AAPS Journal最新文献_第2页

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

IF 5 3区医学

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

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

{"title":"Mass Balance in Pharmaceutical Stress Testing: A Review of Principles and Practical Applications.","authors":"Stacey Marden, John M Campbell, Neal Adams, Ronan Coelho, Chris Foti, Juçara Ribeiro Franca, Steven Hostyn, Zongyun Huang, Mariah Ultramari, Todd Zelesky, Steven W Baertschi","doi":"10.1208/s12248-024-00961-3","DOIUrl":"10.1208/s12248-024-00961-3","url":null,"abstract":"Stress testing (also known as forced degradation) of pharmaceutical drug substances and products is a critical part of the drug development process, providing insight into the degradation pathways of drug substances and drug products. This information is used to support the development of stability-indicating methods (SIMs) capable of detecting pharmaceutically relevant degradation products that might potentially be observed during manufacturing, long-term storage, distribution, and use. Assessing mass balance of stressed samples is a key aspect of developing SIMs and is a regulatory expectation. However, the approaches to measure, calculate, and interpret mass balance can vary among different pharmaceutical companies. Such disparities also pose difficulties for health authorities when reviewing mass balance assessments, which may result in the potential delay of drug application approvals. The authors have gathered input from 10 pharma companies to map out a practical review of science-based approaches and technical details to assess and interpret mass balance results. Key concepts of mass balance are introduced, various mass balance calculations are demonstrated, and recommendations on how to investigate poor mass balance results are presented using real-world case studies. Herein we provide a single source reference on the topic of mass balance in pharmaceutical forced degradation for small molecule drug substances and drug products in support of regulatory submissions with the goal of facilitating a shared understanding among pharmaceutical scientists and health authorities.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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

IF 5 3区医学

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

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

引用次数: 0

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

IF 5 3区医学

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

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

{"title":"Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease.","authors":"Andrew Shahidehpour, Mudassir Rashid, Mohammad Reza Askari, Mohammad Ahmadasas, Mahmoud Abdel-Latif, Cynthia Fritschi, Lauretta Quinn, Sirimon Reutrakul, Ulf G Bronas, Ali Cinar","doi":"10.1208/s12248-024-00962-2","DOIUrl":"10.1208/s12248-024-00962-2","url":null,"abstract":"Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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

IF 5 3区医学

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

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

{"title":"The Development of Epitope-Based Recombinant Protein Vaccines against SARS-CoV-2.","authors":"Kanwal Khalid, Hui Xuan Lim, Jung Shan Hwang, Chit Laa Poh","doi":"10.1208/s12248-024-00963-1","DOIUrl":"10.1208/s12248-024-00963-1","url":null,"abstract":"The COVID-19 pandemic continues to cause infections and deaths, which are attributable to the SARS-CoV-2 Omicron variant of concern (VOC). Moderna's response to the declining protective efficacies of current SARS-CoV-2 vaccines against Omicron was to develop a bivalent booster vaccine based on the Spike (S) protein from the Wuhan and Omicron BA.4/BA.5 strains. This approach, while commendable, is unfeasible in light of rapidly emerging mutated viral strains. PubMed and Google Scholar were systematically reviewed for peer-reviewed papers up to January 2024. Articles included focused on specific themes such as the clinical history of recombinant protein vaccine development against different diseases, including COVID-19, the production of recombinant protein vaccines using different host expression systems, aspects to consider in recombinant protein vaccine development, and overcoming problems associated with large-scale recombinant protein vaccine production. In silico approaches to identify conserved and immunogenic epitopes could provide broad protection against SARS-CoV-2 VOCs but require validation in animal models. The recombinant protein vaccine development platform has shown a successful history in clinical development. Recombinant protein vaccines incorporating conserved epitopes may utilize a number of expression systems, such as yeast (Saccharomyces cerevisiae), baculovirus-insect cells (Sf9 cells), and Escherichia coli (E. coli). Current multi-epitope subunit vaccines against SARS-CoV-2 utilizing synthetic peptides are unfeasible for large-scale immunizations. Recombinant protein vaccines based on conserved and immunogenic proteins produced using E. coli offer high production yields, convenient purification, and cost-effective production of large-scale vaccine quantities capable of protecting against the SARS-CoV-2 D614G strain and its VOCs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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

IF 5 3区医学

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

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

{"title":"Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach.","authors":"E M Tosca, D Ronchi, M Rocchetti, P Magni","doi":"10.1208/s12248-024-00960-4","DOIUrl":"10.1208/s12248-024-00960-4","url":null,"abstract":"Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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

IF 5 3区医学

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

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

{"title":"Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport.","authors":"Guiqin Liu, Qian Wang, Lu Tian, Mengyue Wang, Delong Duo, Yabin Duan, Yue Lin, Junjun Han, Qiangqiang Jia, Junbo Zhu, Xiangyang Li","doi":"10.1208/s12248-024-00957-z","DOIUrl":"10.1208/s12248-024-00957-z","url":null,"abstract":"Changes to blood-brain barrier structure and function may affect the delivery of drugs into the brain. It is worthwhile to exploring more study on how the blood-brain barrier changes in structure and function and how that affects drug transport in high-altitude hypoxic environment. The DIA high-throughput sequencing technique indicate that the rats blood-brain barrier has been identified to have 7252 proteins overall and 8 tight junction proteins, among which Claudin-7 was a plateau-specific tight junction protein under high-altitude hypoxia, and based on the interaction network study, 2421 proteins are found to interact with one another, with ZO-1 being the primary target. The results of the projected gene function analysis demonstrated that changes in tight junction proteins are related to the control of TRP channels by inflammatory mediators, the wnt signaling pathway, the ABC transporter system, and drug metabolism-CYP450 enzyme regulation. Additionally, the electron microscopy, the Evans blue combination with confocal laser scanning microscopy, and the Western Blot and RT-qPCR revealed that high-altitude hypoxic environment induces blood-brain barrier tight junctions to open, blood-brain barrier permeability increases, ZO-1, Occludin, Claudin-5 protein and mRNA expression decreased. Our research implies that structural and functional alterations in the blood-brain barrier induced by high altitude hypoxia may impact drug transport inside the central nervous system, and that drug transporters and drug-metabolizing enzymes may be key players in this process.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Investigation of In Vitro Anti-Cancer Efficacy of Dihydroartemisinin-Loaded Bovine Milk Exosomes Against Triple-Negative Breast Cancer. 二氢青蒿素载体牛乳外泌体对三阴性乳腺癌的体外抗癌疗效研究

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-06 DOI: 10.1208/s12248-024-00958-y

Dulla Naveen Kumar, Aiswarya Chaudhuri, Udita Shiromani, Dinesh Kumar, Ashish Kumar Agrawal

{"title":"An Investigation of In Vitro Anti-Cancer Efficacy of Dihydroartemisinin-Loaded Bovine Milk Exosomes Against Triple-Negative Breast Cancer.","authors":"Dulla Naveen Kumar, Aiswarya Chaudhuri, Udita Shiromani, Dinesh Kumar, Ashish Kumar Agrawal","doi":"10.1208/s12248-024-00958-y","DOIUrl":"10.1208/s12248-024-00958-y","url":null,"abstract":"Repurposing drugs offers several advantages, including reduced time and cost compared to developing new drugs from scratch. It leverages existing knowledge about drug safety, dosage, and pharmacokinetics, expediting the process of clinical trials and regulatory approval. Dihydroartemisinin (DHA) is a semi-synthetic and active metabolite of all artemisinin molecules and is FDA-approved for the treatment of malaria. Apart from having anti-malarial properties, DHA also possesses anticancer properties. However, its pharmacological actions are limited by toxicity and solubility problems. To overcome these challenges and enhance its anticancer effectiveness, we designed an exosomal formulation of DHA. We isolated exosomes from bovine milk using differential ultracentrifugation and loaded DHA using sonication. Scanning and transition electron microscopy revealed a size of roughly 100 nm, with a spherical shape. Furthermore, in pH 7.4 and 5.5, the exosomes exhibited burst release followed by sustained release. Multiple in vitro cell culture tests demonstrated that Exo-DHA exhibited enhanced anticancer activity, including cytotoxicity, cellular uptake, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, and inhibition of colony formation. Additional evidence supporting Exo-DHA's anti-migration ability came from transwell migration and scratch assays. Based on these results, it was concluded that the anticancer efficacy of DHA was improved when loaded into bovine milk-derived exosomes. While the in vitro results are encouraging, more in vivo testing in suitable animal models and biochemical marker analysis are warranted.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898902","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

Non-Invasive, Continuous, Quantitative Detection of Solvent Content in Vacuum Tray Drying. 无创、连续、定量检测真空托盘干燥过程中的溶剂含量。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-02 DOI: 10.1208/s12248-024-00944-4

Michel Y Louge, Jasdeep Mandur, Plamen Grigorov, William Blincoe, David Lamberto, Colton Bower, Robert F Meyer

引用次数: 0

A Data Driven Strategy and Case Study for Implementation of Singlicate Analysis in Ligand Binding Assays Used for PK Quantitation. 在用于 PK 定量的配体结合试验中实施单一分析的数据驱动策略和案例研究。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-31 DOI: 10.1208/s12248-024-00959-x

Qiang Qu, Susana Liu, Zhiping You, Gregory S Steeno, Lisa A Dyleski, Xue Mu, Ying Wang, Daniel Baltrukonis

{"title":"A Data Driven Strategy and Case Study for Implementation of Singlicate Analysis in Ligand Binding Assays Used for PK Quantitation.","authors":"Qiang Qu, Susana Liu, Zhiping You, Gregory S Steeno, Lisa A Dyleski, Xue Mu, Ying Wang, Daniel Baltrukonis","doi":"10.1208/s12248-024-00959-x","DOIUrl":"10.1208/s12248-024-00959-x","url":null,"abstract":"Duplicate analysis has been a conventional practice in the industry for ligand-binding assays (LBA), particularly for plate-based platforms like Enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) assays. Recent whitepapers and guidance have opened a door to exploring the implementation of single-well (singlicate) analysis approach for LBAs. Although the bioanalytical industry has actively investigated the suitability of singlicate analysis, applications in supporting regulated LBA bioanalysis are limited. The primary reason for this limitation is the absence of appropriate strategy to facilitate the transition from duplicate to singlicate analysis. In this paper we present the first case study with our data-driven approach to implement singlicate analysis in a clinical pharmacokinetics (PK) plate based LBA assay with ISR data. The central aspect of this strategy is a head-to-head comparison with Precision and Accuracy assessment in both duplicate and singlicate formats as the initial stage of assay validation. Subsequently, statistical analysis is conducted to evaluate method variability in both precision and accuracy. The results of our study indicated that there was no impactful difference between duplicate vs singlicate, affirming the suitability of singlicate analysis for the remaining steps of PK assay validation. The validation results obtained through singlicate analysis demonstrated acceptable assay performance characteristics across all validation parameters, aligning with regulatory guidance. The validated PK assay in singlicate has been employed to support a Phase I study. The appropriateness of singlicate analyses is further supported by initial Incurred Sample Reanalysis (ISR) data in which 90.1% of ISR samples fall within the acceptable criteria.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861570","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

Recommendations for Development and Validation of a Fit-For-Purpose Biomarker Assays Using Western Blotting; An-AAPS Sponsored Initiative to Harmonize Industry Practices. 使用 Western 印迹法开发和验证适用于目的的生物标志物检测的建议；AAPS 赞助的协调行业实践的倡议。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-25 DOI: 10.1208/s12248-024-00946-2

Arvind Kinhikar, Mohamed Hassanein, Jake Harman, Catherine Soderstrom, Kimberly Honrine, Amy Lavelle, Marie-Anne Valentin, Joel Mathews

{"title":"Recommendations for Development and Validation of a Fit-For-Purpose Biomarker Assays Using Western Blotting; An-AAPS Sponsored Initiative to Harmonize Industry Practices.","authors":"Arvind Kinhikar, Mohamed Hassanein, Jake Harman, Catherine Soderstrom, Kimberly Honrine, Amy Lavelle, Marie-Anne Valentin, Joel Mathews","doi":"10.1208/s12248-024-00946-2","DOIUrl":"10.1208/s12248-024-00946-2","url":null,"abstract":"Western blot (WB) assays are routinely used for detection and quantification of biomarkers. Although assay validation to measure biomarkers in complex matrices has become a mainstay process for ligand binding assays (LBA) and mass spectrometry (MS), no guidelines exist yet validate biomarker methods using WB techniques. In this cross-industry white paper, we outlined in detail the key steps for development and for validation of WB assays for protein biomarkers under different contexts of use (COU). In addition, we described how to determine the level of assay validation needed for biomarker assays using Western blotting. For simplicity, we described two paths of WB assay validation. The first path (Path 1) is for biomarkers being analyzed for exploratory research or for internal go- or no/go- decision making. The second path (Path 2) is for clinical decision making such as dose determination or drug response that need to be run in a regulated environment. This work is supported through AAPS Biomarkers and Precision Medicine subteam and represents AAPS members opinion.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767970","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