-3p plays an important role in BITC-mediated inhibition of bCSC.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1921-1932"},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Computational Modelling of the Impact of Evaporation on In-Vitro Dermal Absorption. 蒸发对体外皮肤吸收影响的计算模型。
IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-10-01 Epub Date: 2024-10-07 DOI: 10.1007/s11095-024-03779-y
Benjamin N Deacon, Samadhi Silva, Guoping Lian, Marina Evans, Tao Chen

Purpose: Volatiles are common in personal care products and dermatological drugs. Determining the impact of evaporation of volatiles on skin permeation is crucial to evaluate and understand their delivery, bioavailability, efficacy and safety. We aim to develop an in-silico model to simulate the impact of evaporation on the dermal absorption of volatiles.

Method: The evaporation of volatile permeants was modelled using vapour pressure as the main factor. This model considers evaporation as a passive diffusion process driven by the concentration gradient between the air-vehicle interface and the ambient environment. The evaporation model was then integrated with a previously published physiologically based pharmacokinetic (PBPK) model of skin permeation and compared with published in vitro permeation test data from the Cosmetics Europe ADME Task Force.

Results: The evaporation-PBPK model shows improved predictions when evaporation is considered. In particular, good agreement has been obtained for the distributions in the evaporative loss, and the overall percutaneous absorption. The model is further compared with published in-silico models from the Cosmetics Europe ADME Task Force where favourable results are achieved.

Conclusion: The evaporation of volatile permeants under finite dose in vitro permeation test conditions has been successfully predicted using a mechanistic model with the intrinsic volatility parameter vapour pressure. Integrating evaporation in PBPK modelling significantly improved the prediction of dermal delivery.

目的:挥发性物质在个人护理产品和皮肤药物中很常见。确定挥发性物质的蒸发对皮肤渗透的影响对于评估和了解其输送、生物利用度、疗效和安全性至关重要。我们的目标是建立一个模拟挥发性物质蒸发对皮肤吸收影响的硅学模型:方法:以蒸汽压为主要因素模拟挥发性渗透剂的蒸发。该模型认为蒸发是一个被动扩散过程,由空气-车辆界面和周围环境之间的浓度梯度驱动。然后将蒸发模型与之前公布的基于生理的皮肤渗透药代动力学(PBPK)模型进行整合,并与欧洲化妆品 ADME 工作组公布的体外渗透测试数据进行比较:结果:当考虑到蒸发因素时,蒸发-PBPK 模型的预测结果有所改进。特别是在蒸发损失的分布和总体经皮吸收方面取得了良好的一致性。我们还将该模型与欧洲化妆品 ADME 特别工作组已公布的室内模型进行了进一步比较,结果也很理想:结论:利用带有内在挥发性参数蒸汽压的机理模型,成功预测了有限剂量体外渗透试验条件下挥发性渗透剂的蒸发。将蒸发纳入 PBPK 建模大大提高了皮肤给药的预测效果。
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Pharmaceutical Research
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