AAPS Journal最新文献

Correction to: Neutralizing Antibody Sample Testing and Report Harmonization. 更正：中和抗体样本测试和报告协调。

IF 5 3区医学

AAPS Journal Pub Date : 2024-09-04 DOI: 10.1208/s12248-024-00965-z

Darshana Jani, Michele Gunsior, Robin Marsden, Kyra J Cowan, Susan C Irvin, Laura Schild Hay, Bethany Ward, Luke Armstrong, Mitra Azadeh, Liching Cao, Rebecca Carmean, Jason DelCarpini, Sanjay L Dholakiya, Amanda Hays, Sarah Hosback, Zheng Hu, Nadia Kulagina, Seema Kumar, Ching Ha Lai, Marit Lichtfuss, Hsing-Yin Liu, Susana Liu, Reza Mozaffari, Luying Pan, Jason Pennucci, Marie-Eve Poupart, Gurleen Saini, Veerle Snoeck, Kristine Storey, Amy Turner, Inna Vainshtein, Daniela Verthelyi, Iwona Wala, Lili Yang, Lin Yang

引用次数: 0

Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro. 用于鼻脑传递的抗阿尔茨海默氏症药物和 siRNA 脂质体制剂：体外设计、安全性和有效性。

IF 5 3区医学

AAPS Journal Pub Date : 2024-09-04 DOI: 10.1208/s12248-024-00967-x

David Lee, Andrew M Shen, Olga B Garbuzenko, Tamara Minko

{"title":"Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.","authors":"David Lee, Andrew M Shen, Olga B Garbuzenko, Tamara Minko","doi":"10.1208/s12248-024-00967-x","DOIUrl":"https://doi.org/10.1208/s12248-024-00967-x","url":null,"abstract":"β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134371","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

A Risk-Based Assessment for Determining the Pharmacokinetic Comparability Requirements of Biologic-Device Combination Products Administered by Subcutaneous Injection. 基于风险的评估，用于确定皮下注射给药的生物制剂-器械组合产品的药代动力学可比性要求。

IF 5 3区医学

AAPS Journal Pub Date : 2024-09-04 DOI: 10.1208/s12248-024-00968-w

Mark Klitgaard Nøhr, Shaik Rizwan Waheed, Rasmus Juul Kildemoes, Vibeke Hatorp, Tine Aggerholm Bækdal, Charlotte Lindorff Adrian, Lars Peter Korsholm, Eva Lisby Arp-Hansen, Helle Holst, Scott W Roberts

{"title":"A Risk-Based Assessment for Determining the Pharmacokinetic Comparability Requirements of Biologic-Device Combination Products Administered by Subcutaneous Injection.","authors":"Mark Klitgaard Nøhr, Shaik Rizwan Waheed, Rasmus Juul Kildemoes, Vibeke Hatorp, Tine Aggerholm Bækdal, Charlotte Lindorff Adrian, Lars Peter Korsholm, Eva Lisby Arp-Hansen, Helle Holst, Scott W Roberts","doi":"10.1208/s12248-024-00968-w","DOIUrl":"https://doi.org/10.1208/s12248-024-00968-w","url":null,"abstract":"The development of new large molecule drug therapies along with the innovation of biologic-device combination products such as prefilled syringes, autoinjectors and pen injectors have significantly impacted the treatment of new diseases and has improved the process of administering parenteral medicines. To support the regulatory approval of a new biologic-device combination products or subsequent chemistry, manufacturing and control changes impacting a combination product, sponsor companies must thoroughly assess the potential impact to product quality, safety and efficacy. In this report, a risk-based process to determine the potential impact to product quality, safety, and efficacy as well as corresponding regulatory actions supporting a chemistry, manufacturing and control change is presented. The risk assessment includes the standardized assessment of a) chemistry, manufacturing and control risk factors, potential responses and appropriately weighted scoring; b) pharmacokinetic risk factors, potential responses and appropriately weighted scoring; and c) the use of a 2-dimensional risk grid to combine the chemistry, manufacturing and control risks and pharmacokinetic risks to provide a regulatory recommendation. Three case studies (two clinical case studies and a post-approval case study) are provided to demonstrate the assessment process and capabilities.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134369","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

Best Practices for Development and Validation of Enzymatic Activity Assays to Support Drug Development for Inborn Errors of Metabolism and Biomarker Assessment. 开发和验证酶活性测定的最佳做法，以支持先天性代谢异常药物开发和生物标记物评估。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-23 DOI: 10.1208/s12248-024-00966-y

Mitra Azadeh, Jeremy Good, Michele Gunsior, Nadia Kulagina, Yanmei Lu, Jim McNally, Heather Myler, Yan G Ni, Ryan Pelto, Karen J Quadrini, Catherine Vrentas, Lin Yang

{"title":"Best Practices for Development and Validation of Enzymatic Activity Assays to Support Drug Development for Inborn Errors of Metabolism and Biomarker Assessment.","authors":"Mitra Azadeh, Jeremy Good, Michele Gunsior, Nadia Kulagina, Yanmei Lu, Jim McNally, Heather Myler, Yan G Ni, Ryan Pelto, Karen J Quadrini, Catherine Vrentas, Lin Yang","doi":"10.1208/s12248-024-00966-y","DOIUrl":"https://doi.org/10.1208/s12248-024-00966-y","url":null,"abstract":"Aberrant or dysfunctional cellular enzymes are responsible for a wide range of diseases including cancer, neurodegenerative conditions, and metabolic disorders. Deficiencies in enzyme level or biofunction may lead to intracellular accumulation of substrate to toxic levels and interfere with overall cellular function, ultimately leading to cell damage, disease, and death. Marketed therapeutic interventions for inherited monogenic enzyme deficiency disorders include enzyme replacement therapy and small molecule chaperones. Novel approaches of in vivo gene therapy and ex vivo cell therapy are under clinical evaluation and provide promising opportunities to expand the number of available disease-modifying treatments. To support the development of these different therapeutics, assays to quantify the functional activity of protein enzymes have gained importance in the diagnosis of disease, assessment of pharmacokinetics and pharmacodynamic response, and evaluation of drug efficacy. In this review, we discuss the technical aspects of enzyme activity assays in the bioanalytical context, including assay design and format as well as the unique challenges and considerations associated with assay development, validation, and life cycle management.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047471","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

Mass Balance in Pharmaceutical Stress Testing: A Review of Principles and Practical Applications. 药物压力测试中的质量平衡：原理与实际应用综述。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-22 DOI: 10.1208/s12248-024-00961-3

Stacey Marden, John M Campbell, Neal Adams, Ronan Coelho, Chris Foti, Juçara Ribeiro Franca, Steven Hostyn, Zongyun Huang, Mariah Ultramari, Todd Zelesky, Steven W Baertschi

{"title":"Mass Balance in Pharmaceutical Stress Testing: A Review of Principles and Practical Applications.","authors":"Stacey Marden, John M Campbell, Neal Adams, Ronan Coelho, Chris Foti, Juçara Ribeiro Franca, Steven Hostyn, Zongyun Huang, Mariah Ultramari, Todd Zelesky, Steven W Baertschi","doi":"10.1208/s12248-024-00961-3","DOIUrl":"https://doi.org/10.1208/s12248-024-00961-3","url":null,"abstract":"Stress testing (also known as forced degradation) of pharmaceutical drug substances and products is a critical part of the drug development process, providing insight into the degradation pathways of drug substances and drug products. This information is used to support the development of stability-indicating methods (SIMs) capable of detecting pharmaceutically relevant degradation products that might potentially be observed during manufacturing, long-term storage, distribution, and use. Assessing mass balance of stressed samples is a key aspect of developing SIMs and is a regulatory expectation. However, the approaches to measure, calculate, and interpret mass balance can vary among different pharmaceutical companies. Such disparities also pose difficulties for health authorities when reviewing mass balance assessments, which may result in the potential delay of drug application approvals. The authors have gathered input from 10 pharma companies to map out a practical review of science-based approaches and technical details to assess and interpret mass balance results. Key concepts of mass balance are introduced, various mass balance calculations are demonstrated, and recommendations on how to investigate poor mass balance results are presented using real-world case studies. Herein we provide a single source reference on the topic of mass balance in pharmaceutical forced degradation for small molecule drug substances and drug products in support of regulatory submissions with the goal of facilitating a shared understanding among pharmaceutical scientists and health authorities.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037647","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

A Perspective on Evaluating Life Stage Differences in Drug Dosages for Drug Labeling and Instructions. 评估药物标签和说明书中药物剂量的生命阶段差异的视角。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-20 DOI: 10.1208/s12248-024-00964-0

Tianshu Gu, Guiying Wang, Edwin J C van den Oord, Emanuel Goldman, Chengyuan Yang, Ning Xie, Lan Yao, Cong-Yi Wang, Monica Jablonski, Kunal Ray, Fengxia Liu, Wensen Pan, Gonzalo Flores, Lotfi Aleya, Xia Meng, Yan Jiao, Minghui Li, Yongjun Wang, Weikuan Gu

引用次数: 0

Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease. 慢性肾脏病中二甲双胍和达帕格列净的药代动力学模型。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-19 DOI: 10.1208/s12248-024-00962-2

Andrew Shahidehpour, Mudassir Rashid, Mohammad Reza Askari, Mohammad Ahmadasas, Mahmoud Abdel-Latif, Cynthia Fritschi, Lauretta Quinn, Sirimon Reutrakul, Ulf G Bronas, Ali Cinar

{"title":"Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease.","authors":"Andrew Shahidehpour, Mudassir Rashid, Mohammad Reza Askari, Mohammad Ahmadasas, Mahmoud Abdel-Latif, Cynthia Fritschi, Lauretta Quinn, Sirimon Reutrakul, Ulf G Bronas, Ali Cinar","doi":"10.1208/s12248-024-00962-2","DOIUrl":"https://doi.org/10.1208/s12248-024-00962-2","url":null,"abstract":"Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005781","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

The Development of Epitope-Based Recombinant Protein Vaccines against SARS-CoV-2. 开发抗 SARS-CoV-2 的表位重组蛋白疫苗。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-13 DOI: 10.1208/s12248-024-00963-1

Kanwal Khalid, Hui Xuan Lim, Jung Shan Hwang, Chit Laa Poh

{"title":"The Development of Epitope-Based Recombinant Protein Vaccines against SARS-CoV-2.","authors":"Kanwal Khalid, Hui Xuan Lim, Jung Shan Hwang, Chit Laa Poh","doi":"10.1208/s12248-024-00963-1","DOIUrl":"https://doi.org/10.1208/s12248-024-00963-1","url":null,"abstract":"The COVID-19 pandemic continues to cause infections and deaths, which are attributable to the SARS-CoV-2 Omicron variant of concern (VOC). Moderna's response to the declining protective efficacies of current SARS-CoV-2 vaccines against Omicron was to develop a bivalent booster vaccine based on the Spike (S) protein from the Wuhan and Omicron BA.4/BA.5 strains. This approach, while commendable, is unfeasible in light of rapidly emerging mutated viral strains. PubMed and Google Scholar were systematically reviewed for peer-reviewed papers up to January 2024. Articles included focused on specific themes such as the clinical history of recombinant protein vaccine development against different diseases, including COVID-19, the production of recombinant protein vaccines using different host expression systems, aspects to consider in recombinant protein vaccine development, and overcoming problems associated with large-scale recombinant protein vaccine production. In silico approaches to identify conserved and immunogenic epitopes could provide broad protection against SARS-CoV-2 VOCs but require validation in animal models. The recombinant protein vaccine development platform has shown a successful history in clinical development. Recombinant protein vaccines incorporating conserved epitopes may utilize a number of expression systems, such as yeast (Saccharomyces cerevisiae), baculovirus-insect cells (Sf9 cells), and Escherichia coli (E. coli). Current multi-epitope subunit vaccines against SARS-CoV-2 utilizing synthetic peptides are unfeasible for large-scale immunizations. Recombinant protein vaccines based on conserved and immunogenic proteins produced using E. coli offer high production yields, convenient purification, and cost-effective production of large-scale vaccine quantities capable of protecting against the SARS-CoV-2 D614G strain and its VOCs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977183","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

Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach. 从患者衍生异种移植（PDX）模型预测未治疗患者的肿瘤体积倍增时间和无进展生存期：基于转化模型的方法。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-08 DOI: 10.1208/s12248-024-00960-4

E M Tosca, D Ronchi, M Rocchetti, P Magni

{"title":"Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach.","authors":"E M Tosca, D Ronchi, M Rocchetti, P Magni","doi":"10.1208/s12248-024-00960-4","DOIUrl":"https://doi.org/10.1208/s12248-024-00960-4","url":null,"abstract":"Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908271","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

Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport. 高海拔缺氧条件下血脑屏障通透性受紧密连接蛋白表达变化的影响--这可能对脑药物转运产生影响

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-06 DOI: 10.1208/s12248-024-00957-z

Guiqin Liu, Qian Wang, Lu Tian, Mengyue Wang, Delong Duo, Yabin Duan, Yue Lin, Junjun Han, Qiangqiang Jia, Junbo Zhu, Xiangyang Li

{"title":"Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport.","authors":"Guiqin Liu, Qian Wang, Lu Tian, Mengyue Wang, Delong Duo, Yabin Duan, Yue Lin, Junjun Han, Qiangqiang Jia, Junbo Zhu, Xiangyang Li","doi":"10.1208/s12248-024-00957-z","DOIUrl":"https://doi.org/10.1208/s12248-024-00957-z","url":null,"abstract":"Changes to blood-brain barrier structure and function may affect the delivery of drugs into the brain. It is worthwhile to exploring more study on how the blood-brain barrier changes in structure and function and how that affects drug transport in high-altitude hypoxic environment. The DIA high-throughput sequencing technique indicate that the rats blood-brain barrier has been identified to have 7252 proteins overall and 8 tight junction proteins, among which Claudin-7 was a plateau-specific tight junction protein under high-altitude hypoxia, and based on the interaction network study, 2421 proteins are found to interact with one another, with ZO-1 being the primary target. The results of the projected gene function analysis demonstrated that changes in tight junction proteins are related to the control of TRP channels by inflammatory mediators, the wnt signaling pathway, the ABC transporter system, and drug metabolism-CYP450 enzyme regulation. Additionally, the electron microscopy, the Evans blue combination with confocal laser scanning microscopy, and the Western Blot and RT-qPCR revealed that high-altitude hypoxic environment induces blood-brain barrier tight junctions to open, blood-brain barrier permeability increases, ZO-1, Occludin, Claudin-5 protein and mRNA expression decreased. Our research implies that structural and functional alterations in the blood-brain barrier induced by high altitude hypoxia may impact drug transport inside the central nervous system, and that drug transporters and drug-metabolizing enzymes may be key players in this process.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898903","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