Pharmaceutical Research最新文献

{"title":"Comparison of Relative Activity versus Relative Expression Factors (RAF versus REF) in Predicting Glucuronidation Mediated Drug Clearance Using Recombinant UGTs.","authors":"Sandhya Subash, Deepak Ahire, Mitesh Patel, Sahil Shaikh, Dilip Kumar Singh, Sujal Deshmukh, Bhagwat Prasad","doi":"10.1007/s11095-024-03750-x","DOIUrl":"10.1007/s11095-024-03750-x","url":null,"abstract":"<p><strong>Purpose: </strong>Predicting the quantitative fraction of glucuronidation (f_gluc) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict f_gluc based on rUGT data to human liver and intestinal microsomes (HLM and HIM).</p><p><strong>Methods: </strong>REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting f_gluc was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir.</p><p><strong>Results: </strong>The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in f_gluc prediction.</p><p><strong>Conclusion: </strong>The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in f_gluc scaling.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1621-1630"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898015","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}

{"title":"Quality and Safety Considerations for Therapeutic Products Based on Extracellular Vesicles.","authors":"Yoshinobu Takakura, Rikinari Hanayama, Kazunari Akiyoshi, Shiroh Futaki, Kyoko Hida, Takanori Ichiki, Akiko Ishii-Watabe, Masahiko Kuroda, Kazushige Maki, Yasuo Miura, Yoshiaki Okada, Naohiro Seo, Toshihide Takeuchi, Teruhide Yamaguchi, Yusuke Yoshioka","doi":"10.1007/s11095-024-03757-4","DOIUrl":"10.1007/s11095-024-03757-4","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1573-1594"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902603","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}

{"title":"The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.","authors":"Ehsan Nozohouri, Yeseul Ahn, Sumaih Zoubi, Dhavalkumar Patel, Sabrina Rahman Archie, Khondker Ayesha Akter, Muhammad Bilal Siddique, Juyang Huang, Thomas J Abbruscato, Ulrich Bickel","doi":"10.1007/s11095-024-03735-w","DOIUrl":"10.1007/s11095-024-03735-w","url":null,"abstract":"<p><strong>Purpose: </strong>We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABA_A receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo.</p><p><strong>Methods: </strong>Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [¹³C₁₂]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, K_in, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point.</p><p><strong>Results: </strong>The K_in value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma.</p><p><strong>Conclusions: </strong>Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1599-1611"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752375","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}

{"title":"Cytopathic Effect Detection and Clonal Selection using Deep Learning.","authors":"Yu Yuan, Tony Wang, Jordan Sims, Kim Le, Cenk Undey, Erdal Oruklu","doi":"10.1007/s11095-024-03749-4","DOIUrl":"10.1007/s11095-024-03749-4","url":null,"abstract":"<p><strong>Purpose: </strong>In biotechnology, microscopic cell imaging is often used to identify and analyze cell morphology and cell state for a variety of applications. For example, microscopy can be used to detect the presence of cytopathic effects (CPE) in cell culture samples to determine virus contamination. Another application of microscopy is to verify clonality during cell line development. Conventionally, inspection of these microscopy images is performed manually by human analysts. This is both tedious and time consuming. In this paper, we propose using supervised deep learning algorithms to automate the cell detection processes mentioned above.</p><p><strong>Methods: </strong>The proposed algorithms utilize image processing techniques and convolutional neural networks (CNN) to detect the presence of CPE and to verify the clonality in cell line development.</p><p><strong>Results: </strong>We train and test the algorithms on image data which have been collected and labeled by domain experts. Our experiments have shown promising results in terms of both accuracy and speed.</p><p><strong>Conclusion: </strong>Deep learning algorithms achieve high accuracy (more than 95%) on both CPE detection and clonal selection applications, resulting in a highly efficient and cost-effective automation process.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1659-1669"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760270","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}

{"title":"Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.","authors":"Wenxi Song, Na Wang, Ao Li, Xiongtao Ji, Xin Huang, Ting Wang, Hongxun Hao","doi":"10.1007/s11095-024-03748-5","DOIUrl":"10.1007/s11095-024-03748-5","url":null,"abstract":"<p><strong>Purpose: </strong>The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects.</p><p><strong>Methods: </strong>In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques.</p><p><strong>Results: </strong>The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1737-1754"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793051","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}

{"title":"Correction: Comment on the article: In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.","authors":"M J Giménez, L Aguilar, L Alou, D Sevillano","doi":"10.1007/s11095-024-03753-8","DOIUrl":"10.1007/s11095-024-03753-8","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1755"},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898016","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}

{"title":"Predictive Value of Vancomycin AUC₂₄/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.","authors":"Yuki Hanai, Hideki Hashi, Kazumi Hanawa, Aiju Endo, Taito Miyazaki, Tetsuo Yamaguchi, Sohei Harada, Takuya Yokoo, Shusuke Uekusa, Takaya Namiki, Yoshiaki Yokoyama, Daiki Asakawa, Ryo Isoda, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto, Kazuhiro Matsuo","doi":"10.1007/s11095-024-03728-9","DOIUrl":"10.1007/s11095-024-03728-9","url":null,"abstract":"<p><strong>Background: </strong>Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC₂₄/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC₂₄/MIC ratio associated with treatment outcomes of infections treated with vancomycin.</p><p><strong>Methods: </strong>This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC₂₄/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC₂₄/MIC and outcomes.</p><p><strong>Results: </strong>This study included 82 patients. ROC identified a target AUC₂₄/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC₂₄/MIC cutoff (34.1%) than for above AUC₂₄/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC₂₄/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups.</p><p><strong>Conclusions: </strong>In treating severe/complicated MRSA infections, vancomycin AUC₂₄/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC₂₄/MIC ratios.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1381-1389"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420306","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}

{"title":"Duo photoprotective effect via silica-coated zinc oxide nanoparticles and Vitamin C nanovesicles composites.","authors":"Soha M Kandil, Heba M Diab, Amal M Mahfoz, Ahmed Elhawatky, Ebtsam M Abdou","doi":"10.1007/s11095-024-03733-y","DOIUrl":"10.1007/s11095-024-03733-y","url":null,"abstract":"<p><strong>Objective: </strong>Zinc Oxide nanoparticles (ZnO NPs) are used widely in nowadays personal care products, especially sunscreens, as a protector against UV irradiation. Yet, they have some reports of potential toxicity. Silica is widely used to cage ZnO NPs to reduce their potential toxicity. Vitamin C derivative, Magnesium Ascorpyl Phosphate (MAP), is a potent antioxidant that can efficiently protect human skin from harmful impacts of UV irradiation and oxidative stress. The combination of silica coated ZnO NPs and MAP nanovesicles could have potential synergistic protective effect against skin photodamage.</p><p><strong>Methods: </strong>Silica coated ZnO NPs and MAP nanovesicles (ethosomes and niosomes) were synthesized, formulated, and evaluated as topical gels. These gel formulations were evaluated in mice for their photoprotective effect against UV irradiation through histopathology and immuno-histochemistry study. Split-face clinical study was conducted to compare the effect of application of silica coated ZnO NPs either alone or combined with MAP nanovesicles. Their photoprotective action was evaluated, using Antera 3D® camera, for melanin level, roughness index and wrinkles depth.</p><p><strong>Results: </strong>Silica coated ZnO NPs when combined with MAP nanovesicles protected mice skin from UV irradiation and decreased the expression of the proinflammatory cytokines, NF-κB. Clinically, silica coated ZnO NPs, alone or combined with MAP nanovesicles, could have significant effect to decrease melanin level, roughness index and wrinkles depth with higher effect for the combination.</p><p><strong>Conclusion: </strong>A composite of silica coated ZnO NPs and MAP nanovesicles could be a promising cosmetic formulation for skin protection against photodamage signs such as hyperpigmentation, roughness, and wrinkles.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1475-1491"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591016","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}

{"title":"Stability of Protein Pharmaceuticals: Recent Advances.","authors":"Mark Cornell Manning, Ryan E Holcomb, Robert W Payne, Joshua M Stillahn, Brian D Connolly, Derrick S Katayama, Hongcheng Liu, James E Matsuura, Brian M Murphy, Charles S Henry, Daan J A Crommelin","doi":"10.1007/s11095-024-03726-x","DOIUrl":"10.1007/s11095-024-03726-x","url":null,"abstract":"<p><p>There have been significant advances in the formulation and stabilization of proteins in the liquid state over the past years since our previous review. Our mechanistic understanding of protein-excipient interactions has increased, allowing one to develop formulations in a more rational fashion. The field has moved towards more complex and challenging formulations, such as high concentration formulations to allow for subcutaneous administration and co-formulation. While much of the published work has focused on mAbs, the principles appear to apply to any therapeutic protein, although mAbs clearly have some distinctive features. In this review, we first discuss chemical degradation reactions. This is followed by a section on physical instability issues. Then, more specific topics are addressed: instability induced by interactions with interfaces, predictive methods for physical stability and interplay between chemical and physical instability. The final parts are devoted to discussions how all the above impacts (co-)formulation strategies, in particular for high protein concentration solutions.'</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1301-1367"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470042","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}

{"title":"A Combination of Machine Learning and PBPK Modeling Approach for Pharmacokinetics Prediction of Small Molecules in Humans.","authors":"Yuelin Li, Zonghu Wang, Yuru Li, Jiewen Du, Xiangrui Gao, Yuanpeng Li, Lipeng Lai","doi":"10.1007/s11095-024-03725-y","DOIUrl":"10.1007/s11095-024-03725-y","url":null,"abstract":"<p><strong>Purpose: </strong>Recently, there has been rapid development in model-informed drug development, which has the potential to reduce animal experiments and accelerate drug discovery. Physiologically based pharmacokinetic (PBPK) and machine learning (ML) models are commonly used in early drug discovery to predict drug properties. However, basic PBPK models require a large number of molecule-specific inputs from in vitro experiments, which hinders the efficiency and accuracy of these models. To address this issue, this paper introduces a new computational platform that combines ML and PBPK models. The platform predicts molecule PK profiles with high accuracy and without the need for experimental data.</p><p><strong>Methods: </strong>This study developed a whole-body PBPK model and ML models of plasma protein fraction unbound ( <math><msub><mi>f</mi> <mrow><mi>up</mi></mrow> </msub> </math> ), Caco-2 cell permeability, and total plasma clearance to predict the PK of small molecules after intravenous administration. Pharmacokinetic profiles were simulated using a \"bottom-up\" PBPK modeling approach with ML inputs. Additionally, 40 compounds were used to evaluate the platform's accuracy.</p><p><strong>Results: </strong>Results showed that the ML-PBPK model predicted the area under the concentration-time curve (AUC) with 65.0 <math><mo>%</mo></math> accuracy within a 2-fold range, which was higher than using in vitro inputs with 47.5 <math><mo>%</mo></math> accuracy.</p><p><strong>Conclusion: </strong>The ML-PBPK model platform provides high accuracy in prediction and reduces the number of experiments and time required compared to traditional PBPK approaches. The platform successfully predicts human PK parameters without in vitro and in vivo experiments and can potentially guide early drug discovery and development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1369-1379"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451175","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}