Pub Date : 2024-11-01Epub Date: 2024-10-21DOI: 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。
{"title":"Ground Salicornia herbacea Powder Suppresses AOM/DSS-induced Colon Cancer by Inhibiting Wnt/β-catenin Signaling and Nrf2.","authors":"Yeonoh Cho, Ji Hyeon Cha, Yujin Hwang, Hee-Taik Kang, Jong Hun Lee","doi":"10.1007/s11095-024-03784-1","DOIUrl":"10.1007/s11095-024-03784-1","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to evaluate the effects of prebiotics and probiotics on colorectal cancer (CRC) progression in an AOM/DSS-induced mouse model.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2225-2234"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472345","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}
Pub Date : 2024-11-01Epub Date: 2024-11-06DOI: 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。
{"title":"Chemical Distribution Uniformity Assessment of \"Intra-Tablet\" by Hyperspectral Raman Imaging Analysis.","authors":"Ningyun Sun, Jing Zhang, Mingtao Guo, Yibin Mao, Wei Wu, Yi Lu","doi":"10.1007/s11095-024-03778-z","DOIUrl":"10.1007/s11095-024-03778-z","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to develop a new index, Distribution Uniformity Index (DUI), to assess the \"intra-tablet\" homogeneity.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 CaSO<sub>4</sub>·2H<sub>2</sub>O 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.</p><p><strong>Conclusions: </strong>DUI represents a novel index to evaluate the \"intra-tablet\" homogeneity and is beneficial for formulation research and development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2247-2258"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591128","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}
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。
{"title":"Pharmacological Innovations in Space: Challenges and Future Perspectives.","authors":"Zinnet Şevval Aksoyalp, Aybala Temel, Merve Karpuz","doi":"10.1007/s11095-024-03788-x","DOIUrl":"10.1007/s11095-024-03788-x","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2095-2120"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623481","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}
Pub Date : 2024-11-01Epub Date: 2024-11-04DOI: 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.
{"title":"The Current State of Biotransformation Science - Industry Survey of In Vitro and In Vivo Practices, Clinical Translation, and Future Trends.","authors":"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","doi":"10.1007/s11095-024-03787-y","DOIUrl":"10.1007/s11095-024-03787-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2079-2093"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576500","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}
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}
Pub Date : 2024-11-01Epub Date: 2024-10-30DOI: 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.
{"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}
Pub Date : 2024-10-01Epub Date: 2024-10-29DOI: 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).
{"title":"Pharmacokinetic Study of Fingolimod Nasal Films Administered via Nose-to-Brain Route in C57BL/6 J Mice as Potential Treatment for Multiple Sclerosis.","authors":"Paraskevi Papakyriakopoulou, Evangelos Balafas, Nikolaos Kostomitsopoulos, Dimitrios M Rekkas, Kumlesh K Dev, Georgia Valsami","doi":"10.1007/s11095-024-03745-8","DOIUrl":"10.1007/s11095-024-03745-8","url":null,"abstract":"<p><strong>Background: </strong>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 (T<sub>max</sub> = 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.</p><p><strong>Objective: </strong>This study aims to develop and evaluate FH nasal films for enhanced drug delivery.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>FH nasal films efficiently delivered the drug to both serum (C<sub>max(F3)</sub> = 0.35 ± 0.021, C<sub>max(F4)</sub> = 0.38 ± 0.029 μg/mL) and brain (C<sub>max(F3)</sub> = 0.39 ± 0.05, C<sub>max(F4)</sub> = 0.44 ± 0.048 μg/mL), achieving higher levels than oral delivery. Brain relative bioavailability (% F<sub>rel (0-6 h)</sub>) was 519% and 534%, while serum % F<sub>rel (0-6 h)</sub> was 295% and 343%.</p><p><strong>Conclusions: </strong>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).</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1951-1963"},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546709","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}
Pub Date : 2024-10-01Epub Date: 2024-09-25DOI: 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.
{"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}
Pub Date : 2024-10-01Epub Date: 2024-10-07DOI: 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.
{"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}
Pub Date : 2024-10-01Epub Date: 2024-10-07DOI: 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.
{"title":"Computational Modelling of the Impact of Evaporation on In-Vitro Dermal Absorption.","authors":"Benjamin N Deacon, Samadhi Silva, Guoping Lian, Marina Evans, Tao Chen","doi":"10.1007/s11095-024-03779-y","DOIUrl":"10.1007/s11095-024-03779-y","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Method: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1979-1990"},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392335","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}