Pharmaceutics最新文献

{"title":"Evaluation of Complex Drug Interactions Between Elexacaftor-Tezacaftor-Ivacaftor and Statins Using Physiologically Based Pharmacokinetic Modeling.","authors":"Eunjin Hong, Peter S Chung, Adupa P Rao, Paul M Beringer","doi":"10.3390/pharmaceutics17030318","DOIUrl":"10.3390/pharmaceutics17030318","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug-drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. <b>Methods:</b> We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. <b>Results:</b> The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). <b>Conclusions:</b> Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721008","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":"An Overview of the Potential for Pharmacokinetic Interactions Between Drugs and Cannabis Products in Humans.","authors":"Dolly Andrea Caicedo, Clara Pérez-Mañá, Magí Farré, Esther Papaseit","doi":"10.3390/pharmaceutics17030319","DOIUrl":"10.3390/pharmaceutics17030319","url":null,"abstract":"<p><p>Cannabis is the most commonly used illicit substance worldwide. Recent years have seen an increase in cannabis consumption, and with new approvals and therapeutic indications, there are challenges in minimizing the risks and interactions between cannabis-based products, cannabis prescription drugs, other approved prescription drugs, and other substances of abuse. Thus, identifying the enzymes metabolizing cannabinoid drugs and their relationship with other prescription drugs is crucial for understanding the potential interactions and effects of their simultaneous use. This article offers a comprehensive review of cannabis and the pharmacokinetic interactions between cannabis products, cannabis prescription drugs, and other approved prescription drugs, as well as other substances of abuse. It also compiles existing evidence of these interactions and describes the clinical outcomes associated with the inhibition or induction of various enzymes.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720983","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":"Formulation of W/O/W Emulsion-Based Chitosan-Alginate Microcapsules for Encapsulation of Cannabidiol and <i>A. annua</i> L. Extract Containing Luteolin and Apigenin: A Response Surface Optimization Approach.","authors":"Emilija Nemickaite, Ugne Zlabiene, Agne Mazurkeviciute, Mindaugas Marksa, Jurga Bernatoniene","doi":"10.3390/pharmaceutics17030309","DOIUrl":"10.3390/pharmaceutics17030309","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Chitosan-alginate microcapsules were produced to encapsulate bioactive compounds from <i>Artemisia annua</i> L. extract (apigenin, luteolin) and cannabidiol (CBD). The study aimed to optimize emulsion composition and encapsulation parameters for potential applications in food supplements and pharmaceuticals. <b>Methods:</b> A water-in-oil-in-water (W/O/W) emulsion and a modified coacervation extrusion technique were employed. The study was conducted in two phases using response surface methodology. Key metrics included encapsulation efficiency (EE), yield (EY), cumulative release in vitro, and physicochemical and morphological properties, analyzed via scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), high-performance liquid chromatography with a diode array detector (HPLC-DAD), and gas chromatography with flame ionization detection (GC-FID). <b>Results:</b> The optimal conditions were identified as 0.1% Tween 20, 3.8% Span 80, 3.8% CBD, 19.9% <i>A. annua</i> L. extract, 1.5% outer-phase Tween 20, 48.5% sodium alginate, 200 rpm stirring for 30 min, and a 0.05 mL/min flow rate. The EE values were 80.32 ± 4.11% for CBD, 88.13 ± 3.13% for apigenin, and 88.41 ± 4.17% for luteolin, with respective cumulative releases of 77.18 ± 4.4%, 75.12 ± 4.81%, and 75.32 ± 4.53%. <b>Conclusions:</b> The developed microcapsules demonstrated high encapsulation efficiency and controlled release, highlighting their potential for further development in food supplements and pharmaceuticals. Future studies should focus on refining the formulation for improved bioavailability and stability.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721039","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":"Refined ADME Profiles for ATC Drug Classes.","authors":"Luca Menestrina, Raquel Parrondo-Pizarro, Ismael Gómez, Ricard Garcia-Serna, Scott Boyer, Jordi Mestres","doi":"10.3390/pharmaceutics17030308","DOIUrl":"10.3390/pharmaceutics17030308","url":null,"abstract":"<p><p><b>Background:</b> Modern generative chemistry initiatives aim to produce potent and selective novel synthetically feasible molecules with suitable pharmacokinetic properties. General ranges of physicochemical properties relevant for the absorption, distribution, metabolism, and excretion (ADME) of drugs have been used for decades. However, the therapeutic indication, dosing route, and pharmacodynamic response of the individual drug discovery program may ultimately define a distinct desired property profile. <b>Methods:</b> A methodological pipeline to build and validate machine learning (ML) models on physicochemical and ADME properties of small molecules is introduced. <b>Results:</b> The analysis of publicly available data on several ADME properties presented in this work reveals significant differences in the property value distributions across the various levels of the anatomical, therapeutic, and chemical (ATC) drug classification. For most properties, the predicted data distributions agree well with the corresponding distributions derived from experimental data across fourteen drug classes. <b>Conclusions:</b> The refined ADME profiles for ATC drug classes should be useful to guide the <i>de novo</i> generation of advanced lead structures directed toward specific therapeutic indications.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720967","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":"Reshaping [^99mTc]Tc-DT11 to DT14D Tagged with Trivalent Radiometals for NTS₁R-Positive Cancer Theranostics.","authors":"Panagiotis Kanellopoulos, Berthold A Nock, Eric P Krenning, Theodosia Maina","doi":"10.3390/pharmaceutics17030310","DOIUrl":"10.3390/pharmaceutics17030310","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Radiotheranostics of neurotensin subtype 1 receptor (NTS₁R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [^99mTc]Tc-DT11 (DT11, N₄-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N₄, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS₁R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH₂ of Lys⁷. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys⁷ but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)₃ spacer at the α-NH₂ of Lys⁷. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS₁R-positive lesions only by single-photon emission computed tomography (SPECT). <b>Methods</b>: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS₁R-expressing pancreatic cancer AsPC-1 cells and mice models. <b>Results</b>: [⁶⁷Ga]Ga/[¹¹¹In]In/[¹⁷⁷Lu]Lu-DT14D displayed high affinity for human NTS₁R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice's circulation, displaying NTS₁R-specific uptake in AsPC-1 xenografts. <b>Conclusions</b>: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS₁R-positive cancer.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720969","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":"Nanomedicine Approaches for Intervertebral Disc Regeneration: From Bench to Bedside.","authors":"Yifan Ding, Fan Li, Yunyun Wang, Weizhen Pan, Xiangning Fu, Songwei Tan","doi":"10.3390/pharmaceutics17030313","DOIUrl":"10.3390/pharmaceutics17030313","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IDD) is a leading cause of low back pain (LBP) and neurological dysfunction, contributing significantly to disability-adjusted life years globally. The progression of IDD is driven by excessive oxidative stress, inflammation, apoptosis, and fibrosis, which disrupt the balance between anabolic and catabolic processes, leading to extracellular matrix (ECM) degradation and IDD. Current treatment options, such as conservative therapy and surgical intervention, are limited in halting the disease progression and often exacerbate degeneration in adjacent discs. This review highlights the challenges in treating IDD, particularly due to the limited drug delivery efficiency to the intervertebral disc (IVD). It explores the potential of nanobiomedicine and various nanomaterial-based delivery systems, including nanoparticles, microspheres, gene-nanocomplexes, fullerene, exosomes, and nanomaterial-composite hydrogels. These advanced delivery systems can enhance targeted drug delivery, improve local drug concentration, and sustain drug retention within the IVD, offering promising therapeutic strategies to address IDD. The review also examines the therapeutic effects of these nanomaterials on IDD, focusing on their impact on metabolism, inflammation, apoptosis, fibrosis, and stem cell migration and differentiation, aiming to provide innovative strategies for intervertebral disc regeneration.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720954","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":"Special Issue \"Pharmaceutical Solid Forms: From Crystal Structure to Formulation\".","authors":"Philippe Espeau","doi":"10.3390/pharmaceutics17030312","DOIUrl":"10.3390/pharmaceutics17030312","url":null,"abstract":"<p><p>This Special Issue aims to highlight the interest of characterizing the structural aspects of an API before its formulation, as much work is required between the discovery of a molecule with a therapeutic effect and its formulation [...].</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719876","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":"A Step Towards Real-Time Release Testing of Pharmaceutical Tablets: Utilization of CIELAB Color Space.","authors":"René Brands, Trieu Nam Le, Jens Bartsch, Markus Thommes","doi":"10.3390/pharmaceutics17030311","DOIUrl":"10.3390/pharmaceutics17030311","url":null,"abstract":"<p><p><b>Background:</b> The pharmaceutical industry is shifting from end-product testing towards real-time release testing. This approach is based on the continuous collection of process data and product information, which is finally utilized for the release decision. For continuous direct compression, spectroscopic technologies are preferred due to their short acquisition time and non-destructive nature. <b>Methods:</b> Here, the feasibility of the CIELAB color space was demonstrated for porosity and tensile strength. Five different formulations were processed, varying in particle size and deformation behavior. The compression forces were varied from 3 to 18 kN and the CIELAB color space was measured in-line using a UV/Vis probe implemented in the ejection position of the tablet machine. <b>Results:</b> Increasing the main compression force during tableting decreases the tablet surface roughness and porosity. In addition, the tablet tensile strength increases. These changes affected the reflection behavior of radiation on the tablet surface, resulting in a change in the chroma value C*. These dependencies were utilized for the in-line monitoring of porosity and tensile strength. Linear relations were observed for all formulations as exemplary, indicated by sufficient coefficients of determination and verification runs. <b>Conclusions:</b> Finally, UV/Vis diffuse reflectance spectroscopy in combination with a CIELAB color space transformation was demonstrated to be a suitable real-time release tool.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720950","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":"Fluorescent Rhein-Loaded Liposomes for In Vivo Biodistribution Study.","authors":"Silviu Iulian Filipiuc, Natalia Simionescu, Gabriela Dumitrița Stanciu, Adina Coroaba, Narcisa Laura Marangoci, Leontina Elena Filipiuc, Mariana Pinteala, Cristina Mariana Uritu, Bogdan Ionel Tamba","doi":"10.3390/pharmaceutics17030307","DOIUrl":"10.3390/pharmaceutics17030307","url":null,"abstract":"<p><p><b>Objectives:</b> This work aimed to develop and investigate liposomes incorporating Rhein (Lip-Rh) into the liposomal membrane to enhance the compound's water solubility and oral bioavailability. <b>Methods:</b> Liposomes were produced by the thin lipid film technique, with a phosphatidylcholine-to-cholesterol molar ratio of 5:1, dissolved in chloroform and methanol, and thereafter hydrated with ultrapure water and subjected to sonication. The resultant liposomes were studied from a physicochemical perspective using DLS, zeta potential, STEM, UV-Vis, and fluorescence spectroscopies, while oral bioavailability was assessed by fluorescence imaging. Additionally, cell viability assays were performed on tumour cells (MCF-7) in comparison to normal cells (HGFs). <b>Results:</b> The resultant nanoparticles exhibited relatively uniform sizes and narrow size distribution. In vivo fluorescence imaging studies performed on Wistar rats demonstrated significantly enhanced oral bioavailability for Lip-Rh, with rapid absorption into the bloodstream observed one hour after administration, in contrast to the free compound dissolved in vegetable oil. Cell viability assays demonstrated higher cytotoxicity of Lip-Rh towards MCF-7 cells compared to HGF cells, highlighting the selective therapeutic potential of the product. Moreover, we determined that the optimal dose of Rhein per kilogram of body weight, when encapsulated in liposomes, is approximately 2.5 times less than when Rhein is delivered in its unencapsulated form. <b>Conclusions:</b> Lip-Rh is a promising candidate for oncological treatments, presenting three key advantages: increased cytotoxicity towards tumour cells, protection of normal tissues, and the practicality of oral delivery. Additional investigation is required to explore its application in anticancer therapy, whether as monotherapy or as a complementary treatment.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721031","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":"Azithromycin-Loaded Nanoparticles Incorporated in Chitosan-Based Soft Hydrogels: A Novel Approach for Dental Drug Delivery.","authors":"Jakub Kwiatek, Magdalena Paczkowska-Walendowska, Anna Rył, Tomasz M Karpiński, Andrzej Miklaszewski, Ewelina Swora-Cwynar, Marta Leśna, Judyta Cielecka-Piontek","doi":"10.3390/pharmaceutics17030304","DOIUrl":"10.3390/pharmaceutics17030304","url":null,"abstract":"<p><p><b>Background:</b> Azithromycin (AZC), a BCS class II/IV antibiotic with broad-spectrum antimicrobial activity, has poor water solubility, limiting its formulation potential. This study aimed to develop and optimize AZC-based soft hydrogels for the first time for improved solubility, local controlled drug release, and local dental applications. <b>Methods:</b> AZC nanoparticles (based on polyvinylpyrrolidone) were synthesized via electrospinning enhanced solubility 40-fold. These were incorporated into chitosan (CS) hydrogels with varying concentrations and degrees of deacetylation (DDA), optimized using a factorial design. Hydrogels were characterized for drug release, mucoadhesion, antioxidant, anti-inflammatory, and antimicrobial properties, with Principal Component Analysis (PCA) assessing correlations. <b>Results:</b> Soft hydrogels with 3% CS and 80% DDA achieved sustained drug release (62.9-94.7% over 48 h), strong mucoadhesion, and enhanced biological activity. Higher CS and DDA improved antioxidant and anti-inflammatory effects due to increased free amino groups. Antimicrobial tests showed efficacy against <i>Streptococcus mutans</i> and <i>Staphylococcus aureus</i>. PCA revealed an inverse correlation between AZC release and mucoadhesion and positive correlations between release and anti-inflammatory activity. <b>Conclusions:</b> AZC-based soft hydrogels significantly improved solubility, controlled release, and biological activity, showing strong potential for dental drug delivery. Further clinical validation and optimization are recommended.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720995","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}