International Journal of Pharmaceutics最新文献

{"title":"Challenges and opportunities in targeting epigenetic mechanisms for pulmonary arterial hypertension treatment","authors":"Jie Feng ,&nbsp;Yunman Liu ,&nbsp;Kai Li,&nbsp;Yanqing Wu","doi":"10.1016/j.ijpharm.2025.125332","DOIUrl":"10.1016/j.ijpharm.2025.125332","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by elevated pulmonary vascular resistance and pulmonary artery pressure, resulting from a multitude of etiological factors. If left untreated, PAH progressively leads to right heart failure and is associated with high mortality. The etiology of PAH is multifactorial, encompassing both congenital genetic predispositions and acquired secondary influences. Epigenetics, which refers to the regulation of gene expression through chromosomal alterations that do not involve changes in the DNA sequence, has garnered significant attention in PAH research. This includes mechanisms such as DNA methylation, histone modification, and RNA modification. Aberrant epigenetic modifications have been closely linked to the dysregulated proliferation and apoptosis of pulmonary artery smooth muscle cells and endothelial cells, suggesting that these alterations may serve as pivotal drivers of the pathophysiological changes observed in PAH.</div><div>This review examines the potential impact of epigenetic alterations on the pathogenesis of PAH, highlighting their promise as therapeutic targets. Furthermore, we explore emerging therapeutic strategies and compounds aimed at modulating these epigenetic markers, and discusses their potential applications in both preclinical models and clinical trials. As our understanding of epigenetics deepens, it holds the potential to unlock novel avenues for the precise, individualized treatment of PAH, offering a new frontier in the fight against this debilitating disease.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125332"},"PeriodicalIF":5.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387358","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":"Excipient-free inhalable combination shell-core microparticles with clofazimine as shell for extended pulmonary retention of isoniazid in core","authors":"Kolimi Prashanth Reddy ,&nbsp;Lakshmi Tulasi Naraharisetti ,&nbsp;Vani Sai Prasanna ,&nbsp;Srivalliputturu Sarath Babu ,&nbsp;Iman Ehsan ,&nbsp;Chandraiah Godugu ,&nbsp;Pallab Datta","doi":"10.1016/j.ijpharm.2025.125310","DOIUrl":"10.1016/j.ijpharm.2025.125310","url":null,"abstract":"<div><div>Pulmonary delivery of combination anti-tubercular drugs can prevent emergence of drug resistance and improve therapeutic efficacy. However, several drugs in anti-Tuberculosis combinations possess contrasting physicochemical properties that necessitate precise particle engineering with meticulous design for successful co-delivery. High dose requirements further constrain addition of excipients in the formulation. In this work, a clofazimine shell − isoniazid core combination, excipient-free dry powder inhalable microparticle formulation (CFZ INH DPMs) is designed to extend release and prolong pulmonary retention of the short-half-life INH. Firstly, INH-acetone incompatibility was resolved by employing 3 fluid-nozzle spray drying as conventional spray drying of pure INH yielded large particle sizes (D₅₀-26.64 µm) and poor yield for CFZ, whereas CFZ INH DPMs formulation exhibited desired aerodynamic size (D₅₀-3.04 µm; 3.36 µm for INH and 3.28 µm for CFZ). Shell-core morphology was confirmed using TEM and confocal microscopy. DSC and XRD revealed CFZ and INH existed in their inherent crystalline form in CFZ INH DPMs. Solubility of CFZ from the combination DPMs in simulated lung fluid was improved 2 times compared to pure CFZ, while INH dissolution was retarded (85 % in 4 h). The interfacial behavior of DPPC with CFZ using Langmuir-Blodgett isotherms revealed interactions that explain improved solubility of CFZ in pulmonary lipids. In a RAW macrophage culture study, cellular internalization of prepared formulation within 4 h was observed whereas intratracheal administration to Wistar rats demonstrated retention of INH in lungs upto 4 h compared to clearance of pure INH within 1 h. In summation, CFZ INH DPMs demonstrate promising potential for pulmonary targeting and retention of combination anti-TB drugs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125310"},"PeriodicalIF":5.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382391","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":"Evaluation of the dissociation behavior of hydrophobic ion pairs via HPLC analysis.","authors":"Daniel Stengel, Christa Nestl, Annika Postina, Florina Veider, Odile Fernández, Matthias Sandmeier, Marcel Kwiatkowski, Tobias Kipura, Doris Braun, Andreas Bernkop-Schnürch","doi":"10.1016/j.ijpharm.2025.125311","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125311","url":null,"abstract":"<p><strong>Aim: </strong>The objective of this study was to investigate the stability of hydrophobic ion pairs (HIP) of tuftsin and perfluorooctanoic acid in physiological media via high performance liquid chromatography (HPLC) METHODS: HIP was formed between the model peptide tuftsin and perfluorooctanoic acid (PFOA). Precipitation efficiency and logP of HIP was determined via HPLC. HIP was characterized via mass spectrometry (MS). Furthermore, the impact of monovalent salts (NaCl, KCl), divalent salts (CaCl₂, MgCl₂), phosphate containing media (pure phosphate, PBS), bile salts (sodium taurocholate, sodium deoxycholate) and fatty acid (sodium myristate) as well as the impact of pH on dissociation of HIP was analyzed via HPLC.</p><p><strong>Results: </strong>HIP formed in a charge ratio of 1:1 (tuftsin: PFOA) showed a 2512-fold increase in lipophilicity compared to tuftsin. The formation of HIP 1:1 was confirmed by mass spectrometry, showing a peak at the expected mass of 1327 m/z. Pure tuftsin eluted from a C18 reversed phase column after 1.8 min, while the peak of HIP eluted at 6.6 min. The stability of HIP in presence of physiological relevant compounds decreased in the following rank order: sodium deoxycholate > sodium myristate > magnesium chloride = calcium chloride > phosphate > sodium taurocholate > sodium chloride = potassium chloride. The lower the pH, the lower was the stability of HIP.</p><p><strong>Conclusion: </strong>HPLC analysis offers a valuable method to study the dissociation of hydrophobic ion pairs in physiological relevant media.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125311"},"PeriodicalIF":5.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382399","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":"Advances in the application of natural/synthetic hybrid hydrogels in tissue engineering and delivery systems: A comprehensive review","authors":"Zheqi Liu ,&nbsp;Xiyuan Ma ,&nbsp;Jingsheng Liu,&nbsp;Hao Zhang,&nbsp;Daping Fu","doi":"10.1016/j.ijpharm.2025.125323","DOIUrl":"10.1016/j.ijpharm.2025.125323","url":null,"abstract":"<div><div>Hydrogels are widely used in biomedicine because of their excellent biocompatibility, physicochemical properties, three-dimensional cross-linked polymer networks capable of absorbing and retaining a large amount of water, and various excellent properties that can be endowed to hydrogels through modification and material integration. This review focuses on the polymer compositions and applications of natural/synthetic hybrid hydrogels. Firstly, the physical and chemical crosslinking mechanisms of hybrid hydrogels with different natural/synthetic polymer combinations were discussed in depth. In addition, polymers for the preparation of natural/synthetic hybrid hydrogels and their advantages and disadvantages are widely introduced, focusing on polysaccharides, proteins, natural aromatic polymers and common synthetic polymers. Finally, this review will focus on the applications of natural/synthetic hybrid hydrogels in tissue engineering and delivery systems. Such as bone tissue engineering, nerve tissue engineering and drug delivery.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125323"},"PeriodicalIF":5.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378034","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":"Macrophage membrane coated functionalized nanoparticles for targeted drug delivery and neural function repair in cerebral ischemia–reperfusion injury","authors":"Ting Li ,&nbsp;Wenzhu Wang ,&nbsp;Weijin Liu ,&nbsp;Mingming Sun ,&nbsp;Qiuying Wang ,&nbsp;Zihan Li ,&nbsp;Jie Hao ,&nbsp;Yan Yu","doi":"10.1016/j.ijpharm.2025.125329","DOIUrl":"10.1016/j.ijpharm.2025.125329","url":null,"abstract":"<div><div>Vascular dementia (VD) is the second leading cause of cognitive impairment after Alzheimer’s disease, posing a heavy burden to families and society. The majority of causes of VD are vascular diseases such as stroke, with ischemic stroke accounting for a large proportion. After ischemia–reperfusion, factors such as mitochondrial damage and increased xanthine oxidase lead to excessive production of reactive oxygen species (ROS) at the ischemic site, further exacerbating brain injury. Therefore, developing effective ROS scavengers is crucial. Polydopamine has become one of the widely used surface functionalized materials in recent years, due to its excellent biocompatibility and antioxidant properties. This paper proposed a macrophage membrane disguised polydopamine (PDA) nanoplatform for loading the neuroprotective drug puerarin (PUE). The as made PUE@PDA@CMs (PPCs) nanoplatforms can significantly and effectively clear ROS, alleviate oxidative microenvironment, and protect neurons from oxidative stress damage. The macrophage membranes modification enables PPCs to respond to lymphocyte recruitment at the site of cerebral ischemia–reperfusion injury, thereby targeting and aggregating to the injury site. In a mouse model of vascular dementia, PPCs treatment significantly reduced neuronal apoptosis and provided significant cognitive and memory function recovery, providing new strategies and prospects for the treatment of central nervous system diseases.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125329"},"PeriodicalIF":5.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382392","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":"Optimizing mRNA delivery: A microfluidic exploration of DOTMA vs. DOTAP lipid nanoparticles for GFP expression on human PBMCs and THP-1 cell line","authors":"Erwin Pavel Lamparelli ,&nbsp;Elena Ciaglia ,&nbsp;Maria Camilla Ciardulli ,&nbsp;Valentina Lopardo ,&nbsp;Francesco Montella ,&nbsp;Alessandro Annibale Puca ,&nbsp;Giovanna Della Porta","doi":"10.1016/j.ijpharm.2025.125324","DOIUrl":"10.1016/j.ijpharm.2025.125324","url":null,"abstract":"<div><div>This study highlights lipid nanoparticle (LNP) formulations incorporating DOTMA or DOTAP as cationic lipids for the delivery of mRNA encoding Enhanced Green Fluorescent Protein (eGFP-mRNA). The performance of these tailored formulations was benchmarked against a commercial formulation (<em>LipidFlex</em>®, Precigenome), which can also be combined with DOTMA or DOTAP but contains helper lipids of undisclosed composition. LNPs were synthesized using a microfluidic device equipped with a passive Y-shaped microchip, operating at an optimized total flow rate of 6 mL/min and a flow rate ratio of 1:3, with a total lipid concentration ranging from 0.7 to 30 mM. This method produced <em>Single Unilamellar Vesicles</em> (SUVs) with an average size of 150 ± 53 nm and a surface charge of 18 mV. The nitrogen-to-phosphate (N/P) ratio was varied between 250 and 6, modulating the surface charge (from 48 to 18 mV) and the mRNA-eGFP encapsulation efficiency (from 80 % to 70 %, respectively). Cytotoxicity assays and IC₅₀ evaluations on a Hamster Ovarian cell line confirmed that the c-DOTMA formulation achieved an optimal balance of low toxicity and high transfection efficiency. In THP-1 cells, c-DOTMA delivered the highest eGFP expression, reaching up to 25 % transfection efficiency, extremely higher if compared to those observed in the total PBMC population under similar conditions. This selective behavior highlights its potential for precise mRNA delivery to specific immune cell subsets, though further research is required to assess in vivo performance, biodistribution, and immunogenicity.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125324"},"PeriodicalIF":5.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374114","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":"Chitosan based surface modulation of core-shell nanoparticles for oral delivery of exenatide via balancing mucus penetration and cellular uptake","authors":"Yiyao Li ,&nbsp;Huixian Tian ,&nbsp;Han Zeng ,&nbsp;Yu Zhang ,&nbsp;Tian Yin ,&nbsp;Haibing He ,&nbsp;Jingxin Gou ,&nbsp;Xing Tang","doi":"10.1016/j.ijpharm.2025.125319","DOIUrl":"10.1016/j.ijpharm.2025.125319","url":null,"abstract":"<div><div>Oral delivery of peptide and protein drugs (PDs) is hindered by the impermeable intestinal mucosa, which consists of both the mucus layer and the epithelium. Therefore, double-layer (mucus layer and epithelium) overcoming nanocarriers need to be designed to enhance the transporting efficiency of PDs. However, the requirements for surface properties to penetrate these two barriers are quite distinct. In this study, nanoparticles (NPs) with balanced mucus permeation and cellular uptake were developed by modulating surface properties to improve the endocytosis efficiency of exenatide (EXT). The EXT-loaded ovolecithin (Lipoid E 80)/dextran/bovine serum albumin (EDB) NPs, solidified by sodium trimetaphosphate (STMP), were prepared through double emulsification combined with interfacial crosslinking solidification. The EDB NPs were then coated with cationic polyelectrolyte chitosan (CS) shell to form CS-EDB NPs, which exhibited 83.50 ± 0.44 % of encapsulation efficiency (EE), a particle size of approximately 277.0 ± 3.96 nm, and a Zeta potential of −16.2 ± 0.71 mV. Compared to uncoated EDB NPs, CS-EDB NPs showed a 1.1-fold reduction in mucus penetration (P_app), as measured using the Transwell mucus-penetrating model. However, CS-EDB NPs demonstrated a 2.15-fold and 1.77-fold increase in cellular uptake and transepithelial transport efficiency across a Caco-2/E-12 co-culture model, respectively, primarily driven by energy-dependent endocytosis and partially mediated by macropinocytosis. Furthermore, CS-EDB NPs achieved 13.29 % of pharmacological bioavailability and effectively regulated blood glucose, serum lipid levels, and improved islet function upon long-term administration. In conclusion, the core–shell structured CS-EDB NPs successfully protected against the harsh gastrointestinal tract (GIT) environment, providing improved endocytosis efficiency by slightly compromising mucus penetration while significantly enhancing cellular uptake, offering a promising approach for the oral delivery of PDs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125319"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372044","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":"Data-driven model predictive control for continuous pharmaceutical manufacturing","authors":"Consuelo Vega-Zambrano ,&nbsp;Nikolaos A. Diangelakis ,&nbsp;Vassilis M. Charitopoulos","doi":"10.1016/j.ijpharm.2025.125322","DOIUrl":"10.1016/j.ijpharm.2025.125322","url":null,"abstract":"<div><div>This study demonstrates that the development of interpretable, data-driven models for pharmaceutical continuous manufacturing is feasible using a machine learning method called Dynamic Mode Decomposition with Control (DMDc). This approach facilitates adoption within Good Manufacturing Practice (GMP)-regulated areas in the pharmaceutical industry. Furthermore, since the pharmaceutical industry needs to be more operationally efficient to be profitable and sustainable, we present a real-time monitoring strategy framework using an interpretable DMDc dynamic model for the design and tuning of a model predictive control (MPC) system for granule size control in a twin-screw granulation process. This model exhibits low computational complexity without requiring first principles knowledge, while effectively capturing nonlinear dynamics of this multiple input multiple output (MIMO) system, with enhanced performance (e.g., R² &gt; 0.93 for D50 predictions) in the reconstruction of unseen test data in comparison with benchmark data-driven methods for system identification. The DMDc-MPC was implemented and tested on setpoint tracking and disturbance rejection and the proposed advanced process control framework guaranteed both.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125322"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374112","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":"Corrigendum to \"IFN-γ gene loaded human umbilical mesenchymal stromal cells targeting therapy for Graft-versus-host disease\" [Int. J. Pharm. 592 (2021) 120058].","authors":"Hui Li, Qi Liu, Xiaofeng Gao, Di Zhang, Shengjun Mao, Yongqian Jia","doi":"10.1016/j.ijpharm.2025.125301","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125301","url":null,"abstract":"","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125301"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364714","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":"StatGel: An Innovative hydrogel carrying STAT3-targeted small molecule inhibitor for the treatment of abdominal adhesions.","authors":"Fan Chen, Wang Yijie, Tang Kexin, Zhao Qin, Wan Sha, Gu Xin, Yao Dongping, Wu Junjie, Zhou Haoxuan, Song Dan, Yao Qian, Hu Xiuzhen, Dou Qingyu, Kong Qingquan, Xie Yongmei","doi":"10.1016/j.ijpharm.2025.125320","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125320","url":null,"abstract":"<p><p>Adhesions in the abdominal cavity are among the most common complications post abdominal surgery, resulting from excessive fibrous tissue proliferation and collagen synthesis due to various factors. To date, physical barrier materials have been approved for preventing adhesions, though their effectiveness remains unsatisfactory. One of the important causes of abdominal adhesions is the excessive proliferation of fibrotic cells, and our previous research indicated that STAT3 is a promising therapeutic target for anti-fibrosis. This study designed and synthesized a STAT3 targeted small molecule inhibitor compound 16 K and evaluated its anti-fibrotic effects using the CCK-8 assay on fibroblasts. Compound 16 K was then combined with GelMA (methacryloyl gelatin) hydrogel through UV curing to prepare StatGel, a 16 K-loaded hydrogel with both anti-fibrotic activity and physical barrier properties. Material property assessments showed that StatGel does not alter the inherent properties of GelMA while maintaining the capability of sustained release of compound 16 K. StatGel significantly inhibited the proliferation of L929 cells and TGF-β1-induced fibrotic differentiation, and down-regulated p-STAT3 protein without affecting the STAT3 protein. Furthermore, StatGel was demonstrated to prevent the formation of abdominal adhesions in a mouse model induced by CLP as assessed by histological examination and adhesion index. Overall, StatGel offers a potential approach for effectively preventing the formation of abdominal adhesions.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125320"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374053","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}