AAPS Journal最新文献_第9页

Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications. 调节乳液性质会影响用于药物递送应用的聚（己内酯）颗粒的尺寸。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00869-4

Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens

{"title":"Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications.","authors":"Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens","doi":"10.1208/s12248-023-00869-4","DOIUrl":"10.1208/s12248-023-00869-4","url":null,"abstract":"Advances in drug delivery have been accelerated with the addition of polymeric drug carriers. Direct delivery to a target site is a promising step in developing effective drug and gene therapies to treat disease. The efficacy of these drug carriers heavily relies on cell uptake without compromising critical cellular processes that promote cell viability. Drug release from biodegradable polymers is mediated largely by polymer degradation, and therefore the rate of polymer degradation dictates the feasibility of drug delivery applications. Traditionally, poly(caprolactone) (PCL) has only been used in long-term biomedical applications because the degradation time is much slower than other polymers. However, the biocompatibility of this polymer and the potential for longer delivery windows renders it a promising polymer candidate for drug delivery. In this work, we outline sixteen emulsion solvent evaporation preparation methods for PCL nanoparticles and microparticles to develop particles between 300 nm and 1.7 μm and with zeta potentials of -1.8 mV. We further investigated particles in a size range suitable for systemic tumor delivery and inhaled aerosol delivery to determine cell biocompatibility with the polymer in lung adenocarcinoma, endometrial adenocarcinoma, and human embryonic kidney cells. We determined these particles aren't detrimental to cell viability below particle monolayer coverage atop cells and therefore these formulations hold promise for the next stage of development as sustained-release drug delivery carriers.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566038","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

Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors. 用于病毒载体基因治疗的转基因产物的种间标度：使用来自11种病毒载体的数据的方法评估。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00867-6

Tao Zhang, Peng Zou

{"title":"Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.","authors":"Tao Zhang, Peng Zou","doi":"10.1208/s12248-023-00867-6","DOIUrl":"10.1208/s12248-023-00867-6","url":null,"abstract":"The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566037","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

Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development. 建模和模拟在临床前和临床长效注射药物开发中的作用。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-17 DOI: 10.1208/s12248-023-00864-9

Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal

{"title":"Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development.","authors":"Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal","doi":"10.1208/s12248-023-00864-9","DOIUrl":"10.1208/s12248-023-00864-9","url":null,"abstract":"Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240633","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: 1

Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans. 从重组CYP1A1到人的底物内在清除的定量翻译。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-05 DOI: 10.1208/s12248-023-00863-w

Li Di

{"title":"Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans.","authors":"Li Di","doi":"10.1208/s12248-023-00863-w","DOIUrl":"10.1208/s12248-023-00863-w","url":null,"abstract":"CYP1A1 is a cytochrome P450 family 1 enzyme that is mostly expressed in the extrahepatic tissues. To understand the CYP1A1 contribution to drug clearance in humans, we examined the in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CLint) for a set of drugs that are in vitro CYP1A1 substrates. Despite being strong in vitro CYP1A1 substrates, 82% of drugs gave good IVIVE with predicted CLint within 2-3-fold of the observed values using human liver microsomes and hepatocytes, suggesting they were not in vivo CYP1A1 substrates due to the lack of extrahepatic contribution to CLint. Only three drugs (riluzole, melatonin and ramelteon) that are CYP1A2 substrates yielded significant underprediction of in vivo CLint up to 11-fold. The fold of CLint underprediction was linearly proportional to human recombinant CYP1A1 (rCYP1A1) CLint, indicating they were likely to be in vivo CYP1A1 substrates. Using these three substrates, a calibration curve can be developed to enable direct translation from in vitro rCYP1A1 CLint to in vivo extrahepatic contributions in humans. In vivo CYP1A1 substrates are planar and small, which is consistent with the structure of the active site. This is in contrast to the in vitro substrates, which include large and nonplanar molecules, suggesting rCYP1A1 is more accessible than what is in vivo. The impact of CYP1A1 on first-pass intestinal metabolism was also evaluated and shown to be minimal. This is the first study providing new insights on in vivo translation of CYP1A1 contributions to human clearance using in vitro rCYP1A1 data.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164815","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

Applications of Modeling and Simulation Approaches in Support of Drug Product Development of Oral Dosage Forms and Locally Acting Drug Products: a Symposium Summary. 建模和模拟方法在支持口服剂型和局部作用药物产品开发中的应用：研讨会总结。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-02 DOI: 10.1208/s12248-023-00862-x

Eleftheria Tsakalozou, Mohamed-Eslam F Mohamed, Sebastian Polak, Tycho Heimbach

{"title":"Applications of Modeling and Simulation Approaches in Support of Drug Product Development of Oral Dosage Forms and Locally Acting Drug Products: a Symposium Summary.","authors":"Eleftheria Tsakalozou, Mohamed-Eslam F Mohamed, Sebastian Polak, Tycho Heimbach","doi":"10.1208/s12248-023-00862-x","DOIUrl":"10.1208/s12248-023-00862-x","url":null,"abstract":"The number of modeling and simulation applications, including physiologically based pharmacokinetic (PBPK) models, physiologically based biopharmaceutics modeling (PBBM), and empirical models, has been constantly increasing along with the regulatory acceptance of these methodologies. While aiming at minimizing unnecessary human testing, these methodologies are used today to support the development and approval of novel drug products and generics. Modeling approaches are leveraged today for assessing drug-drug interaction, informing dose adjustments in renally or hepatically impaired patients, perform dose selection in pediatrics and pregnant women and diseased populations, and conduct biopharmaceutics-related assessments such as establish clinically relevant specifications for drug products and achieve quality assurance throughout the product life cycle. In the generics space, PBPK analyses are utilized toward virtual bioequivalence assessments within the scope of alternative bioequivalence approaches, product-specific guidance development, and food effect assessments among others. Case studies highlighting the evolving and expanding role of modeling and simulation approaches within the biopharmaceutics space were presented at the symposium titled \"Model Informed Drug Development (MIDD): Role in Dose Selection, Vulnerable Populations, and Biowaivers - Chemical Entities\" and Prologue \"PBPK/PBBM to inform the Bioequivalence Safe Space, Food Effects, and pH-mediated DDIs\" at the American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 Annual Meeting in Boston, MA, on October 16-19, 2022, and are summarized here.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41146395","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

Single Particle Chemical Characterisation of Nanoformulations for Cargo Delivery. 货运用纳米制剂的单粒子化学特性。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-02 DOI: 10.1208/s12248-023-00855-w

Catherine Saunders, Camille A de Villiers, Molly M Stevens

引用次数: 1

RNA Nanomedicine: Delivery Strategies and Applications. RNA纳米医学：递送策略和应用。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-02 DOI: 10.1208/s12248-023-00860-z

Junho Byun, Yina Wu, Jinwon Park, Jung Suk Kim, Qiaoyun Li, Jaehyun Choi, Namjo Shin, Meng Lan, Yu Cai, Jaiwoo Lee, Yu-Kyoung Oh

{"title":"RNA Nanomedicine: Delivery Strategies and Applications.","authors":"Junho Byun, Yina Wu, Jinwon Park, Jung Suk Kim, Qiaoyun Li, Jaehyun Choi, Namjo Shin, Meng Lan, Yu Cai, Jaiwoo Lee, Yu-Kyoung Oh","doi":"10.1208/s12248-023-00860-z","DOIUrl":"10.1208/s12248-023-00860-z","url":null,"abstract":"Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique challenges due to its susceptibility to degradation and the requirement for efficient intracellular delivery. The integration of nanotechnologies with RNA delivery has addressed many of these challenges. In this review, we discuss different strategies employed in the design and development of nanomaterials for RNA delivery. We also highlight recent advances in the pharmaceutical applications of RNA delivered via nanomaterials. Various nanomaterials, such as lipids, polymers, peptides, nucleic acids, and inorganic nanomaterials, have been utilized for delivering functional RNAs, including messenger RNA (mRNA), small interfering RNA, single guide RNA, and microRNA. Furthermore, the utilization of nanomaterials has expanded the applications of functional RNA as active pharmaceutical ingredients. For instance, the delivery of antigen-encoding mRNA using nanomaterials enables the transient expression of vaccine antigens, leading to immunogenicity and prevention against infectious diseases. Additionally, nanomaterial-mediated RNA delivery has been investigated for engineering cells to express exogenous functional proteins. Nanomaterials have also been employed for co-delivering single guide RNA and mRNA to facilitate gene editing of genetic diseases. Apart from the progress made in RNA medicine, we discuss the current challenges and future directions in this field.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41165119","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 Antibody-Dependent Cellular Cytotoxicity Assay for Detecting Ocrelizumab Neutralizing Antibody. 用于检测奥雷利珠单抗中和抗体的抗体依赖性细胞毒性测定。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-02 DOI: 10.1208/s12248-023-00858-7

Van Nguyen, Anthony Cheung, Robert Hendricks, Kun Peng, Shan Chung

{"title":"An Antibody-Dependent Cellular Cytotoxicity Assay for Detecting Ocrelizumab Neutralizing Antibody.","authors":"Van Nguyen, Anthony Cheung, Robert Hendricks, Kun Peng, Shan Chung","doi":"10.1208/s12248-023-00858-7","DOIUrl":"10.1208/s12248-023-00858-7","url":null,"abstract":"Ocrelizumab (OCREVUS®) is a humanized anti-CD20 monoclonal antibody approved for the treatment of adult patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Here, we discuss the strategic and technical considerations needed to develop a robust antibody-dependent cellular cytotoxicity (ADCC)-based neutralizing antibody (NAb) assay to detect anti-ocrelizumab NAb in patients enrolled in the ocrelizumab registered clinical trials. The NAb detection assay consisted of a two-tier assay that included a screening assay and a confirmation assay. In the screening assay, patient samples were analyzed in the presence of ocrelizumab. Samples that tested positive in the screening assay were subsequently analyzed in the confirmatory assay where another anti-CD20 mAb, obinutuzumab, was replaced by ocrelizumab, to verify NAb specificity. Both assays utilized MEC-2 cells, a chronic B cell leukemia cell line, pre-labeled with calcein AM as the target cells, and natural killer (NK) cells engineered to stably express Fc gamma receptor IIIa_ F158 as effector cells. Both cell lines were prepared to be thaw-and-use cells. The NAb assay measures fluorescence from the calcein AM released into the assay media upon the lysis of target cells by ADCC in the presence of ocrelizumab or obinutuzumab. Our validated NAb assay showed a relative sensitivity of 743 ng/mL and can detect 1500 ng/mL of a surrogate positive control antibody in the presence of 1500 ng/mL ocrelizumab. This ADCC assay is the first reported NAb assay that directly measures target cell lysis by using thaw-and-use target and effector cells simultaneously.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41150893","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

Optimization of Peripheral Blood Mononuclear Cell Processing for Improved Clinical ELISpot Assay Performance. 优化外周血单核细胞处理以提高临床ELISpot测定性能。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-28 DOI: 10.1208/s12248-023-00861-y

Xinyuan Li, Shan He, Jaya Thomas, Bonnie Wu, Tong-Yuan Yang, Michael Swanson

{"title":"Optimization of Peripheral Blood Mononuclear Cell Processing for Improved Clinical ELISpot Assay Performance.","authors":"Xinyuan Li, Shan He, Jaya Thomas, Bonnie Wu, Tong-Yuan Yang, Michael Swanson","doi":"10.1208/s12248-023-00861-y","DOIUrl":"10.1208/s12248-023-00861-y","url":null,"abstract":"Cell and gene therapies have demonstrated impressive therapeutic efficacy in various human diseases. Nevertheless, cellular immune response directed against these therapeutic agents is an obstacle for achieving long-lasting clinical efficacy. Therefore, it is crucial to develop robust assays to accurately monitor cellular immunogenicity towards these therapies. Enzyme-linked immunospot (ELISpot) assay is one of the primarily used methods for measuring cellular immune response in clinical programs, which requires isolation of the peripheral blood mononuclear cells (PBMCs). The quality of this clinical material is one of the most critical factors that impact the robust assessment of cellular immune responses. The optimal blood sample processing conditions, however, remain poorly understood. In this study, we examined the impact of blood sample processing time on the performance characteristics of ELISpot to measure antigen-specific cellular responses. Blood samples that were processed after overnight delay resulted in a loss of ELISpot signals. We subsequently optimized several parameters of sample processing, and successfully recovered ELISpot signals for the blood samples that are processed within 32 h. Furthermore, several mitigation strategies were employed that would potentially address the impact of granulocyte contamination on detection of antigen-specific cellular responses. Our investigation provides an extension of sample processing window for clinical studies and is significant for resolving the logistical challenge of whole blood sample shipment for timely PBMC preparation in cell/gene therapy clinical studies.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41146150","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

Addressing Domain Specificity in the Development of a Cell-Based Binding Assay for the Detection of Neutralizing Antibodies Against a CD47xPD-L1 Bispecific Antibody. 在开发用于检测针对CD47xPD-L1双特异性抗体的中和抗体的基于细胞的结合测定中解决结构域特异性。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-22 DOI: 10.1208/s12248-023-00856-9

Michael Luong, Ying Wang, Brianna B Donnelly, Christopher Lepsy

{"title":"Addressing Domain Specificity in the Development of a Cell-Based Binding Assay for the Detection of Neutralizing Antibodies Against a CD47xPD-L1 Bispecific Antibody.","authors":"Michael Luong, Ying Wang, Brianna B Donnelly, Christopher Lepsy","doi":"10.1208/s12248-023-00856-9","DOIUrl":"10.1208/s12248-023-00856-9","url":null,"abstract":"PF-07257876 is a bispecific antibody being developed for the treatment of certain advanced or metastatic solid tumors. To support clinical development of PF-07257876, neutralizing antibody (NAb) assays were developed as part of a tiered immunogenicity testing approach. Because PF-07257876 targets both CD47 and PD-L1, determination of domain specificity of a NAb response may provide additional insight relating to PK, efficacy, and safety. Due to limitations of functional cell systems, two cell-based binding assays were developed using electrochemiluminescence to detect domain-specific NAb. While both NAb assays utilized a cell-based binding approach and shared certain requirements, such as sensitivity and tolerance to potentially interfering substances, the development of each assay faced unique challenges. Among the hurdles encountered, achieving drug tolerance while preserving domain specificity for CD47 proved particularly challenging. Consequently, a sample pretreatment procedure to isolate NAb from potentially interfering substances was necessary. The sample pretreatment procedure developed was based on a bead-extraction and acid dissociation (BEAD) approach. However, the use of the standard BEAD approach with whole drug to capture NAb resulted in loss of NAb detection under certain circumstances. Specifically, mock samples containing a mixture of NAb positive controls against both binding domains of the bispecific antibody produced false-negative results in the cell-based binding assay. An adaptation made to the standard BEAD approach restored domain-specific NAb detection, while also contributing to an assay sensitivity of 1 µg/mL in the presence of a clinically relevant drug tolerance level of up to 400 µg/mL.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153756","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