AAPS Journal最新文献

Pharmacokinetic-pharmacodynamic Modelling of NH600001 in Healthy Subjects and Patients Undergoing Gastroscopy.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-21 DOI: 10.1208/s12248-024-01004-7

Yaxin Liu, Yun Kuang, Jie Huang, Dan Jiang, Yajie Cao, Qi Gao, Zifeng Li, Wen Ouyang, Saiying Wang, Qi Pei, Guoping Yang

{"title":"Pharmacokinetic-pharmacodynamic Modelling of NH600001 in Healthy Subjects and Patients Undergoing Gastroscopy.","authors":"Yaxin Liu, Yun Kuang, Jie Huang, Dan Jiang, Yajie Cao, Qi Gao, Zifeng Li, Wen Ouyang, Saiying Wang, Qi Pei, Guoping Yang","doi":"10.1208/s12248-024-01004-7","DOIUrl":"https://doi.org/10.1208/s12248-024-01004-7","url":null,"abstract":"NH600001 is a new general anaesthetic drug with a structure similar to etomidate. The objective of this study was to investigate the relationship between concentrations of NH600001 and sedation efficacy based on data from phase I-II studies and factors influencing the pharmacokinetics and pharmacodynamics of NH600001. The dataset consisted of 2 phase I studies in healthy subjects and 1 phase II study in patients undergoing gastroscopy. Nonlinear mixed effects modeling was used in developing the population pharmacokinetics and pharmacodynamics (PopPK/PD) model of NH600001. Three-compartment model was used to describe the PK profile of NH600001. Parameters were used for allometric scaling on body weight, where the exponents were set to 0.75 for clearance and 1 for volumes. Co-administration of alfentanil hydrochloride influenced the distribution volume of the central compartment and clearance. Effect of patients undergoing gastroscopy (compared with healthy subjects) on clearance, the distribution volume of the superficial peripheral compartment and inter-compartmental clearance for deep peripheral compartment and central compartment was included the final PopPK model. The effect compartment model well characterized the PK/PD relationship of NH600001. Simulation results showed that an initial dose of 0.25 mg/kg of NH600001 resulted in rapid sedation, and three additional doses at 5-min intervals could maintain sedation for more than 20 min. A PopPK/PD model was successfully constructed for NH600001 in healthy subjects and in patients undergoing gastroscopy that could inform the dosing regimens of the forthcoming phase III study.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"21"},"PeriodicalIF":5.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873153","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

Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-20 DOI: 10.1208/s12248-024-00983-x

Cheng Her, Seth Thacker, Joseph Balsamo, Logan Kelley Baker, Derek Dc Ireland, Eric Pang, Daniela Verthelyi

{"title":"Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin.","authors":"Cheng Her, Seth Thacker, Joseph Balsamo, Logan Kelley Baker, Derek Dc Ireland, Eric Pang, Daniela Verthelyi","doi":"10.1208/s12248-024-00983-x","DOIUrl":"https://doi.org/10.1208/s12248-024-00983-x","url":null,"abstract":"Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials. To date, assays to detect trace levels of IIRMI are being used to support regulatory decisions by FDA for selected synthetic peptide drug products that refer to reference listed drugs of rDNA origin but not recombinant protein or peptide products where more complex mixtures of trace impurities including host cell proteins are expected. Here we describe an exercise to explore whether or not there are differences in the innate immune response elicited by an insulin glargine (produced in E. coli) and its interchangeable biosimilar insulin (produced in P. pastoris) that could indicate differences in IIRMI. Our results suggest the two products elicit comparable innate immune responses as determined by the expression of 90 immune-related genes, including IL-1α, IL-1β, IL-6, CCL3, CCL2, and CXCL8. The data suggest that these assays can provide useful information when assessing recombinant proteins for the presence of IIRMI.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"20"},"PeriodicalIF":5.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873142","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

PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-19 DOI: 10.1208/s12248-024-00998-4

Hsuan-Ping Chang, Shufang Liu, Dhaval K Shah

{"title":"PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions.","authors":"Hsuan-Ping Chang, Shufang Liu, Dhaval K Shah","doi":"10.1208/s12248-024-00998-4","DOIUrl":"https://doi.org/10.1208/s12248-024-00998-4","url":null,"abstract":"Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866133","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

Quantitative Comparison and Clustering of Circular Dichroism Spectra Using a Symmetrized Weighted Spectral Difference. 利用对称加权谱差对圆二色光谱进行定量比较和聚类。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-19 DOI: 10.1208/s12248-024-01005-6

Karim Chouchane, Marina Kirkitadze, Rahul Misra, Przemyslaw Kowal, Olivier Dalloz-Bourguignon, Frederic Greco, Sylvie Fayard, Sergio Marco, Didier Clenet

{"title":"Quantitative Comparison and Clustering of Circular Dichroism Spectra Using a Symmetrized Weighted Spectral Difference.","authors":"Karim Chouchane, Marina Kirkitadze, Rahul Misra, Przemyslaw Kowal, Olivier Dalloz-Bourguignon, Frederic Greco, Sylvie Fayard, Sergio Marco, Didier Clenet","doi":"10.1208/s12248-024-01005-6","DOIUrl":"https://doi.org/10.1208/s12248-024-01005-6","url":null,"abstract":"Spectroscopy (UV-visible, circular dichroism, infrared, Raman, fluorescence, etc.) is of fundamental importance to determine the structures of macromolecules and monitor their stability, especially for drug products, based on proteins or nucleic acids. In their 2014 article, Dinh et al. proposed Weighted Spectral Difference (WSD) as a method to quantitatively compute the dissimilarity of a given spectrum to a reference one. Despite the various properties of this method, its lack of symmetry and dependence on the selection of a reference limits the range of possible applications. Here, we propose a reference-free, symmetrized version of WSD (SWSD) that allows the computation of a semi-distance between two spectra. SWSD can be applied to perform group comparisons, track spectral kinetics, or construct a SWSD matrix leading to the hierarchical clustering of spectra. This method was tested on circular dichroism spectra from a split-virus-based (influenza) vaccine and a recombinant spike protein (COVID-19 vaccine). This approach resulted, first, in a perfect clustering of influenza A and B viruses into two distinct clusters, and second, in the detection of the change of secondary structure of the spike protein during a heating experiment, identifying two main temperatures of denaturation (Tm) by SWSD kinetics, in agreement with results obtained by conventional DSC. In summary, we have shown that SWSD is a versatile and efficient tool for quantitative spectral comparison, tracking spectral kinetics and enabling relevant unsupervised classification.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"17"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866135","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

Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays. 临床抗药物抗体免疫测定的生物分析方法比较策略。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-19 DOI: 10.1208/s12248-024-00999-3

R J Elliott, T Pourmohamad, Y Webb-Vargas, W Yan, I Nijem, P Siguenza, Y Song

{"title":"Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays.","authors":"R J Elliott, T Pourmohamad, Y Webb-Vargas, W Yan, I Nijem, P Siguenza, Y Song","doi":"10.1208/s12248-024-00999-3","DOIUrl":"https://doi.org/10.1208/s12248-024-00999-3","url":null,"abstract":"Per FDA guidance, method comparability should be established if an anti-drug antibody (ADA) assay is run by two or more independent laboratories during a study. Genentech, Inc. is evaluating an immunogenicity risk-based comparability approach consisting of both technical and clinical aspects. Technical comparability of the relative sensitivity (RS) is assessed using the Two One-Sided T-tests (TOST) statistical analysis which evaluates if the difference (in absolute value) of the RS means of the two laboratories is less than a pre-specified level of comparability, the practically significant difference (PSD). Clinical comparability is based on the molecule's immunogenicity risk. A basic and in-depth assessment for low and high-risk molecules are used, respectively. An alternative strategy for molecules with limited incurred sample availability is to be used. In the basic assessment, samples are either unfortified or fortified with surrogate ADA positive control at method appropriate concentrations in a representative biological matrix. Acceptable comparability requires in both methods i) at least 80% of the unfortified samples screen and confirm negative, ii) at least 90% of the low concentration samples screen and confirm positive; and iii) 100% of the high concentration samples screen and confirm positive. The in-depth assessment uses at least 100 incurred samples from 30 or more ADA-positive and ADA-negative patients. The results are evaluated using a 2 by 2-confusion matrix and Cohen's Kappa score where 1 indicates perfect agreement. Acceptable comparability requires a Cohen's Kappa score of greater than 0.40. This strategy allows for a robust technical and clinical method comparability assessment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"19"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulatory Considerations for Stability Studies of Co-Processed Active Pharmaceutical Ingredient.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-17 DOI: 10.1208/s12248-024-00995-7

Robert K Orr, Thimma Rawalpally, Lindsey Saunders Gorka, Llorente R Bonaga, Luke Schenck, Stacy Osborne, Deniz Erdemir, Robert J Timpano, Haitao Zhang

{"title":"Regulatory Considerations for Stability Studies of Co-Processed Active Pharmaceutical Ingredient.","authors":"Robert K Orr, Thimma Rawalpally, Lindsey Saunders Gorka, Llorente R Bonaga, Luke Schenck, Stacy Osborne, Deniz Erdemir, Robert J Timpano, Haitao Zhang","doi":"10.1208/s12248-024-00995-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00995-7","url":null,"abstract":"A co-processed active pharmaceutical ingredient (CP API) is the combination of an active pharmaceutical ingredient (API) with non-active component(s). This technology has been demonstrated to offer numerous benefits, including but not limited to improved API properties and stability. The infrastructure requirements are such that the manufacture of a CP API is typically best suited for an API facility. CP API has been regulated as either an API or as a drug product intermediate (DPI). This variability in the designation has led to ambiguities on the regulatory CMC expectations in the CP API including the stability of CP API and CP API containing products which, in turn has hampered the broader application of this technology in the pharmaceutical industry. This difference in designation also resulted in challenges to the lifecycle management of the regulatory documentation for the CMC information of the CP API.This white paper represents the proposals for the regulatory requirements on stability studies related to CP API and to drug product containing CP API by the CP API Working Group (WG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). Additionally, considerations and the WG's recommendations on the stability studies of CP API from different manufacturing sites or processes and post-approval changes for product containing CP API are described.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"16"},"PeriodicalIF":5.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848379","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

Evaluation of Incurred Subject Period Re-analysis (ISPR) as a Tool to Distinguish Fraudulent Pharmacokinetic Profile Pairs from Non-fraudulent Pairs.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-16 DOI: 10.1208/s12248-024-01000-x

Anders Fuglsang, Anshul Dogra, Naveen Sharma

{"title":"Evaluation of Incurred Subject Period Re-analysis (ISPR) as a Tool to Distinguish Fraudulent Pharmacokinetic Profile Pairs from Non-fraudulent Pairs.","authors":"Anders Fuglsang, Anshul Dogra, Naveen Sharma","doi":"10.1208/s12248-024-01000-x","DOIUrl":"https://doi.org/10.1208/s12248-024-01000-x","url":null,"abstract":"Duplicate pharmacokinetic profiles in bioequivalence trials is an issue which has caused hundreds of retracted marketing authorizations. No formal test for profile duplication exists in spite of the existence of profile comparison algorithms, so defining a threshold that distinguishes a naturally occurring pair from a duplication remains difficult. An idea called ISPR (incurred subject period analysis) was aired in 2023 and is evaluated in this paper along with three new profile comparison methods. ISPR involves analysis of entire PK-profiles within a study. It is shown that when ISPR is combined with appropriate PK-profile comparison methods, the duplicate pairs display a lower score (better similarity) than pair that do not arise out of duplication. Therefore, ISPR may help establish a threshold that distinguishes fraudulent profile pairs from non-fraudulent profile pairs. ISPR therefore may be used as QA tool, serves as a method by which a CRO can -to some extent- show that their studies do not contain duplicates in the primary analysis, and thus also may be a means by which sponsor can argue that their studies are trustworthy, in case the suspicion about duplication arises. This paper does not introduce a formal test for this type of fraud; rather the authors see it as a first moderate step in that direction. Hopefully, if or when ISPR data is submitted to authorities as part of general dossier submission, data will accumulate to the extent that they may be able to develop models that allow formal testing for profile duplication.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"15"},"PeriodicalIF":5.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840191","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

Rejoinder to the 'Letter to the Editor' on "Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies".

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-16 DOI: 10.1208/s12248-024-01008-3

Helmut Schütz, Divan A Burger, Erik Cobo, David Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy

引用次数: 0

Reformation of a Clinical Anti-Drug Antibody Assay to Enable the Immunogenicity Assessment of a Bispecific Antibody Biotherapeutic.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-12 DOI: 10.1208/s12248-024-00996-6

Wenyu Liu, Jie Yang, Weili Yan, Kun Peng

{"title":"Reformation of a Clinical Anti-Drug Antibody Assay to Enable the Immunogenicity Assessment of a Bispecific Antibody Biotherapeutic.","authors":"Wenyu Liu, Jie Yang, Weili Yan, Kun Peng","doi":"10.1208/s12248-024-00996-6","DOIUrl":"https://doi.org/10.1208/s12248-024-00996-6","url":null,"abstract":"An enzyme-linked immunosorbent assay (ELISA) based anti-drug antibody (ADA) assay was developed to support the clinical development of a bispecific antibody biotherapeutic anti-A/B. This anti-A/B clinical ADA Version 1 (V1) assay was successfully validated initially using commercial samples from the target indication. However, applying the validation cut point factors (CPFs) led to a high untreated ADA positive rate in the Phase 1 study baseline sample analysis. While implementing the in-study CPFs was effective to mitigate the high baseline prevalence, this led to unfavorable assay sensitivity with no drug tolerance, which necessitated an assay re-optimization. The re-optimized Version 2 assay (V2) was able to mitigate the matrix interference observed in the clinical sample testing using the V1 assay, proven to be a more suitable method. The V2 assay optimization work was discussed, and the performance of the V1 and V2 assays during validation and clinical sample analysis was compared. Preliminary sample testing results generated using the two versions of the assay were compared and the ADA clinical impact was discussed. Our experience insinuates that a successfully validated method does not guarantee to be appropriate for sample testing. Adjustments of the method may be required to ensure that it performs as expected during sample testing and throughout the assay's lifecycle. This work highlights the importance of verifying the assay suitability during clinical sample testing and making appropriate adjustments as needed, especially in the first clinical study and the first study for a new indication.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"12"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814995","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

Prediction of Drug-Drug Interactions for Highly Plasma Protein Bound Compounds.

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-12 DOI: 10.1208/s12248-024-00987-7

David Tess, Makayla Harrison, Jian Lin, Rui Li, Li Di

{"title":"Prediction of Drug-Drug Interactions for Highly Plasma Protein Bound Compounds.","authors":"David Tess, Makayla Harrison, Jian Lin, Rui Li, Li Di","doi":"10.1208/s12248-024-00987-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00987-7","url":null,"abstract":"Accurate prediction of drug-drug interactions (DDI) from in vitro data is important, as it provides insights on clinical DDI risk and study design. Historically, the lower limit of plasma fraction unbound (fu,p) is set at 1% for DDI prediction of highly bound compounds by the regulatory agencies due to the uncertainty of the fu,p measurements. This leads to high false positive DDI predictions for highly bound compounds. The recently published ICH M12 DDI guideline allows the use of experimental fu,p for DDI prediction of highly bound compounds. To further build confidence in DDI prediction of highly bound compounds using experimental fu,p values, we evaluated a set of drugs with fu,p < 1% and clinical DDI > 20% using both basic and mechanistic static models. All the compounds evaluated were flagged for DDI risk with the mechanistic model using experimental fu,p values. There was no false negative DDI prediction. Similarly, using the basic model, the DDI risk of all the compounds was identified except for CYP2D6 inhibition of almorexant. The totality of the data demonstrates that the DDI potential of highly bound compounds can be predicted accurately when actual protein binding numbers are measured.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"13"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814994","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