Clinical Pharmacology & Therapeutics最新文献

{"title":"Effect of Dapagliflozin on Measured vs. Panel-Estimated Glomerular Filtration Rate.","authors":"Esben Iversen, Line Juel Nielsen, Viktor Rotbain Curovic, Anne Byriel Walls, Mie Klessen Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Morten Baltzer Houlind","doi":"10.1002/cpt.3480","DOIUrl":"10.1002/cpt.3480","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (⁵¹Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m², P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"515-522"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations.","authors":"Ksenia A Vekhova, Eugenia D Namiot, Jörgen Jonsson, Helgi B Schiöth","doi":"10.1002/cpt.3478","DOIUrl":"10.1002/cpt.3478","url":null,"abstract":"<p><p>Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)-ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment-resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014-2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term \"Ketamine.\" The highest number of trials were found for the FDA-approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non-psychiatric conditions with pharmacological and non-pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub-anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"374-386"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utility of Biomarker-Informed Drug Interaction Evaluation in Drug Development and Regulatory Decision Making.","authors":"Akihiro Ishiguro, Hiroyuki Kusuhara, Emi Kimoto, So Miyoshi, Katsuhiko Mizuno, Motohiro Hoshino, Hiroshi Suzuki","doi":"10.1002/cpt.3436","DOIUrl":"10.1002/cpt.3436","url":null,"abstract":"<p><p>The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making. This meeting report facilitates stakeholders involved in drug development in better understanding the utility of biomarker approaches and promotes early implementation of biomarker-informed DDI evaluation in regulatory use.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"398-402"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Building Confidence in Physiologically Based Pharmacokinetic Modeling of CYP3A Induction Mediated by Rifampin: An Industry Perspective.","authors":"Micaela B Reddy, Tamara D Cabalu, Loeckie de Zwart, Diane Ramsden, Martin E Dowty, Kunal S Taskar, Justine Badée, Jayaprakasam Bolleddula, Laurent Boulu, Qiang Fu, Masakatsu Kotsuma, Alix F Leblanc, Gareth Lewis, Guiqing Liang, Neil Parrott, Venkatesh Pilla Reddy, Chandra Prakash, Kushal Shah, Kenichi Umehara, Dwaipayan Mukherjee, Jessica Rehmel, Niresh Hariparsad","doi":"10.1002/cpt.3477","DOIUrl":"10.1002/cpt.3477","url":null,"abstract":"<p><p>Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, f_m,CYP3A4, and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of f_m,CYP3A4 (0.086-1.0), Fg (0.11-1.0) and hepatic availability (0.09-0.96) were included. Predictions were most often accurate for compounds that are not P-gp substrates or that are P-gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first-order absorption model might be more appropriate for a P-gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P-gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"403-420"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Off-Label Use of Mycophenolate: Can Real-World Evidence Fetch Regulatory Approval for Lupus Nephritis and Other Indications?","authors":"Nisha Sharma, Smita Pattanaik","doi":"10.1002/cpt.3472","DOIUrl":"10.1002/cpt.3472","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"332-334"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Cimetidine and Dolutegravir on the Endogenous Drug-Drug Interaction Biomarkers for Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Protein 1 in Healthy Volunteers.","authors":"Tomoki Koishikawa, Kaku Fujiwara, Kunal Taskar, Maciej J Zamek-Gliszczynski, Kenta Yoshida, Xiaoyan Chu, Hideki Hirabayashi, Jialin Mao, Kevin Rockich, Tadayuki Takashima, Yoshiyuki Yamaura, Yurong Lai, Yukana Tomoda, Tomoko Kito, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara","doi":"10.1002/cpt.3482","DOIUrl":"10.1002/cpt.3482","url":null,"abstract":"<p><p>This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m¹A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CL_r) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CL_r ratio (CL_rR) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CL_rR of m¹A was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CL_r of creatinine was significantly decreased only by cimetidine 800 mg. Individual CL_rR of 1-NMN and m¹A showed a positive correlation with the corresponding CL_rR of metformin with r² of 0.58 and 0.55, respectively. When evaluated individually, m¹A showed a better correlation during cimetidine periods (r² 0.64) than 1-NMN (r² 0.36), but vice versa during dolutegravir periods (r² 1-NMN, 0.80; m¹A, 0.32). These results suggest that 1-NMN and m¹A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CL_rR change.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"523-533"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Systems Pharmacology-Based Digital Twins Approach Supplements Clinical Trial Data for Enzyme Replacement Therapies in Pompe Disease.","authors":"Chanchala Kaddi, Mengdi Tao, Silke Bergeler, Kelly George, Hugo Geerts, Piet H van der Graaf, Julie L Batista, Meredith Foster, Catherine Ortemann-Renon, Atef Zaher, Kristina An Haack, Susana Zaph","doi":"10.1002/cpt.3498","DOIUrl":"10.1002/cpt.3498","url":null,"abstract":"<p><p>Pompe disease is a rare, progressive neuromuscular disease caused by deficient lysosomal glycogen degradation, and includes both late-onset (LOPD) and severe infantile-onset (IOPD) phenotypes. Due to very small patient numbers in IOPD and the high phenotypic heterogeneity observed in this population, a quantitative systems pharmacology (QSP)-based \"digital twin\" approach was developed to perform an in silico comparison of the efficacy of avalglucosidase alfa vs. the standard of care, in a virtual population of IOPD patients. A QSP model was developed that represents key elements of Pompe disease pathophysiology, including tissue glycogen accumulation and the elevation of the biomarker urine Hex4 in both LOPD and IOPD patients. In this approach, the QSP model was used to generate digital twins of each IOPD patient enrolled in the avalglucosidase alfa clinical program, considering their respective disease burden, demographics, and treatment history. This virtual cohort supplemented clinical observations by simulating and comparing tissue glycogen and urine Hex4 following avalglucosidase alfa treatment vs. the standard of care. The digital twin analysis supports the interpretation that the enhanced reduction in urine Hex4 observed following avalglucosidase alfa treatment is attributable to greater tissue glycogen clearance. Overall, this study provides mechanism-based insight into avalglucosidase alfa efficacy across the phenotypic spectrum of Pompe disease and demonstrates the value of applying a QSP-based digital twin analysis to support rare disease drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"579-588"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program.","authors":"Huan Mo, Yamna Channa, Tracey M Ferrara, Bennett J Waxse, David J Schlueter, Tam C Tran, Anas H Awan, Slavina B Goleva, Ariel Williams, Anav Babbar, Onajia Stubblefield, Jacob M Keaton, Eric A Larson, Russell A Wilke, Joshua C Denny","doi":"10.1002/cpt.3484","DOIUrl":"10.1002/cpt.3484","url":null,"abstract":"<p><p>Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"534-543"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial Intelligence in European Medicines Regulation: From Vision to Action. Harnessing the Capabilities of Artificial Intelligence for the Benefit of Public and Animal Health.","authors":"Luis Correia Pinheiro, Peter Arlett, Kit Roes, Flora Musuamba Tshinanu, Gabriel Westman, Zaide Frias, Hilmar Hamann, Joaquim Berenguer Jornet, Iftekhar Khan, Jeppe Larsen, Karl Broich, Emer Cooke","doi":"10.1002/cpt.3494","DOIUrl":"10.1002/cpt.3494","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"335-336"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Genomic and Transcriptomic Risk Factors of Clopidogrel Response in African Americans.","authors":"Guang Yang, Cristina Alarcon, Catherine Chanfreau, Norman H Lee, Paula Friedman, Edith Nutescu, Matthew Tuck, Travis O'Brien, Li Gong, Teri E Klein, Kyong-Mi Chang, Philip S Tsao, David O Meltzer, Julie A Lynch, Sony Tuteja, Minoli A Perera","doi":"10.1002/cpt.3552","DOIUrl":"https://doi.org/10.1002/cpt.3552","url":null,"abstract":"<p><p>Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10^-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}