Pharmaceutical Research最新文献_第3页

Advanced Manufacturing, Modeling And Analytical Tools In Injectable Products.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-03-01 Epub Date: 2025-02-26 DOI: 10.1007/s11095-025-03815-5

Howard Stamato, Maxwell Korang-Yeboah, Jyothi Rangineni, Xiaoming Xu, Robin Bogner

引用次数: 0

Synthesis and Biological Evaluation of Novel Triazine Analogs as Rad6 Inhibitors.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-03-01 Epub Date: 2025-02-28 DOI: 10.1007/s11095-025-03838-y

Qian Lin, Ambikai Gajan, Ignatius Nguyen, Shiv Sharma, Pratima Nangia-Makker, Steven Firestine, Malathy P Shekhar

{"title":"Synthesis and Biological Evaluation of Novel Triazine Analogs as Rad6 Inhibitors.","authors":"Qian Lin, Ambikai Gajan, Ignatius Nguyen, Shiv Sharma, Pratima Nangia-Makker, Steven Firestine, Malathy P Shekhar","doi":"10.1007/s11095-025-03838-y","DOIUrl":"10.1007/s11095-025-03838-y","url":null,"abstract":"Rad6 is an E2 ubiquitin-conjugating enzyme that plays critical roles in genome maintenance and proteostasis. Rad6 is frequently overexpressed in many cancers and promotes cancer development, progression, and chemotherapy resistance.Purpose: Given its role in cancer development and progression, Rad6 is an underexplored therapeutic target. Previous research identified compound SMI#9 as a small molecule inhibitor of Rad6. Despite its potency, SMI#9 has limited efficacy in vivo due to its limiting water solubility and the presence of a labile ester group.Methods: To address these limitations, we prepared a series of SMI#9 analogs in which the ester group was replaced with a secondary amine, and their effects on Rad6B-mediated ubiquitination of histone H2A were evaluated. In vivo interaction with Rad6 was assessed using cellular thermal shift assays. SMI#9 analog effects on cell survival and migration of triple negative and endocrine-resistant breast cancer, and melanoma cells were measured using MTT and Boyden chamber assays. Autophagy, mitochondrial function, and β-catenin localization were measured using CytoID, Mitotracker, and immunostaining, respectively. Cellular uptakes of analogs were determined by mass spectroscopy.Results: Analogs #4 and #6 inhibited H2A ubiquitination, induced autophagy and mitochondrial dysfunction, downregulated intracellular β-catenin, and inhibited proliferation. #6 targets Rad6 in vivo. #4 and #6 are chemically related, and #4 undergoes in vivo conversion to #6.Conclusions: #6 retains all the properties of SMI#9 but with lesser potency. However, its improved water solubility and metabolic stability allows for in vivo studies that were previously precluded due to the poor physicochemical properties of SMI#9.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"511-527"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531010","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

Leveraging Model Master Files from a Technology Company Perspective: Facilitating Quantitative Medicine in Regulatory Frameworks.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-26 DOI: 10.1007/s11095-025-03833-3

Jan De Backer, James Clarke, Hosein Sadafi, William Ganley, Jessica Spires

{"title":"Leveraging Model Master Files from a Technology Company Perspective: Facilitating Quantitative Medicine in Regulatory Frameworks.","authors":"Jan De Backer, James Clarke, Hosein Sadafi, William Ganley, Jessica Spires","doi":"10.1007/s11095-025-03833-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03833-3","url":null,"abstract":"Model Master Files (MMFs) offer a much needed approach to integrating computational modelling into drug development and regulatory frameworks, supporting the growth of quantitative medicine. By acting as confidential repositories for validated models, MMFs enable streamlined submissions, model reuse, and context-specific reviews while safeguarding intellectual property. For technology companies (such as software providers), MMFs provide a structured pathway to engage with the FDA, align innovations with regulatory standards, and expand the use of models across diverse applications. A challenge with the current framework is the need to provide the same validation and verification information to multiple drug companies each time the submit an application. With an MMF in place, drug companies can refer to this same document which the technology provider can add to over time. However, challenges persist, including limited direct interaction with the FDA outside (A)NDA submissions and the need for consistent model validation and version management. Addressing these issues through enhanced collaboration and clear guidelines will maximize the potential of MMFs, fostering broader adoption of modelling and simulation in drug development and advancing personalized medicine.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516319","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

Regulatory and Industry Perspective on the Model Master File Framework for Locally Acting Drug Products.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-26 DOI: 10.1007/s11095-025-03823-5

Ross L Walenga, Khondoker Alam, James F Clarke, Jan De Backer, Markus Fridén, Abdullah Hamadeh, Jay Mowli, Sujatha Sonti, Jessica Spires, Ming-Liang Tan, Flora T Musuamba, Eleftheria Tsakalozou

引用次数: 0

Correction: Leveraging Model Master Files for Long-Acting Injectables.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-12 DOI: 10.1007/s11095-025-03832-4

Yuqing Gong, Robert Hopefl, Tonglei Li, Andrew C Hooker, Daniela Amaral Silva, Khondoker Alam, Murray Ducharme, Rebecca Moody, Pratik Saha, Andrew Babiskin

引用次数: 0

Structure Bioinformatics of Six Human Integral Transmembrane Enzymes and their AlphaFold3 Predicted Water-Soluble QTY Analogs: Insights into FACE1 and STEA4 Binding Mechanisms.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-02-18 DOI: 10.1007/s11095-025-03822-6

Edward Chen, Emily Pan, Shuguang Zhang

{"title":"Structure Bioinformatics of Six Human Integral Transmembrane Enzymes and their AlphaFold3 Predicted Water-Soluble QTY Analogs: Insights into FACE1 and STEA4 Binding Mechanisms.","authors":"Edward Chen, Emily Pan, Shuguang Zhang","doi":"10.1007/s11095-025-03822-6","DOIUrl":"10.1007/s11095-025-03822-6","url":null,"abstract":"Objective: Human integral membrane enzymes are essential for catalyzing a wide range of biochemical reactions and regulating key cellular processes. However, studying these enzymes remains challenging due to their hydrophobic nature, which necessitates the use of detergents. This study explores whether applying the QTY code can reduce the hydrophobicity of these enzymes while preserving their structures and functions, thus facilitating bioinformatics analysis of six key integral membrane enzymes: MGST2, LTC4S, PTGES, FACE1, STEA4, and SCD.Methods: The water-soluble QTY analogs of the six membrane enzymes were predicted using AlphaFold3. The predicted structures were superposed with CyroEM determined native structures in PyMOL to observe changes in structure and protein-ligand binding ability.Results: The native membrane enzymes superposed well with their respective QTY analogs, with the root mean square deviation (RMSD) ranging from 0.273 Å to 0.875 Å. Surface hydrophobic patches on the QTY analogs were significantly reduced. Importantly, the protein-ligand interactions in FACE1 and STEA4 were largely preserved, indicating maintained functionality.Conclusion: Our structural bioinformatics studies using the QTY code and AlphaFold3 not only provide the opportunities of designing more water-soluble integral membrane enzymes, but also use these water-soluble QTY analogs as antigens for therapeutic monoclonal antibody discovery to specifically target the key integral membrane enzymes.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"291-305"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetics of Nivolumab and Erythropoietin in a Rat Model of Diet-Induced Obesity.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-01-23 DOI: 10.1007/s11095-025-03819-1

Yi-Hua Sheng, Celine Park, Yae Eun Chong, Christine Yohn, Anna Siemiątkowska, Katarzyna Kosicka-Noworzyń, Amrit Kaur, Karan Sapra, Luigi Brunetti, Leonid Kagan

{"title":"Pharmacokinetics of Nivolumab and Erythropoietin in a Rat Model of Diet-Induced Obesity.","authors":"Yi-Hua Sheng, Celine Park, Yae Eun Chong, Christine Yohn, Anna Siemiątkowska, Katarzyna Kosicka-Noworzyń, Amrit Kaur, Karan Sapra, Luigi Brunetti, Leonid Kagan","doi":"10.1007/s11095-025-03819-1","DOIUrl":"10.1007/s11095-025-03819-1","url":null,"abstract":"Purpose: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.Method: Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.Results: When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.Conclusions: Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"271-280"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dietary phytochemical indole-3-carbinol regulates metabolic reprogramming in mouse prostate tissue.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-02-04 DOI: 10.1007/s11095-025-03820-8

Rebecca Mary Peter, Md Shahid Sarwar, Lujing Wang, Pochung Chou, Chao Wang, Yujue Wang, Xiaoyang Su, Ah-Ng Kong

{"title":"Dietary phytochemical indole-3-carbinol regulates metabolic reprogramming in mouse prostate tissue.","authors":"Rebecca Mary Peter, Md Shahid Sarwar, Lujing Wang, Pochung Chou, Chao Wang, Yujue Wang, Xiaoyang Su, Ah-Ng Kong","doi":"10.1007/s11095-025-03820-8","DOIUrl":"10.1007/s11095-025-03820-8","url":null,"abstract":"Purpose: Indole-3-carbinol (I3C) is shown to possess multiple pharmacological activities such as anti-inflammatory, antimicrobial, antioxidant, antiviral, and anti-cancer activities. It is widely accepted as modulator of multiple signaling pathways particularly those related to cell cycle, cell growth and division, angiogenesis, apoptosis and immunity. We explored the metabolic reprogramming based on treatment with I3C in mice prostate tissue.Methods: In this study we utilized Pten knockout (KO)-induced prostate tumorigenesis mouse model to examine mechanism of action of I3C via metabolic rewiring. Phosphatase and tensin homolog deleted on chromosome 10 (Pten), a tumor suppressor gene is frequently found to be mutated or deleted in prostate cancer. Untargeted metabolomics was performed using liquid-chromatography mass-spectrometry (LC-MS) based platform to investigate Pten-dependent and Pten-independent metabolic targets of I3C.Results: The most impacted pathways by I3C included pyrimidine metabolism, arginine and proline metabolism, porphyrin metabolism, citrate cycle and lipoic acid metabolism.Conclusion: These pathways taken together help in understanding the overall health beneficial effects of I3C.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"237-247"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Theranostic Near-Infrared Monoamine Oxidase Inhibitor (NMI) Protein Binding Interactions with MAOA and Albumin.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-02-04 DOI: 10.1007/s11095-025-03827-1

Ronald W Irwin, Unnati H Shah, Shivani Soni, Heinz Josef Lenz, Jean C Shih

{"title":"Theranostic Near-Infrared Monoamine Oxidase Inhibitor (NMI) Protein Binding Interactions with MAOA and Albumin.","authors":"Ronald W Irwin, Unnati H Shah, Shivani Soni, Heinz Josef Lenz, Jean C Shih","doi":"10.1007/s11095-025-03827-1","DOIUrl":"10.1007/s11095-025-03827-1","url":null,"abstract":"Purpose: The protein binding interactions of near-infrared monoamine oxidase inhibitor (NMI) are reported here.Methods: NMI-bound proteins were examined by fluorescent SDS-PAGE and mass spectrometry using tumor tissues from brain and colon cancer mouse models.Results: This study shows protein interactions with NMI, a chemical conjugate of MAOA inhibitor clorgyline and tumor-seeking dye, MHI-148. NMI fluorescence in MAOA knock-out (KO) mice was significantly lower compared to WT mice, including whole animal, organs, and tissue lysates which indicated that NMI binds to MAOA. Pure recombinant MAOA protein was detectable as a single fluorescent band that migrated at ~ 65kD. NMI inhibited MAOA activity (IC50 1-5 µM). In a glioma mouse model, NMI targeted specifically to tumor with high contrast to adjacent normal brain, shown by a 65 kD protein band. Recent studies demonstrated heptamethine cyanine dyes (e.g., MHI-148) interact with serum albumin, contributing to tumor uptake and cancer cell internalization. Our study shows NMI binds to albumin but highly prefers MAOA, providing a plausible mechanism for systemic drug delivery via serum albumin to the tumor target and subsequent MAOA inhibition. Further studies in a colon cancer mouse model found the ~ 65 kD SDS-PAGE band, bound to NMI, contained both MAOA and albumin proteins by mass spectrometry.Conclusion: NMI was shown to interact with MAOA and the blood carrier protein, albumin. This study provides insights for drug delivery and protein target specificity of NMI to image and treat cancer.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"307-318"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of the Extent of Blood-Brain Barrier Transport Using Machine Learning and Integration into the LeiCNS-PK3.0 Model.

IF 3.5 3区医学

Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-02-10 DOI: 10.1007/s11095-025-03828-0

Berfin Gülave, Helle W van den Maagdenberg, Luke van Boven, Gerard J P van Westen, Elizabeth C M de Lange, J G Coen van Hasselt

{"title":"Prediction of the Extent of Blood-Brain Barrier Transport Using Machine Learning and Integration into the LeiCNS-PK3.0 Model.","authors":"Berfin Gülave, Helle W van den Maagdenberg, Luke van Boven, Gerard J P van Westen, Elizabeth C M de Lange, J G Coen van Hasselt","doi":"10.1007/s11095-025-03828-0","DOIUrl":"10.1007/s11095-025-03828-0","url":null,"abstract":"Introduction: The unbound brain-to-plasma partition coefficient (Kp,uu,BBB) is an essential parameter for predicting central nervous system (CNS) drug disposition using physiologically-based pharmacokinetic (PBPK) modeling. Kp,uu,BBB values for specific compounds are however often unavailable, and are moreover time consuming to obtain experimentally. The aim of this study was to develop a quantitative structure-property relationship (QSPR) model to predict the Kp,uu,BBB and to demonstrate how QSPR-model predictions can be integrated into a physiologically-based pharmacokinetic model for the CNS.Methods: Rat Kp,uu,BBB values were obtained for 98 compounds from literature or in house historical data. For all compounds, 2D and 3D physico-chemical and structural properties were derived using the Molecular Operating Environment (MOE) software. Multiple machine learning (ML) regression models were compared for prediction of the Kp,uu,BBB, including random forest, support vector machines, K-nearest neighbors, and (sparse-) partial least squares. Finally, we demonstrate how the developed QSPR model predictions can be integrated into a CNS PBPK modeling workflow.Results: Among all ML algorithms, a random forest showed the best predictive performance for Kp,uu,BBB on test data with R2 value of 0.61 and 61% of all predictions were within twofold error. The obtained Kp,uu,BBB were successfully integrated into the LeiCNS-PK3.0 CNS PBPK model.Conclusions: The developed random forest QSPR model for Kp,uu,BBB prediction was found to have adequate performance, and can support drug discovery and development of novel investigational drugs targeting the CNS in conjunction with CNS PBPK modeling.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"281-289"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0