Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-10-14DOI: 10.1080/03602532.2024.2410747
Prince S Gameli, Marilyn A Huestis, Aurora Balloni, Francesco P Busardò, Jeremy Carlier
{"title":"Metabolism and detection of designer benzodiazepines: a systematic review.","authors":"Prince S Gameli, Marilyn A Huestis, Aurora Balloni, Francesco P Busardò, Jeremy Carlier","doi":"10.1080/03602532.2024.2410747","DOIUrl":"10.1080/03602532.2024.2410747","url":null,"abstract":"<p><p>Synthesis and illicit use of designer benzodiazepines are growing concerns, with these new psychoactive substances (NPS) posing serious health consequences and new hurdles for toxicologists. Consumption marker identification and characterization is paramount in confirming their use. The benzodiazepine core structure is a fusion of benzene and a seven-membered heterocycle with two nitrogen atoms forming the diazepine ring. Minor variations on the core structure produce different classes of benzodiazepines with marked differences in physiological effects. The present review provides a comprehensive designer benzodiazepines metabolism overview and suggests suitable human consumption biomarkers for toxicology casework. A systematic literature search of PubMed<sup>®</sup>, Scopus<sup>TM</sup>, Web of Science<sup>TM</sup>, and Cochrane databases was conducted independently by two coauthors adhering to PRISMA guidelines. Data from 30 <i>in vitro</i> and <i>in vivo</i> models of designer benzodiazepines metabolism from January 2007 to February 2023 were included. 1,4-benzodiazepines (<i>n</i> = 10), 2,3-benzodiazepines (<i>n</i> = 1), triazolo-benzodiazepines (<i>n</i> = 9), and thieno-triazolo-benzodiazepines (<i>n</i> = 3) study design, sample pretreatment, analytical techniques, and major metabolites detected in various matrices are addressed. Metabolites following hydroxylation and phase II glucuronide conjugation were the most prevalent analytes. <i>N</i>-Glucuronidation of parent azole-fused benzodiazepines, and nitro-reduced and <i>N</i>-acetylated metabolites of nitro-containing designer benzodiazepines were also common. From these data, we propose a generic metabolic pathway for designer benzodiazepines. The sporadic illicit market presents challenges in toxicological casework and necessitates comprehensive biomarker investigations, especially in cases with legal implications. There are few metabolism data for many designer benzodiazepines, emphasizing the need for research focusing on closing these gaps.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"359-384"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343669","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-09-11DOI: 10.1080/03602532.2024.2399523
Paresh P Chothe, Upendra A Argikar, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Philip Sandoval, Kimio Tohyama
{"title":"Drug transporters in drug disposition - highlights from the year 2023.","authors":"Paresh P Chothe, Upendra A Argikar, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Philip Sandoval, Kimio Tohyama","doi":"10.1080/03602532.2024.2399523","DOIUrl":"10.1080/03602532.2024.2399523","url":null,"abstract":"<p><p>Drug transporter field is rapidly evolving with significant progress in <i>in vitro</i> and <i>in vivo</i> tools and, computational models to assess transporter-mediated drug disposition and drug-drug interactions (DDIs) in humans. On behalf of all coauthors, I am pleased to share the fourth annual review highlighting articles published and deemed influential in the field of drug transporters in the year 2023. Each coauthor independently selected peer-reviewed articles published or available online in the year 2023 and summarized them as shown previously (Chothe et al. 2021; Chothe et al. 2022, 2023) with unbiased perspectives. Based on selected articles, this review was categorized into four sections: (1) transporter structure and <i>in vitro</i> evaluation, (2) novel <i>in vitro</i>/<i>ex vivo</i> models, (3) endogenous biomarkers, and (4) PBPK modeling for evaluating transporter DDIs (Table 1). As the scope of this review is not to comprehensively review each article, readers are encouraged to consult original paper for specific details. Finally, I appreciate all the authors for their time and continued support in writing this review.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"318-348"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105410","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-06-13DOI: 10.1080/03602532.2024.2366948
Kunhong Mao, Can Liu, Zhongwen Tang, Zhouzhou Rao, Jie Wen
{"title":"Advances in drug resistance of osteosarcoma caused by pregnane X receptor.","authors":"Kunhong Mao, Can Liu, Zhongwen Tang, Zhouzhou Rao, Jie Wen","doi":"10.1080/03602532.2024.2366948","DOIUrl":"10.1080/03602532.2024.2366948","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a prevalent malignancy among adolescents, commonly manifesting during childhood and adolescence. It exhibits a high degree of malignancy, propensity for metastasis, rapid progression, and poses challenges in clinical management. Chemotherapy represents an efficacious therapeutic modality for OS treatment. However, chemotherapy resistance of OS is a major problem in clinical treatment. In order to treat OS effectively, it is particularly important to explore the mechanism of chemotherapy resistance in OS.The Pregnane X receptor (PXR) is a nuclear receptor primarily involved in the metabolism, transport, and elimination of xenobiotics, including chemotherapeutic agents. PXR involves three stages of drug metabolism: stage I: drug metabolism enzymes; stage II: drug binding enzyme; stage III: drug transporter.PXR has been confirmed to be involved in the process of chemotherapy resistance in malignant tumors. The expression of PXR is increased in OS, which may be related to drug resistance of OS. Therefore, wereviewed in detail the role of PXR in chemotherapy drug resistance in OS.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"385-398"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317153","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-10-08DOI: 10.1080/03602532.2024.2402751
Xiongfei Zou, Hongjun Xu, Wenwei Qian
{"title":"The role and current research status of resveratrol in the treatment of osteoarthritis and its mechanisms: a narrative review.","authors":"Xiongfei Zou, Hongjun Xu, Wenwei Qian","doi":"10.1080/03602532.2024.2402751","DOIUrl":"10.1080/03602532.2024.2402751","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a chronic degenerative disease caused by various factors such as aging, obesity, trauma, and genetics. It is a challenging condition faced by orthopedic doctors in clinical practice and places a heavy burden on patients and their families. Currently, the treatment of OA primarily focuses on symptomatic relief and lacks ideal therapeutic methods. Resveratrol is a natural polyphenolic compound with anti-inflammatory and antioxidant properties, and in recent years, it has gained attention as a candidate drug for OA treatment. This article provides an overview of the research status on the role and mechanisms of resveratrol in treating OA. It has been found that resveratrol can prevent the development of OA by inhibiting inflammatory responses, protecting chondrocytes, maintaining cartilage homeostasis, promoting autophagy, and has shown certain therapeutic effects. This process may be related to the regulation of signaling pathways such as nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR4), and silent information regulator 1 (SIRT1). We summarize the current molecular mechanisms of resveratrol in treating OA, hoping to provide a reference for further research and application of resveratrol in OA treatment.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"399-412"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388856","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}
Laura E Russell, Katrina G Claw, Kaja M Aagaard, Sarah M Glass, Kuheli Dasgupta, F Leah Nez, Alex Haimbaugh, Benjamin J Maldonato, Jaydeep Yadav
{"title":"Insights into pharmacogenetics, drug-gene interactions, and drug-drug-gene interactions.","authors":"Laura E Russell, Katrina G Claw, Kaja M Aagaard, Sarah M Glass, Kuheli Dasgupta, F Leah Nez, Alex Haimbaugh, Benjamin J Maldonato, Jaydeep Yadav","doi":"10.1080/03602532.2024.2385928","DOIUrl":"https://doi.org/10.1080/03602532.2024.2385928","url":null,"abstract":"<p><p>This review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput <i>in vitro</i> approach to study the impact of genetic variation on protein function and/or expression <i>in vitro</i>. We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-19"},"PeriodicalIF":3.4,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999580","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}
Drug Metabolism ReviewsPub Date : 2024-08-01Epub Date: 2024-06-19DOI: 10.1080/03602532.2024.2368247
Anam Hammid, Paavo Honkakoski
{"title":"Ocular drug-metabolizing enzymes: focus on esterases.","authors":"Anam Hammid, Paavo Honkakoski","doi":"10.1080/03602532.2024.2368247","DOIUrl":"10.1080/03602532.2024.2368247","url":null,"abstract":"<p><p>This review describes current knowledge on the expression of ocular phase I and II drug-metabolizing enzymes in the main animal species used in ocular drug development and in humans, with a focus on ocular esterases and their prodrug substrates. The eye possesses a unique metabolic profile, exhibiting a lower and restricted expression of major cytochrome P450s (CYPs) and most transferases apart from glutathione S-transferases (GST) when compared to the liver. In contrast, hydrolytic enzymes are abundant in many ocular tissues. These enzymes have attracted interest because of their role in prodrug activation and drug elimination. A literature survey suggests profound variations in tissue expression levels and activities between different species but also points out significant gaps in knowledge. These uncertainties highlight a need for more detailed characterization of enzymes in individual ocular tissues and across species to aid future translational studies in ophthalmic drug research. Thus, an in-depth analysis of ocular drug metabolism and species differences is crucial for ocular drug development.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"175-189"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418321","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}
Drug Metabolism ReviewsPub Date : 2024-08-01Epub Date: 2024-08-09DOI: 10.1080/03602532.2024.2388203
Lulin Zhu, Xinxin Yang, Shanshan Wu, Rong Dong, Youyou Yan, Nengming Lin, Bo Zhang, Biqin Tan
{"title":"Hepatotoxicity of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs).","authors":"Lulin Zhu, Xinxin Yang, Shanshan Wu, Rong Dong, Youyou Yan, Nengming Lin, Bo Zhang, Biqin Tan","doi":"10.1080/03602532.2024.2388203","DOIUrl":"10.1080/03602532.2024.2388203","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"302-317"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906213","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}
Drug Metabolism ReviewsPub Date : 2024-08-01Epub Date: 2024-07-17DOI: 10.1080/03602532.2024.2376023
Shuai Wang, Upendra A Argikar, Maria Chatzopoulou, Sungjoon Cho, Rachel D Crouch, Deepika Dhaware, Ting-Jia Gu, Carley J S Heck, Kevin M Johnson, Amit S Kalgutkar, Joyce Liu, Bin Ma, Grover P Miller, Jessica A Rowley, Herana Kamal Seneviratne, Donglu Zhang, S Cyrus Khojasteh
{"title":"Bioactivation and reactivity research advances - 2023 year in review.","authors":"Shuai Wang, Upendra A Argikar, Maria Chatzopoulou, Sungjoon Cho, Rachel D Crouch, Deepika Dhaware, Ting-Jia Gu, Carley J S Heck, Kevin M Johnson, Amit S Kalgutkar, Joyce Liu, Bin Ma, Grover P Miller, Jessica A Rowley, Herana Kamal Seneviratne, Donglu Zhang, S Cyrus Khojasteh","doi":"10.1080/03602532.2024.2376023","DOIUrl":"10.1080/03602532.2024.2376023","url":null,"abstract":"<p><p>Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved <i>in silico</i> models and experimental techniques that better reflect <i>in vivo</i> environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"247-284"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497396","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}
Drug Metabolism ReviewsPub Date : 2024-08-01Epub Date: 2024-07-05DOI: 10.1080/03602532.2024.2370331
Bin Ma, Upendra A Argikar, Lionel Cheruzel, Sungjoon Cho, Simon Hauri, Kevin M Johnson, Joyce Liu, Simone Schadt, Shuai Wang, S Cyrus Khojasteh
{"title":"Metabolism of new drug modalities research advances - 2023 year in review.","authors":"Bin Ma, Upendra A Argikar, Lionel Cheruzel, Sungjoon Cho, Simon Hauri, Kevin M Johnson, Joyce Liu, Simone Schadt, Shuai Wang, S Cyrus Khojasteh","doi":"10.1080/03602532.2024.2370331","DOIUrl":"10.1080/03602532.2024.2370331","url":null,"abstract":"<p><p>With contributions from colleagues across academia and industry, we have put together the annual reviews of research advances on drug biotransformation and bioactivation since 2016 led by Cyrus Khojasteh. While traditional small molecules and biologics are still predominant in drug discovery, we start to notice a paradigm shift toward new drug modalities (NDMs) including but not limited to peptide and oligonucleotide therapeutics, protein degraders (heterobifunctional degraders and molecule glues), conjugated drugs and covalent inhibitors. The readers can learn more on each new drug modality from several recent comprehensive reviews (Blanco et al. 2022; Hillebrand et al. 2024; Phuna et al. 2024). Based on this trend, we put together this stand-alone review branched from our previous efforts (Baillie et al. 2016; Khojasteh et al. 2023) with a focus on the metabolism of NDMs. We collected 11 articles which exemplify recent discoveries and perspectives in this field.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"223-246"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418226","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}
Drug Metabolism ReviewsPub Date : 2024-08-01Epub Date: 2024-08-12DOI: 10.1080/03602532.2024.2386597
Victoria O Oyanna, John D Clarke
{"title":"Mechanisms of intestinal pharmacokinetic natural product-drug interactions.","authors":"Victoria O Oyanna, John D Clarke","doi":"10.1080/03602532.2024.2386597","DOIUrl":"10.1080/03602532.2024.2386597","url":null,"abstract":"<p><p>The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"285-301"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792208","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}