Pharmaceutical Research最新文献

{"title":"High-Throughput Fluorometric Assay For Quantifying Polysorbate In Biopharmaceutical Products Using Micelle Activated Fluorescence Probe N-Phenyl-1-Naphthylamine.","authors":"Ximeng Y Dow, Qi Gao, John L Sperduto, Xiaona Wen, Christopher Thai, Lei Zhang, Mark A McCoy","doi":"10.1007/s11095-024-03723-0","DOIUrl":"10.1007/s11095-024-03723-0","url":null,"abstract":"<p><strong>Purpose: </strong>Polysorbates are among the most used surfactants in biopharmaceutical products containing proteins. Our work aims to develop a high-throughput fluorometric assay to further diversify the analytical toolbox for quantification of PSs.</p><p><strong>Method: </strong>The assay leverages the micelle activated fluorescence signal from N-Phenyl-1-Naphthylamine (NPN). The development and optimization of assay parameters were guided by the pre-defined analytical target profile. Furthermore, NMR was used to probe the interaction between protein, PS80 and NPN in the measurement system and understand protein interference.</p><p><strong>Results: </strong>All assay parameters including excitation and emission wavelengths, standard curve, NPN concentration, and incubation time have been optimized and adapted to a microplate format, making it compatible with automated solutions that will be pursued in the near future to drive consistency and efficiency in our workflows. The specificity, accuracy, and precision of the assay have been demonstrated through a case study. Furthermore, NMR results provided additional insight into the change of the interaction dynamics between PS80 and NPN as the protein concentration increases. The results indicate minimal interaction between the protein and PS80 at lower concentration. However, when the concentration exceeds 75 mg/mL, there is a significant interaction between the protein and PS-80 micelle and monomer.</p><p><strong>Conclusion: </strong>A high-throughput fluorometric assay has been developed for quantification of polysorbates in biopharmaceutical samples including in-process samples, drug substance and drug product. The assay reported herein could serve as a powerful analytical tool for polysorbate quantification and control, complementing the widely used liquid chromatography with charged aerosol detection method.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1455-1473"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492991","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":"Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I-Bioequivalence of Acyclovir Topical Creams.","authors":"Y H Mohammed, S N Namjoshi, N Jung, M Windbergs, H A E Benson, J E Grice, S G Raney, M S Roberts","doi":"10.1007/s11095-024-03736-9","DOIUrl":"10.1007/s11095-024-03736-9","url":null,"abstract":"<p><strong>Purpose: </strong>To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT).</p><p><strong>Methods: </strong>Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system.</p><p><strong>Results: </strong>A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams.</p><p><strong>Conclusions: </strong>This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1507-1520"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Structure and Function of Cationic and Ionizable Lipids for Nucleic Acid Delivery.","authors":"Da Sun, Zheng-Rong Lu","doi":"10.1007/s11095-024-03714-1","DOIUrl":"10.1007/s11095-024-03714-1","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1543-1545"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451176","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":"Role of Charge Heterogeneity on Physical Stability of Monoclonal Antibody Biotherapeutic Products.","authors":"Surbhi Gupta, Ankita Dubey, Anurag S Rathore","doi":"10.1007/s11095-024-03730-1","DOIUrl":"10.1007/s11095-024-03730-1","url":null,"abstract":"<p><strong>Purpose: </strong>Chemical modifications in monoclonal antibodies can change hydrophobicity, charge heterogeneity as well as conformation, which eventually can impact their physical stability. In this study, the effect of the individual charge variants on physical stability and aggregation propensity in two different buffer conditions used during downstream purification was investigated.</p><p><strong>Methods: </strong>The charge variants were separated using semi-preparative cation exchange chromatography and buffer exchanged in the two buffers with pH 6.0 and 3.8. Subsequently each variant was analysed for size heterogeneity using size exclusion chromatography and dynamic light scattering, conformational stability, colloidal stability, and aggregation behaviour under accelerated stability conditions.</p><p><strong>Results: </strong>Size variants in each charge variant were similar in both pH conditions when analyzed without extended storage. However, conformational stability was lower at pH 3.8 than pH 6.0. All charge variants showed similar apparent melting temperature at pH 6.0. In contrast, at pH 3.8 variants A3, A5, B2, B3 and B4 display lower Tm, suggesting reduced conformational stability. Further, A2, A3 and A5 exhibit reduced colloidal stability at pH 3.8. In general, acidic variants are more prone to aggregation than basic variants.</p><p><strong>Conclusion: </strong>Typical industry practice today is to examine in-process intermediate stability with acidic species and basic species taken as a single category each. We suggest that perhaps stability evaluation needs to be performed at specie level as different acidic or basic species have different stability and this knowledge can be used for clever designing of the downstream process to achieve a stable product.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1443-1454"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477215","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 the Finite Absorption Time (F.A.T.) Concept in the Assessment of Bioequivalence.","authors":"Athanasios A Tsekouras, Panos Macheras","doi":"10.1007/s11095-024-03727-w","DOIUrl":"10.1007/s11095-024-03727-w","url":null,"abstract":"<p><strong>Purpose: </strong>Το formulate a methodology for the assessment of bioequivalence using metrics, which are based on the physiologically sound F.A.T.</p><p><strong>Concept: </strong></p><p><strong>Methods: </strong>The equations of the physiologically based finite time pharmacokinetic models for the one-and two-compartment model with one and two input stages of absorption were solved to derive metrics for the extent and rate of absorption. Simulated data were used to study the proper way for the estimation of metrics. A bioequivalence study was analyzed using these metrics.</p><p><strong>Results: </strong>The rate of drug absorption was found to be equal to the slope of the amount absorbed versus time curve. The amount of drug absorbed at the end of the absorption process, corresponding to the blood concentration at F.A.T. is an indicator of the extent of absorption. The plot of the ratio test/reference of the simulated data for the amount absorbed as a function of time becomes constant beyond the end of drug absorption from the formulation exhibiting the longer absorption. The assessment of the bioequivalence study was based on the slope of the amount absorbed versus time curve for the rate of absorption, while the estimate for the constant ratio test/reference for the amount absorbed was used for the assessment of extent of absorption.</p><p><strong>Conclusions: </strong>The assessment of rate in bioequivalence studies can be based on the estimation of slope of the percent absorbed versus time curve while the constant ratio test/reference for the amount of drug absorbed is an indicator of the extent of absorption.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1413-1425"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427378","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":"Pharmacokinetic Modeling of the Effect of Tariquidar on Ondansetron Disposition into the Central Nervous System.","authors":"Manting Chiang, Hyunmoon Back, Jong Bong Lee, Sarah Oh, Tiffany Guo, Simone Girgis, Celine Park, Simon Haroutounian, Leonid Kagan","doi":"10.1007/s11095-024-03739-6","DOIUrl":"10.1007/s11095-024-03739-6","url":null,"abstract":"<p><strong>Purpose: </strong>Serotonin (5-HT₃) receptor antagonists are promising agents for treatment of neuropathic pain. However, insufficient drug exposure at the central nervous system (CNS) might result in lack of efficacy. The goal of this study was to evaluate the impact of administration of a Pgp inhibitor (tariquidar) on ondansetron exposure in the brain, spinal cord, and cerebrospinal fluid in a wild-type rat model.</p><p><strong>Methods: </strong>Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.</p><p><strong>Results: </strong>The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination.</p><p><strong>Conclusions: </strong>The study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1401-1411"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.","authors":"Beiqian Tian, Na Wang, Jinyue Yang, Zhicheng Jiang, Yaoguang Feng, Ting Wang, Lina Zhou, Xin Huang, Hongxun Hao","doi":"10.1007/s11095-024-03734-x","DOIUrl":"10.1007/s11095-024-03734-x","url":null,"abstract":"<p><strong>Purpose: </strong>Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations.</p><p><strong>Methods: </strong>The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations.</p><p><strong>Results: </strong>The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively.</p><p><strong>Conclusion: </strong>PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1521-1531"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492992","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":"Distribution Clearance: Significance and Underlying Mechanisms.","authors":"Michael Weiss","doi":"10.1007/s11095-024-03738-7","DOIUrl":"10.1007/s11095-024-03738-7","url":null,"abstract":"<p><strong>Purpose: </strong>Evaluation of distribution kinetics is a neglected aspect of pharmacokinetics. This study examines the utility of the model-independent parameter whole body distribution clearance (CL_D) in this respect.</p><p><strong>Methods: </strong>Since mammillary compartmental models are widely used, CL_D was calculated in terms of parameters of this model for 15 drugs. The underlying distribution processes were explored by assessment of relationships to pharmacokinetic parameters and covariates.</p><p><strong>Results: </strong>The model-independence of the definition of the parameter CL_D allowed a comparison of distributional properties of different drugs and provided physiological insight. Significant changes in CL_D were observed as a result of drug-drug interactions, transporter polymorphisms and a diseased state.</p><p><strong>Conclusion: </strong>Total distribution clearance CL_D is a useful parameter to evaluate distribution kinetics of drugs. Its estimation as an adjunct to the model-independent parameters clearance and steady-state volume of distribution is advocated.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1391-1400"},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing Engineered Nano-Immunopotentiators for the Stimulation of Dendritic Cells and Inhibition and Prevention of Melanoma.","authors":"Sitah Alharthi, Seyed Zeinab Alavi, Mehr Un Nisa, Maedeh Koohi, Aun Raza, Hasan Ebrahimi Shahmabadi, Seyed Ebrahim Alavi","doi":"10.1007/s11095-024-03722-1","DOIUrl":"10.1007/s11095-024-03722-1","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to utilize PEGylated poly (lactic-co-glycolic acid) (PLGA) nanoparticles as a delivery system for simultaneous administration of the BRAF^V600E peptide, a tumor-specific antigen, and imiquimod (IMQ). The objective is to stimulate dendritic cell (DC) maturation, activate macrophages, and facilitate antigen presentation in C57BL6 mice.</p><p><strong>Methods: </strong>PEG-PLGA-IMQ-BRAF^V600E nanoparticles were synthesized using a PLGA-PEG-PLGA tri-block copolymer, BRAF^V600E, and IMQ. Characterization included size measurement and drug release profiling. Efficacy was assessed in inhibiting BPD6 melanoma cell growth and activating immature bone marrow DCs, T cells, macrophages, and splenocyte cells through MTT and ELISA assays. In vivo, therapeutic and immunogenic effects potential was evaluated, comparing it to IMQ + BRAF^V600E and PLGA-IMQ-BRAF^V600E nanoparticles in inhibiting subcutaneous BPD6 tumor growth.</p><p><strong>Results: </strong>The results highlight the successful synthesis of PEG-PLGA-IMQ-BRAF^V600E nanoparticles (203 ± 11.1 nm), releasing 73.4% and 63.2% of IMQ and BARF^V600E, respectively, within the initial 48 h. In vitro, these nanoparticles demonstrated a 1.3-fold increase in potency against BPD6 cells, achieving ~ 2.8-fold enhanced cytotoxicity compared to PLGA-IMQ-BRAF^V600E. Moreover, PEG-PLGA-IMQ-BRAF^V600E exhibited a 1.3-fold increase in potency for enhancing IMQ cytotoxic effects and a 1.1- to ~ 2.4-fold increase in activating DCs, T cells, macrophages, and splenocyte cells compared to IMQ-BRAF^V600E and PLGA-IMQ-BRAF^V600E. In vivo, PEG-PLGA-IMQ-BRAF^V600E displayed a 1.3- to 7.5-fold increase in potency for inhibiting subcutaneous BPD6 tumor growth compared to the other formulations.</p><p><strong>Conclusions: </strong>The findings suggest that PEG-PLGA nanoparticles effectively promote DC maturation, T cell activation, and potentially macrophage activation. The study highlights the promising role of this nanocomposite in vaccine development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1163-1181"},"PeriodicalIF":3.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261229","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":"Effect of mPEG-PLGA on Drug Crystallinity and Release of Long-Acting Injection Microspheres: In Vitro and In Vivo Perspectives.","authors":"Dandan Xing, Lihua Tang, Hongyu Yang, Mingjiao Yan, Panao Yuan, Yulan Wu, Yu Zhang, Tian Yin, Yanjiao Wang, Jingxin Gou, Xing Tang, Haibing He","doi":"10.1007/s11095-024-03717-y","DOIUrl":"10.1007/s11095-024-03717-y","url":null,"abstract":"<p><strong>Purpose: </strong>Traditional progesterone (PRG) injections require long-term administration, leading to poor patient compliance. The emergence of long-acting injectable microspheres extends the release period to several days or even months. However, these microspheres often face challenges such as burst release and incomplete drug release. This study aims to regulate drug release by altering the crystallinity of the drug during the release process from the microspheres.</p><p><strong>Methods: </strong>This research incorporates methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-PLGA) into poly(lactide-co-glycolide) (PLGA) microspheres to enhance their hydrophilicity, thus regulating the release rate and drug morphology during release. This modification aims to address the issues of burst and incomplete release in traditional PLGA microspheres. PRG was used as the model drug. PRG/mPEG-PLGA/PLGA microspheres (PmPPMs) were prepared via an emulsification-solvent evaporation method. Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were employed to investigate the presence of PRG in PmPPMs and its physical state changes during release.</p><p><strong>Results: </strong>The addition of mPEG-PLGA altered the crystallinity of the drug within the microspheres at different release stages. The crystallinity correlated positively with the amount of mPEG-PLGA incorporated; the greater the amount, the faster the drug release from the formulation. The bioavailability and muscular irritation of the long-acting injectable were assessed through pharmacokinetic and muscle irritation studies in Sprague-Dawley (SD) rats. The results indicated that PmPPMs containing mPEG-PLGA achieved low burst release and sustained release over 7 days, with minimal irritation and self-healing within this period. PmPPMs with 5% mPEG-PLGA showed a relative bioavailability (Frel) of 146.88%.</p><p><strong>In conclusion: </strong>In summary, adding an appropriate amount of mPEG to PLGA microspheres can alter the drug release process and enhance bioavailability.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1271-1284"},"PeriodicalIF":3.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261232","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}