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Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery - A Modeling Approach. 探索药理学靶点介导的低血浆暴露对药物发现中铅化合物选择的影响--一种建模方法。
IF 5 3区 医学
AAPS Journal Pub Date : 2024-10-28 DOI: 10.1208/s12248-024-00979-7
Min Xu, Duxin Sun, Guohua An
{"title":"Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery - A Modeling Approach.","authors":"Min Xu, Duxin Sun, Guohua An","doi":"10.1208/s12248-024-00979-7","DOIUrl":"10.1208/s12248-024-00979-7","url":null,"abstract":"<p><p>Small-molecule drug development faces the challenge of low success rate. In this paper, we propose one potential cause that may occur in the preclinical phase and has rarely been brought up before - the neglected target-mediated low plasma exposure, and the subsequent lead compound mis-selection due to conventional pharmacokinetic criteria requiring sufficient plasma exposure and desired half-life. To evaluate the concept of target-mediate low plasma exposure, we established a minimal physiologically-based pharmacokinetic (mPBPK) model to evaluate the concentration-time profiles of a group of virtual lead series analogs in plasma and in tissues with and without pharmacological target expression. Simulation results demonstrated that the candidate with the highest target binding has the lowest plasma exposure due to target-mediated tissue retention. The traditional PK criteria, such as the requirement of sufficient plasma exposure and desired half-life, may potentially result in lead compound mis-selection by discarding the appropriate and best candidate(s). The mPBPK model was partially validated using 4 tyrosine kinase inhibitors based on our in-house PK and tissue distribution data obtained in animals. The association rate constant (K<sub>ass</sub>) was estimated to be 49.8 h<sup>-1</sup>, 31.4 h<sup>-1</sup>, 8.58 h<sup>-1</sup>, and 1.91 h<sup>-1</sup> for afatinib, dasatinib, gefitinib, and sorafenib, respectively. Among these four model drugs, a strong correlation was observed between their K<sub>ass</sub> values and AUC<sub>high-perfused tissue</sub> /AUC<sub>plasma</sub> ratios, a metric of tissue retention. Our mPBPK modeling and simulation results indicated that the concept of target-mediated low plasma exposure should be kept in mind during the lead compound selection process.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"112"},"PeriodicalIF":5.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523603","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
Luteolin Protects against Vascular Calcification by Modulating SIRT1/CXCR4 Signaling Pathway and Promoting Autophagy. 木犀草素通过调节 SIRT1/CXCR4 信号通路和促进自噬防止血管钙化
IF 5 3区 医学
AAPS Journal Pub Date : 2024-10-22 DOI: 10.1208/s12248-024-00982-y
Xiaoyu Yu, Lei Xu, Ce Su, Changyuan Wang, Zimeng Wang, Yanna Wang, Xiaolong Lu, Huijun Sun
{"title":"Luteolin Protects against Vascular Calcification by Modulating SIRT1/CXCR4 Signaling Pathway and Promoting Autophagy.","authors":"Xiaoyu Yu, Lei Xu, Ce Su, Changyuan Wang, Zimeng Wang, Yanna Wang, Xiaolong Lu, Huijun Sun","doi":"10.1208/s12248-024-00982-y","DOIUrl":"10.1208/s12248-024-00982-y","url":null,"abstract":"<p><p>Vascular calcification (VC) is a common pathological manifestation of atherosclerosis, hypertension, diabetes vascular disease, vascular injury, chronic kidney disease and aging, which is mainly manifested as increased stiffness of the vascular wall. Oxidative stress and autophagy dysfunction are key factors in the pathogenesis of vascular calcification, but the specific mechanisms and the therapeutic strategy of vascular calcification have not been clarified. In the present study, Sirtuin 1 (SIRT1) was screened as the therapeutic targets for vascular calcification by the bioinformatics. SIRT1 is a nicotinamide adenine dinucleotide, which plays an important role in inhibiting oxidative stress and promoting autophagy. Luteolin (LUT), a kind of natural tetrahydroxyl flavonoid, exists in many plants and has many pharmacological effects such as anti-oxidation and anti-apoptosis. We have reported that luteolin has certain anti-osteoporosis effects in the previous study, and it is accepted that the development of vascular calcification is similar to bone formation, indicating that luteolin may also resist vascular calcification. And luteolin is known to activate SIRT1 to some extent. Moreover, the molecular docking analysis predicted that SIRT1 could bind directly to luteolin. Therefore, the purpose of this study was to investigate the potential role of luteolin in inhibiting oxidative stress and promoting autophagy during vascular calcification via modulating SIRT1 expression. The results showed that luteolin significantly improved vascular calcification induced by a high-fat diet (HFD) and vitamin D<sub>3</sub> in rats in vivo. In addition, luteolin significantly repressed the formation of mineralized nodules and ALP activity in H<sub>2</sub>O<sub>2</sub>-treated A7r5 cells. Luteolin reduced the level of MDA, LDH and ROS generation, inhibited the protein expression of cleaved caspase-3, cleaved caspase-9, β-catenin and BMP-2 in the aortic tissue of the rat and rat smooth muscle cells (A7r5) treated with hydrogen peroxide. At the same time, luteolin could promote the expression of autophagy related proteins. Moreover, luteolin also produced effects to increase the protein expression levels of SIRT1 more than 2 times both in vivo and in vitro. In terms of mechanism, luteolin attenuated vascular calcification by inhibiting oxidative stress and improving autophagy level, via modulating SIRT1 / CXCR4 signaling pathway. In conclusion, this experiment for the first time revealed that LUT protected against VC via modulating SIRT1 / CXCR4 signaling pathway to promote autophagy and inhibit vascular calcification and may be developed as a new therapeutic agent for vascular calcification and atherosclerosis.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"111"},"PeriodicalIF":5.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512462","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
Case Studies on the use of Microsampling for Nonclinical Studies in Pharmaceutical Drug Discovery and Development. 在药物发现和开发的非临床研究中使用微取样的案例研究。
IF 5 3区 医学
AAPS Journal Pub Date : 2024-10-18 DOI: 10.1208/s12248-024-00975-x
Shefali R Patel, Jason Barricklow, Peter Bryan, Chiara Rospo, Neil Spooner, Ming Wang, Joleen T White, Amanda Wilson
{"title":"Case Studies on the use of Microsampling for Nonclinical Studies in Pharmaceutical Drug Discovery and Development.","authors":"Shefali R Patel, Jason Barricklow, Peter Bryan, Chiara Rospo, Neil Spooner, Ming Wang, Joleen T White, Amanda Wilson","doi":"10.1208/s12248-024-00975-x","DOIUrl":"10.1208/s12248-024-00975-x","url":null,"abstract":"<p><p>The implementation of microsampling approaches for use in nonclinical discovery and development pharmaceutical studies can have a major impact on improving animal ethics through the use of fewer animals and less invasive procedures for the collection of toxicokinetic and pharmacokinetic samples. In addition, the approach offers the opportunity for obtaining improved quality of data for these studies. This can include the determination of additional timepoints and endpoints, and the ability to obtain exposure data from the same animals utilized to measure other study endpoints. This manuscript presents a number of cases where a variety of microsampling approaches have been successfully implemented by a number of organizations and serves as a guide for those considering the use of microsampling approaches as part of their drug discovery and development programs, as the adoption of these approaches are not yet universal.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"110"},"PeriodicalIF":5.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142480020","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
Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan. 在日本的药品审查和处方信息中评估免疫原性。
IF 5 3区 医学
AAPS Journal Pub Date : 2024-10-08 DOI: 10.1208/s12248-024-00980-0
Mitsuru Ishibai, Megumi Kai, Hirokazu Wakuda, Ichiro Oikawa, Naoto Uemura
{"title":"Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan.","authors":"Mitsuru Ishibai, Megumi Kai, Hirokazu Wakuda, Ichiro Oikawa, Naoto Uemura","doi":"10.1208/s12248-024-00980-0","DOIUrl":"10.1208/s12248-024-00980-0","url":null,"abstract":"<p><p>Anti-drug antibodies (ADAs) generated in response to biopharmaceuticals can significantly impact pharmacokinetics (PK) and overall drug efficacy. Thus, the ICH M4 guidelines mandate summarizing immunogenicity data from clinical trials in drug approval applications. However, following the approval of the first antibody drug in Japan in 2001, no cross-sectional investigation has focused on immunogenicity during the regulatory review process. Therefore, this study aims to examine the review reports and prescribing information of antibody drugs approved in Japan to identify key points related to immunogenicity evaluation. We conducted a cross-sectional analysis of review reports for antibody drugs approved between June 2001 and July 2022 by the Japanese regulatory authority. Specifically, we evaluated the ADA positivity rate, presence of neutralizing antibodies, antibody titers, and effects of ADA on PK, efficacy, and safety. We also compared this information with that provided in the prescribing information. Our analysis revealed that the ADA positivity rate and its effects on PK, efficacy, and safety were critical aspects of the review process. The emphasis on these factors varied depending on the number of applications and disease area. The information presented in the prescribing information was largely consistent with that discussed in the review reports. Overall, this study provides the first cross-sectional evaluation of immunogenicity considerations in the regulatory review of antibody drugs in Japan. Our findings can contribute to the efficiency of clinical trial planning and preparation of approval applications, to potentially improve the overall drug development process and address the drug loss problem in Japan.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"109"},"PeriodicalIF":5.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395015","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
Temperature Excursion Management: A Tier-Based Approach for Commercial Oral Solid Dosage Forms. 温度偏移管理:商用口服固体制剂的分级管理方法。
IF 5 3区 医学
AAPS Journal Pub Date : 2024-10-01 DOI: 10.1208/s12248-024-00976-w
Shalini Raj Unnikandam Veettil, Gianna Respicio, DeeDee Zhang, Daniel Garcia, Stephanie Malta, Hong Long
{"title":"Temperature Excursion Management: A Tier-Based Approach for Commercial Oral Solid Dosage Forms.","authors":"Shalini Raj Unnikandam Veettil, Gianna Respicio, DeeDee Zhang, Daniel Garcia, Stephanie Malta, Hong Long","doi":"10.1208/s12248-024-00976-w","DOIUrl":"10.1208/s12248-024-00976-w","url":null,"abstract":"<p><p>Temperature excursions during product storage, transportation, and handling can deteriorate product quality. Following a temperature excursion event, the impact of the event on the product quality should be evaluated to determine if the product can be used or if it needs to be discarded. Pharmaceutical companies are required to have defined procedures for managing temperature excursions and performing impact assessment after an excursion occurs. In an increasingly complex supply chain, it is vital to develop processes that can expedite the review of these events. A tier-based approach is presented for analyzing the impact of temperature excursion on commercial small molecule drug products intended to be stored at room temperature. Utilization of each of the three tiers is based on whether the excursion temperature and/or excursion duration are within a predetermined, product-specific, allowable range. The stress study temperature defines the allowable temperature range, while the allowable duration is determined using a mathematical approach outlined in this article. Tier 1, specific to the product, allows products to be dispositioned for use without further assessment when temperature excursion events fall within both the product-specific allowable excursion temperature and duration ranges. Tier 2 applies when the excursion temperature is within the allowable range, but the duration exceeds it. Lot-specific release data is used for impact assessment in this tier. Finally, Tier 3 utilizes Arrhenius extrapolation to predict the final degradation and perform the impact assessment when the excursion temperature surpasses the allowable temperature range.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"108"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362399","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
UGT2B10 is the Major UDP-Glucuronosyltransferase 2B Isoform Involved in the Metabolism of Lamotrigine and is Implicated in the Drug-Drug Interaction with Valproic Acid. UGT2B10 是参与拉莫三嗪代谢的主要 UDP-Glucuronosyl 转移酶 2B 异构体,并与丙戊酸的药物相互作用有关。
IF 5 3区 医学
AAPS Journal Pub Date : 2024-09-25 DOI: 10.1208/s12248-024-00978-8
Lloyd Wei Tat Tang, Kimberly Lapham, Theunis C Goosen
{"title":"UGT2B10 is the Major UDP-Glucuronosyltransferase 2B Isoform Involved in the Metabolism of Lamotrigine and is Implicated in the Drug-Drug Interaction with Valproic Acid.","authors":"Lloyd Wei Tat Tang, Kimberly Lapham, Theunis C Goosen","doi":"10.1208/s12248-024-00978-8","DOIUrl":"10.1208/s12248-024-00978-8","url":null,"abstract":"<p><p>Lamotrigine is a phenyltriazine anticonvulsant that is primarily metabolized by phase II UDP-glucuronosyltransferases (UGT) to a quaternary N2-glucuronide, which accounts for ~ 90% of the excreted dose in humans. While there is consensus that UGT1A4 plays a predominant role in the formation of the N2-glucuronide, there is compelling evidence in the literature to suggest that the metabolism of lamotrigine is catalyzed by another UGT isoform. However, the exact identity of the UGT isoform that contribute to the formation of this glucuronide remains uncertain. In this study, we harnessed a robust reaction phenotyping strategy to delineate the identities and its associated fraction metabolized (f<sub>m</sub>) of the UGTs involved in lamotrigine N2-glucuronidation. Foremost, human recombinant UGT mapping experiments revealed that the N2-glucuronide is catalyzed by multiple UGT isoforms. (i.e., UGT1A1, 1A3, 1A4, 1A9, 2B4, 2B7, and 2B10). Thereafter, scaling the apparent intrinsic clearances obtained from the enzyme kinetic experiments with our in-house liver-derived relative expression factors (REF) and relative activity factors (RAF) revealed that, in addition to UGT1A4, UGT2B10 was involved in the N2-glucuronidation of lamotrigine. This was further confirmed via chemical inhibition in human liver microsomes with the UGT1A4-selective inhibitor hecogenin and the UGT2B10-selective inhibitor desloratadine. By integrating various orthogonal approaches (i.e., REF- and RAF-scaling, and chemical inhibition), we quantitatively determined that the f<sub>m</sub> for UGT1A4 and UGT2B10 ranged from 0.42 - 0.64 and 0.32 - 0.57, respectively. Finally, we also provided nascent evidence that the pharmacokinetic interaction between lamotrigine and valproic acid likely arose from the in vivo inhibition of its UGT2B10-mediated pathway.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 6","pages":"107"},"PeriodicalIF":5.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331797","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
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
{"title":"Correction to: Neutralizing Antibody Sample Testing and Report Harmonization.","authors":"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","doi":"10.1208/s12248-024-00965-z","DOIUrl":"10.1208/s12248-024-00965-z","url":null,"abstract":"","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"98"},"PeriodicalIF":5.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134370","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":"10.1208/s12248-024-00968-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"100"},"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
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":"10.1208/s12248-024-00967-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"99"},"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
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":"10.1208/s12248-024-00966-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"97"},"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
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