AAPS Journal最新文献

{"title":"In Vitro-In Silico Models to Elucidate Mechanisms of Bile Acid Disposition and Cellular Aerobics in Human Hepatocytes.","authors":"Kristof De Vos, Raf Mols, Sagnik Chatterjee, Miao-Chan Huang, Patrick Augustijns, Justina Clarinda Wolters, Pieter Annaert","doi":"10.1208/s12248-024-01010-9","DOIUrl":"10.1208/s12248-024-01010-9","url":null,"abstract":"<p><p>Understanding the kinetics of hepatic processes, such as bile acid (BA) handling and cellular aerobic metabolism, is crucial for advancing our knowledge of liver toxicity, particularly drug-induced cholestasis (DiCho). This article aimed to construct interpretable models with parameter estimations serving as reference values when investigating these cell metrics. Longitudinal datasets on BA disposition and oxygen consumption rates were collected using sandwich-cultured human hepatocytes. Chenodeoxycholic acid (CDCA), lithocholic acid (LCA), as well as their amidated and sulfate-conjugated metabolites were quantified with liquid chromatography-mass spectrometry. The bile salt export pump (BSEP) abundance was monitored with targeted proteomics and modelled for activity assessment. Oxygen consumption was measured using Seahorse XFp analyser. Ordinary differential equation-based models were solved in R. The basolateral uptake and efflux clearance of glycine-conjugated CDCA (GCDCA) were estimated at 1.22 µL/min/10⁶ cells (RSE 14%) and 0.11 µL/min/10⁶ cells (RSE 10%), respectively. The GCDCA clearance from canaliculi back to the medium was 2.22 nL/min/10⁶ cells (RSE 17%), and the dissociation constant between (G)CDCA and FXR for regulating BSEP abundance was 25.73 nM (RSE 11%). Sulfation clearance for LCA was 0.19 µL/min/10⁶ cells (RSE 11%). Model performance was further demonstrated by a maximum two-fold deviation of the 95% confidence boundaries from parameter estimates. These in vitro-in silico models provide a quantitative framework for exploring xenobiotic impacts on BA disposition, BSEP activity, and cellular aerobic metabolism in hepatocytes. Model simulations were consistent with reported in vivo data in progressive familial intrahepatic cholestasis type II patients.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"51"},"PeriodicalIF":5.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524564","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":"From Guidelines to Implementation: A Case Study on Applying ICH M10 for Bioanalytical Assay Cross-Validation.","authors":"Mianzhi Gu, Andrew Gehman, Brady Nifong, Andrew P Mayer, Vicky Li, Mary Birchler, Kai Wang, Huaping Tang","doi":"10.1208/s12248-025-01038-5","DOIUrl":"10.1208/s12248-025-01038-5","url":null,"abstract":"<p><p>Bioanalytical cross-validation plays a crucial role in ensuring data exchangeability throughout the assay life cycle for data generated between methods or laboratories. The ICH M10 guideline addresses gaps from previous guidelines concerning the conduct and data analysis of cross-validation studies. While the guideline provides high-level direction, it allows flexibility for sponsors to implement their own statistical analysis and acceptance criteria. This flexibility can lead to variability in interpretation and practices across the industry. This manuscript presents a practical framework for implementing ICH M10 in cross-validation studies, with an emphasis on rigorous experimental design and robust statistical analysis. Our approach integrates Incurred Sample Reanalysis (ISR) criteria, Bland-Altman analysis, and Deming regression. A case study illustrates the application of this framework in cross-validating a pharmacodynamic biomarker assay across multiple laboratories. Our study revealed significant inter-laboratory variability in post-dose measurements, driven by the dynamic equilibrium between free and complexed forms of the biomarker. Assay conditions, such as temperature and incubation time, were found to significantly contribute to the observed variability, suggesting that cross-laboratory comparisons of post-dose results are not reliable. In contrast, pre-treatment baseline samples, with no drug on board, exhibited strong alignment across laboratories. Our experimental design captures variability reflective of clinical trial datasets, and the integrated statistical methodology ensures a robust assessment of method variability. This framework supports reliable bioanalytical data integration for Pharmacokinetic/Pharmacodynamic (PK/PD) modeling and regulatory submissions.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"54"},"PeriodicalIF":5.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532152","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":"Unraveling Ceftriaxone Dosing: Free Drug Prediction, Threshold Optimization, and Model Validation.","authors":"Johnny Michel, Francesco Monti, Fabien Lamoureux, Djibril Diagouraga, Manuel Etienne, Muriel Quillard, Camille Molkhou, Fabienne Tamion, Sandrine Dahyot, Tania Petersen, Tony Pereira, Martine Pestel-Caron, Julien Grosjean, Thomas Duflot","doi":"10.1208/s12248-025-01041-w","DOIUrl":"10.1208/s12248-025-01041-w","url":null,"abstract":"<p><p>Ceftriaxone is pivotal in treating severe infections; however, predicting unbound plasma ceftriaxone (CEF_u) from total ceftriaxone (CEF_tot) remains challenging. This study aimed to (1) predict CEF_u from CEF_tot, (2) determine optimal target for CEF_tot trough concentration in plasma, (3) perform an external validation of published models, and (4) to ascertain whether the CEF dosing regimen was sufficient to achieve the therapeutic objectives. CEF_u predictions based on CEF_tot were evaluated using previously published models. Optimal CEF_tot targets for an MIC of 1mg/L were calculated to achieve CEF_u concentrations above MIC and 4xMIC 100% of the time. External validation was conducted assessing serum albumin, CEF_tot and CEF_u and comparing predicted CEF_u across models. Retrospective data, comprising 408 CEF_tot from 222 patients, were analyzed to assess the probability of target attainment (PTA) based on model predicted CEF_u. CEF_u predictions based on CEF_tot were evaluated using previously published models. Optimal CEF_tot targets for an MIC of 1mg/L were calculated to achieve CEF_u concentrations above MIC and 4xMIC 100% of the time. External validation was conducted assessing serum albumin, CEF_tot and CEF_u and comparing predicted CEF_u across models. Retrospective data, comprising 408 CEF_tot from 222 patients, were analyzed to assess the probability of target attainment (PTA) based on model predicted CEF_u. Optimal CEF_tot trough concentration targets ranged from 2.0 mg/L to 16.9 mg/L (1xMIC) and from 7.9 mg/L to 56.2 mg/L (4xMIC) across models. Some models accurately predicted CEF_u obtained from prospective external validation. In the retrospective cohort, PTA ranged from 94.4% to 98.7% for 1xMIC and from 66.9% to 97.3% for 4xMIC. Modeling or direct quantification of CEF_u may improve patient outcomes, but achieving this requires standardized analytical approaches and further research to assess the ability of published models to accurately predict CEF_u.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"50"},"PeriodicalIF":5.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517358","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":"Blend Uniformity and Content Uniformity in Oral Solid Dosage Manufacturing: an IQ Consortium Industry Position Paper.","authors":"Manel Bautista, Seb Caille, Claudia Corredor, Sankaran Anantharaman, Joseph Bradbury, Bei Chen, W Mark Eickhoff, Gregory Harmon, Mark Johnson, Fasheng Li, Anja Keubler, Laura Pfund, Alexander Russell, Kevin Sutcliffe, Claire Tridon","doi":"10.1208/s12248-025-01028-7","DOIUrl":"10.1208/s12248-025-01028-7","url":null,"abstract":"<p><p>The IQ Consortium Uniformity Testing Working Group reviewed the current BU and CU testing practices among ten member companies. All ten companies presented their current approach to BU and CU testing at the three stages of Product Lifecycle Management: the Process Design Stage, the Process Qualification Stage, and the Continuous Verification Stage. With this information on hand, the Uniformity Testing Working Group members developed a risk-based approach to BU and CU testing, and proposed innovative methods to reduce or eliminate blend sampling based on risk to Uniformity of Dosage Unit (UDU) testing. This approach uses prior knowledge, mechanistic understanding, and structured risk assessment tools to classify formulations as low-risk or high-risk, thus guiding the testing strategy. A decision tree was outlined on this basis for low-risk and high-risk formulations. The Working Group aims to influence health authorities on the matter, enabling streamlined testing expectations.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"49"},"PeriodicalIF":5.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517350","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":"AI-Driven Analysis of Drug Marketing Efficiency: Unveiling FDA Approval to Market Release Dynamics.","authors":"Yoshiyasu Takefuji","doi":"10.1208/s12248-025-01039-4","DOIUrl":"10.1208/s12248-025-01039-4","url":null,"abstract":"<p><p>This paper explores a novel approach using generative AI to enhance drug marketing strategies in the US pharmaceutical sector. By leveraging an official dataset sourced from the US government, the AI generates Python code to analyze the time interval between FDA approval dates and market release dates. The analysis identifies 370 manufacturers who achieved \"zero-day\" marketing-referring to drugs marketed immediately upon FDA approval-and 174 manufacturers who marketed their products within less than seven days of approval. Notably, 947 drug products were found to have been marketed prior to FDA approval, raising significant regulatory and ethical concerns that necessitate further discussion. The findings indicate that 174 drug manufacturers have the potential to optimize their marketing strategies to achieve zero-day timelines, prompting an examination of the feasibility of such acceleration within the current regulatory framework and its implications for industry practices. Additionally, this paper discusses the broader impact of AI-driven strategies in the pharmaceutical sector, highlighting their potential to not only enhance marketing speed but also improve aspects such as compliance and decision-making efficiency.　Furthermore, a tutorial on implementing generative AI is provided, detailing how it can be utilized to achieve marketing objectives through interactive conversations with the AI. This practical application demonstrates the technology's capabilities using real dataset analysis and reveals significant findings that could inform future strategies within the industry. The research objectives and their broader implications underscore the need for ongoing dialogue about the ethical and regulatory dimensions of AI in pharmaceutical marketing.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"48"},"PeriodicalIF":5.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469871","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":"Bioequivalence of ANDA Data using a Non-Informative Bayesian Procedure (BEST) Compared with the Two One‑Sided t‑Tests (TOST).","authors":"Jing Wang, Gregory Campbell, Jae H Lee, Meng Hu, Kairui Feng, Somesh Chattopadhyay, Liang Zhao, Carl C Peck","doi":"10.1208/s12248-024-00981-z","DOIUrl":"10.1208/s12248-024-00981-z","url":null,"abstract":"<p><p>The regulatory statistical standard for evaluating average bioequivalence (BE) in generic drug testing, formulation bridging, and 505b2 drug comparisons has traditionally employed the two one-sided t-tests (TOST) procedure. A comparison of BE determinations of TOST and a t-distribution-based, non-informative Bayesian procedure (Bayes_T) was conducted on 2341 pharmacokinetic parameter datasets in 678 anonymized abbreviated new drug applications (ANDAs) to assess the influence of deviations from lognormality and the presence of extreme values. This research has been motivated to assess reliability of statistical inference procedures for accurate and fair regulatory assessments of BE and non-BE (NBE). The BE criterion of 90% confidence (CI) or Bayesian credible (CrI) intervals of log test/reference ratios for TOST and Bayes_T was 0.80-1.25. TOST. Bayes_T agreed on BE conclusions in 98.9% of cases. There were 20 disagreed cases in which TOST rejected BE and Bayes_T concluded BE, wherein all cases failed the lognormality test and 17 of which contained extreme values (4.2% of 409 cases that contained extreme values). In this circumstance, TOST can be overly conservative in the presence of extreme values. There were 7 cases in which TOST concluded BE at outer BE bounds, while Bayes_T marginally rejected BE, despite these cases successfully passing the lognormality test. While TOST remains a widely accepted method for BE assessment, the presence of extreme values and deviations from lognormality may lead to faulty inference of BE. The Bayes_T methodology offers an alternative approach to TOST that can be prespecified to assess BE in such scenarios. Pre-specified application of the Bayes_T procedure may ensure more reliable outcomes in regulatory assessments of BE.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"47"},"PeriodicalIF":5.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460492","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":"Addressing Clinical Challenges in Aberrant Pharmacokinetics of Biologic Therapeutic Drugs: Investigating Sample Processing Procedure in the Immunoassays.","authors":"Yih-Wen Chen, Olinda Davenport, Nancy Yu, Rachel Melendez, James Nugteren, Ihsan Nijem, Weili Yan, Robert Hendricks, Yuan Song","doi":"10.1208/s12248-025-01036-7","DOIUrl":"10.1208/s12248-025-01036-7","url":null,"abstract":"<p><p>Bioanalytical Pharmacokinetics (PK) methods are designed for robust performance under rigorous regulatory compliance requirements to ensure the generated data is reliable and maintains integrity. In a phase 1 dose-finding clinical study, aberrant PK profiles of two co-administered biologics drugs were observed. Unexpectedly, we discovered high fill levels in collection tubes from the majority of samples. This led to the hypothesis that the highly filled tubes might cause difficulty in achieving complete sample thaw and thorough mixing at the time of sample analysis, potentially contributing to the abnormalities observed in the PK dataset. Evaluation of the impact of sample fill levels and processing procedure can be challenging since PK concentrations of study samples were unknown. Therefore, a systematic approach was employed to conduct a thorough examination using mock samples. The data illustrate a correlation between sample thawing and mixing process and the variability in the PK data. The concentrations from properly filled mock samples that underwent complete thawing and mixing showed 100% data reproducibility. In contrast, the concentrations from fully filled mock samples that did not follow the proper procedure showed sample recovery deviating by ± 30% from nominal value and exhibited considerable lack of precision. This data identified the root cause of aberrant PK, justifying revised sample preparation guidance and sample re-assay. Improved sample handling and subsequent reassay resolved the aberrant PK profile issues. In conclusion, this study reiterated that sample handling plays a crucial role in quality and reproducibility of PK data with immunoassays.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"46"},"PeriodicalIF":5.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450894","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":"Stability of Anti-Drug Antibodies Against Antibody Therapeutics.","authors":"Parul Sirohi, Kelly Hainline, Heather Bullock, Sihe Wang, Robert J Konrad, Yi Wen","doi":"10.1208/s12248-025-01030-z","DOIUrl":"10.1208/s12248-025-01030-z","url":null,"abstract":"<p><p>Biotherapeutics have the potential to elicit unwanted immune responses that can lead to the production of anti-drug antibodies (ADA). It is critical that ADA responses are detected, characterized, and monitored to understand the safety and efficacy of a drug. ADA samples must remain stable in long- and short-term storage conditions to ensure reliable analysis. Whereas the stability of anti-vaccine antibodies has been well-studied, there are few reports examining the stability of anti-therapeutic antibodies using clinical samples. In this study, ADA samples from four clinical trials of antibody therapeutics were found to be stable after long-term storage (1-10 years) at -80°C and short-term storage (24 h to two weeks) at 4°C, 22°C, and 37°C. In addition, samples were stable after 16 freeze/thaw cycles. The results demonstrate the stability of ADA in clinical samples under various conditions. Consequently, the results observed herein suggest that the routine assessment of ADA sample stability may not be warranted.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"45"},"PeriodicalIF":5.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426647","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":"Analysis on the Impact of U.S. FDA's Narrow Therapeutic Index Bioequivalence Criteria on Generic Drug Applications.","authors":"Krista Anim Anno, Mirette Mina, Zhen Zhang, Lei Zhang, Wenlei Jiang","doi":"10.1208/s12248-025-01020-1","DOIUrl":"10.1208/s12248-025-01020-1","url":null,"abstract":"<p><p>Since 2012, the U.S. Food and Drug Administration (FDA) has developed classification criteria of narrow therapeutic index (NTI) drug products and tightened bioequivalence (BE) standards for these products by recommending a fully replicated, two-sequence, two-treatment, four-period crossover study design where BE is based on passing both scaled average BE criterion and within-subject variability comparison criterion, as well as the average BE criterion of 80.00%-125.00%. Currently, the BE study design and criteria for NTI drugs are somewhat different across regulatory agencies. The objective of this study is to survey pharmacokinetic BE data of abbreviated new drug applications (ANDAs) of NTI drugs submitted to the FDA with initial submission dates between January 1, 2013 and October 1, 2022 to identify the impact of FDA's current BE approach on generic NTI approval. Thirty-three NTI drug products from 100 ANDAs were identified with 93 ANDAs included in analysis. Eighty-seven ANDAs had four-way crossover studies, with 69 and 106 fed and fasting BE studies, respectively. For all NTI drugs, the range of average S_WR for C_max, AUC_t, and AUC_inf was between 0.05 and 0.27. Of the 20 studies that failed BE, 90%, 5%, and 5% failed reference scaled criteria only, variability comparison criteria only, and both, respectively. Further communication of this work with global regulatory agencies and the scientific community will help better understand current FDA NTI BE criteria and review experiences. These efforts will support the development of harmonized BE criteria for NTI drugs, in turn improving patient access to generic NTI drugs.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"42"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411457","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":"Application of a Physiologically Based Pharmacokinetic Approach to Predict Tenofovir Pharmacokinetics During Pregnancy.","authors":"Khaled Abduljalil, Mailys De Sousa Mendes, Farzaneh Salem, Sihem Benaboud, Iain Gardner","doi":"10.1208/s12248-025-01031-y","DOIUrl":"10.1208/s12248-025-01031-y","url":null,"abstract":"<p><p>Pharmacotherapy during pregnancy requires a better understanding of the impact of changes in maternal physiology on the maternal and fetal drug exposure. The physiologically based pharmacokinetic (PBPK) modelling approach can be applied to predict maternal and fetal exposure. In vitro and in vivo PK data in non-pregnant individuals were compiled and used to develop and verify a PBPK model for tenofovir. The model was then used to predict the maternal and fetal tenofovir exposure during pregnancy, after incorporation of current knowledge on maternal and fetal physiological changes during pregnancy. Predicted concentrations and parameters from the PBPK model were compared to observed data. Predicted tenofovir PK agreed with observations in non-pregnant (13 studies) and pregnant (7 studies with differing gestational weeks) individuals. Observed concentrations fell within the PBPK 5th - 95th prediction intervals. Predicted PK parameters were within twofold of the reported parameters. The predicted tenofovir steady state cord-to-maternal exposure ratio at term was 0.85 (range: 0.62-0.98), which agrees with clinically observed ratios ranging between 0.60-1.00. A PBPK model for tenofovir was constructed and used to simulate the maternal and fetal exposure to tenofovir in virtual pregnant women population at different gestational weeks. Applying a similar approach to other drugs or chemicals may allow exposure prediction and risk assessment in the fetus following maternal administration of drugs or unintended exposure to environmental toxicants.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"43"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411459","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}