European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Enhancing leuprolide penetration through enterocytes via the ER-Golgi pathway using lipophilic complexation","authors":"Jia Meng,&nbsp;May Yee Chan,&nbsp;Cheng Peng,&nbsp;Xuling Jiang,&nbsp;Feng Qian","doi":"10.1016/j.ejpb.2024.114624","DOIUrl":"10.1016/j.ejpb.2024.114624","url":null,"abstract":"<div><div>Oral delivery of peptide drugs remains one of the most formidable challenges in the frontier of pharmaceutical research. Peptide drugs typically suffer from exceptionally low oral bioavailability, primarily attributed to rigorous enzymatic degradation within the gastrointestinal (GI) tract, limited ability to traverse the enterocyte barrier, and significant first-pass hepatic metabolism. Absorption of peptide drugs via the lymphatic route could potentially bypass intracellular lysosome degradation and hepatic first-pass metabolism. In this study, we present a strategy to enhance the lymphatic absorption of the model peptide leuprolide (LEU) by diverting its intracellular trafficking towards the endoplasmic-reticulum (ER)-Golgi pathway. Complexes were formed between LEU and lipophilic excipient and then formulated as an oral emulsion. We observed that the penetration of LEU in the emulsion across the Caco-2 cell monolayer model was diverted from the endosome-lysosome pathway, and LEU entered the bloodstream via the mesenteric lymph nodes (MLNs). The data obtained illustrates that the lipophilic LEU complexes could improve enterocyte permeability and bypass lysosomal degradation, and the change of absorption pathway may reduce hepatic first pass metabolism.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114624"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902366","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":"Design and evaluation of multicomponent systems as a potential strategy to enhance the pharmaceutical performance of albendazole desmotropes","authors":"Agustina Bongioanni ,&nbsp;Belén A. Mezzano ,&nbsp;Marcela R. Longhi ,&nbsp;Claudia Garnero","doi":"10.1016/j.ejpb.2024.114620","DOIUrl":"10.1016/j.ejpb.2024.114620","url":null,"abstract":"<div><div>Albendazole, an anthelmintic recognized by the World Health Organization as an essential medicine, is known to have limitations in solubility and bioavailability. To improve these properties, binary and ternary multicomponent systems were designed employing different combinations of albendazole desmotropes with maltodextrin and aspartic acid. The impact of these systems in solution was evaluated through phase solubility analysis. Moreover, solid systems were produced using the kneading method and evaluated with a combination of techniques, including dissolution tests, Fourier-Transform infrared spectroscopy, X-ray powder diffraction, and scanning electron microscopy. These studies demonstrated that multicomponent systems had higher solubility than free desmotropes, with the system formulated using solid form II of albendazole exhibiting the most significant improvement. Additionally, the dissolution percentage of each solid system in simulated gastric fluid was significantly increased. It can therefore be concluded that these innovative systems offer promising alternatives for improving the oral bioavailability of albendazole, generating significant interest in the pharmaceutical field.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114620"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885472","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":"Risk assessment tool for compatibility of concurrent administration of intravenous medications with parenteral nutrition admixture","authors":"Mahmoud Farhan ,&nbsp;Joanne Bennett ,&nbsp;Anne Cram ,&nbsp;Naomi McCallion ,&nbsp;Fiona O’Brien","doi":"10.1016/j.ejpb.2024.114614","DOIUrl":"10.1016/j.ejpb.2024.114614","url":null,"abstract":"<div><div>Compatibility of parenteral nutrition admixture (PNA) and intravenous medications (IVMs) is a major consideration for clinicians and clinical pharmacists, especially when concurrent administration of PNA with IVMs is unavoidable. This is relatively common in children and neonates, where limited vascular access can be challenging. The purpose of this paper is to create a risk assessment tool that will assist clinical judgment in evaluating the potential incompatibility risk between PNA media and the IVMs when they are administered together through the same intravenous line. The tool will help to provide a more structured approach for healthcare professionals involved in the provision and administration of PNA to assess the risk of incompatibility of IVMs with PNA media.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114614"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853455","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":"A comparative study of gellan gum and xanthan gum versus commercial vehicles as pharmaceutical thickening agents in oral suspensions","authors":"Pauline Claraz ,&nbsp;Luc Fillaudeau ,&nbsp;Chloé Jadoul ,&nbsp;Thomas Storme ,&nbsp;Coralie Guillemot ,&nbsp;Mélanie White-Koning ,&nbsp;Florent Puisset ,&nbsp;Cécile Arellano","doi":"10.1016/j.ejpb.2024.114622","DOIUrl":"10.1016/j.ejpb.2024.114622","url":null,"abstract":"<div><div>Pharmaceutical oral suspensions are the main form used for patients with dysphagia. Compounding these forms is challenging because they are thermodynamically unstable but must remain physically stable. Ready-to-use vehicles such as Inorpha® or Orablend® exist but these are not optimal, and physical stability can be improved using a thickening or suspending agent. High-acyl gellan gum is a European food additive (E418), also used in pharmaceutical preparations, as a gelling agent, stabilizer or thickener but never as a suspending agent. This study aimed to investigate and characterize the properties of high-acyl gellan gum as a suspending agent and to compare it with ready-to-use vehicles and with another suspending agent, xanthan gum. Rheological behaviour, sedimentation and resuspension of vehicles were studied with and without irbesartan used as a model insoluble drug. Viscosity stability was studied for 90 days at room temperature and controlled temperature. We show that the high-acyl gellan gum vehicle offers the best viscosity and stability results for use in pharmaceutical suspensions because it exhibits stable homogeneity and viscosity in time, regardless of storage temperature, and is compatible with safe administration in dysphagic patients after 90 days. High-acyl gellan gum appears to be a good suspending agent for pharmaceutical suspensions.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114622"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143173971","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":"New solubility model for solid drugs in pure solvents based on solute-solvent interfacial tension","authors":"Yueqiang Zhao","doi":"10.1016/j.ejpb.2025.114653","DOIUrl":"10.1016/j.ejpb.2025.114653","url":null,"abstract":"<div><div>The solubility of drugs in biological fluids is associated with pharmacokinetic properties (absorption, biotransformation and excretion), efficacy and toxicity. It is a fascinating and challenging task to uncover the intrinsic reason underlying the dissolution behavior of pharmaceuticals. The classical thermodynamic method estimates the drug solubility in liquid solvent via Solid-Liquid Equilibrium (SLE) equation plus activity coefficient models (UNIFAC, COSMO-RS, COSMO-SAC, etc), where the molar dissolution energy (partial molar excess Gibbs energy) of solute molecules in solution is calculated through activity coefficient models. The new method predicts the solute solubility via the transfer free energy (from solid phase to liquid phase) of solute molecules in terms of fusion properties and solute–solvent (liquid–liquid) interfacial tension, where the molar dissolution energy of solute molecules is determined by solute–solvent interfacial tension, and the solute–solvent (liquid–liquid) interfacial tension is obtained from the cohesive energy calculation results of COSMO-UCE (Conductor-Like Screening Model for Universal Cohesive Energy estimation) based merely on the molecular structure. The application of this model in solubility prediction of solid drugs in pure liquid solvents has been verified extensively with successful results. This model yields similar solute solubility representation performance as that of SLE + UNIFAC, and obtains much better solubility prediction results than SLE + COSMO-SAC.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114653"},"PeriodicalIF":4.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074265","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":"A novel directly compressible co-processed excipient, based-on rice starch for extended-release of tablets","authors":"Karnkamol Trisopon ,&nbsp;Nisit Kittipongpatana ,&nbsp;Pimjai Doungsaard ,&nbsp;Neungreuthai Chomchoei ,&nbsp;Ornanong Suwannapakul Kittipongpatana","doi":"10.1016/j.ejpb.2024.114623","DOIUrl":"10.1016/j.ejpb.2024.114623","url":null,"abstract":"<div><div>The development of a direct compression excipient with extended-release property is crucial for improving tablet manufacturing and drug delivery. This research focuses on developing a novel co-processed excipient composed of rice starch (RS), methylcellulose (MC), and colloidal silicon dioxide (CSD) using a wet granulation technique. The ratios of RS: MC (1.66:1–1:3) and CSD concentrations (1.0 – 8.26 %) on the properties of co-processed material were evaluated. The RS co-processed with MC and CS (RMSs) formed agglomerate particles (199 – 294 μm of average particle size) with irregular shapes and rough surfaces due to the wet granulation technique. FT-IR spectroscopy confirmed that there was no change in the chemical structure during co-processing, while the amorphous characteristic of MC considerably decreased the crystallinity of the RMSs. The increase in the particle size and the bulk density of the RMSs improved material flowability (17 – 18° for angle of repose) and facilitated particle rearrangement during die filling. RS plasticity promoted material compressibility, while the brittleness of CSD contributed to the increased tablet tensile strength. The elastic recovery of RMSs relied on the ratio of RS, which facilitated permanent bonding, whereas incorporating CSD reduced the lubricant sensitivity of material. The co-processing with MC significantly improved material swellability and effectively maintained the polymer matrix for a long period in media with pH 1.2, 4.5, and 7.5. The <em>in vitro</em> release study confirmed the ability of RMSs to prolong drug release from the matrix tablets, where the cumulative drug release of RMS-2 tablets met the specification and conformed with Higuchi model. Among the RMSs, RMS-2 (RS co-processed with 48.7 % MC and 2.68 % CSD) exhibited the optimal ratio of co-processing, as it demonstrated more favorable compression behavior and extended-release property than other RMSs. These findings indicated that RMSs could potentially be used as a direct compression excipient with extended-release properties.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114623"},"PeriodicalIF":4.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046031","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":"Navigating through chemometrics: Unveiling antibiotic-food interactions for improved pediatric formulations ahead","authors":"Agnieszka Wiesner ,&nbsp;Paweł Zagrodzki ,&nbsp;Alicja Gawalska ,&nbsp;Monika Marcinkowska ,&nbsp;Agnieszka Cios ,&nbsp;Paweł Paśko","doi":"10.1016/j.ejpb.2025.114652","DOIUrl":"10.1016/j.ejpb.2025.114652","url":null,"abstract":"<div><h3>Background</h3><div>Given the challenges of pediatric antibacterial therapy, it is crucial to formulate antibiotics with a lower potential for interaction with dietary interventions and tailor them for optimal administration in children. Chemometric methods allow us to analyze multiple interrelated variables simultaneously and uncover correlations.</div></div><div><h3>Aim</h3><div>We applied a chemometric approach to examine how food, beverages, antacids, and mineral supplements affect antibiotic bioavailability in adults and children, aiming to explore relationships between antibiotic structure, physicochemical properties, and post-meal changes in pharmacokinetic (PK) parameters.</div></div><div><h3>Methods</h3><div>We selected 95 antibacterial drugs for analysis, including beta-lactams (32), quinolones (25), macrolides (13), tetracyclines (16), and others (9). The input dataset comprised information from published clinical trials, chemical records, and calculations. We constructed hierarchical partial least squares (PLS) models with changes in PK parameters (ΔAUC, ΔC_max, ΔT_max, and Δ t ½) as response parameters and nine groups of molecular descriptors (M1-M9) as predictor parameters. We performed analyses separately in children and adults for different dietary interventions.</div></div><div><h3>Results</h3><div>In the final 10 PLS models, significant components explained 61–90% and 10.3–54.4% of the variance in the predictor and response parameter sets, respectively. We obtained 59 significant positive and negative correlations between antibiotic structure or physicochemical properties (molecular descriptors) and action in the human body in the presence of food, antacids, or mineral supplements (changes in PK parameters), of which 41 concern pediatric patients.</div></div><div><h3>Conclusions</h3><div>Chemometric methods can be helpful and valuable in investigating the interactions between antibiotics and dietary interventions. Using chemometrics may pave the way for formulating antibiotics for children with a lower potential to interact with food.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114652"},"PeriodicalIF":4.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058492","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":"Impact of stabilizers on particle size and dispersion behavior in biorelevant media in solid nanocrystal formulations","authors":"Nils Christian Böck ,&nbsp;Julius Sundermann ,&nbsp;Mirko Koziolek ,&nbsp;Benjamin-Luca Keller ,&nbsp;Karsten Mäder","doi":"10.1016/j.ejpb.2025.114651","DOIUrl":"10.1016/j.ejpb.2025.114651","url":null,"abstract":"<div><div>Nanocrystalline formulations typically contain stabilizing additives to minimize the risk of particle growth or agglomeration. This risk is particularly relevant when the nanosuspension is converted into a solid drug product as the original state of the nanosuspension should be restored upon redispersion of the drug product <em>in vivo</em>. In this work, the behavior of different nonionic and anionic surfactants in solid nanocrystalline formulations and their effects on redispersibility under biorelevant conditions were investigated. For this purpose, nanocrystalline formulations of basic (itraconazole, ritonavir), acidic (naproxen), and neutral (fenofibrate) API containing nonionic polymers acting as steric stabilizers combined either with anionic (sodium dodecyl sulfate, deoxycholate sodium, docusate sodium) or non-ionic surfactants (polysorbate 80, vitamin E-TPGS) were manufactured by nano-milling. These formulations were turned into a solid drug product by lyophilization and their redispersibility was tested by dispersing them in biorelevant media with different pH values and by characterizing their particle size distribution (PSD) and surface charge. In the absence of an anionic surfactant, it was difficult to achieve particle sizes below 500 nm. However, formulations stabilized anionically were at risk of agglomeration in gastric media. For basic API, the agglomeration was reversible for formulations containing sodium deoxycholate after increasing the pH from acidic to neutral levels, but it was found to be irreversible for those containing sodium dodecyl sulfate and docusate sodium. In summary, the type of anionic stabilizer and its interplay with the physicochemical properties of the API (basic, acidic, or neutral) should be considered in the development of solid nanocrystal formulations.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114651"},"PeriodicalIF":4.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052096","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":"Hexahistidine-metal assembly encapsulated fibroblast growth factor 21 for lipopolysaccharide-induced acute lung injury","authors":"Lanlan Song ,&nbsp;Huihui Ye ,&nbsp;Zhanghang Lv ,&nbsp;Yichen Liu ,&nbsp;Ziyi Lu ,&nbsp;Jun Chen ,&nbsp;Haofeng Pan ,&nbsp;Luqiong Cai ,&nbsp;Yuxin Chen ,&nbsp;Shiqing Huang ,&nbsp;Xingjie Zan ,&nbsp;Xiaoying Huang ,&nbsp;Chang Yu","doi":"10.1016/j.ejpb.2025.114650","DOIUrl":"10.1016/j.ejpb.2025.114650","url":null,"abstract":"<div><div>Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) represents a spectrum of potentially fatal conditions that currently lack effective drug treatment. Recent researches suggest that Fibroblast Growth Factor 21 (FGF21) may protect against ALI/ARDS. However, the clinical use of FGF21 is limited by its rapid degradation, restricted targeting capabilities, and numerous adverse effects. Addressing this challenge, the study employs a pH-responsive nanoparticle delivery system known as Hexahistidine-metal Assembly (HmA) for administering FGF21. The entrapment efficiency (EE%) and loading capacity (LCwt%) of HmA exceed 90 % and 35 %, respectively, while the HmA@FGF21 nanoparticles exhibit an average size of 130 nm, a PDI value of approximately 0.28, and a zeta potential of 24 mV. In animal experiments, HmA@FGF21 administered in lipopolysaccharide (LPS)-induced lung injury significantly exceed those of standalone FGF21, including mitigating the pathological manifestations and reducing the wet/dry ratio, total protein concentration, and overall cell count in BALF of ALI, whether administered via the airway or intravenously. This therapeutic approach therefore shows promise for precise delivery of FGF21 to the lungs to treat ALI, and may offer a novel, and efficient method for delivery of potential pharmacological agents to address other lung diseases.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114650"},"PeriodicalIF":4.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052094","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":"Effect of polymer architecture on the properties and in vitro cytotoxicity of drug formulation: A case study with mono- and di-gradient amphiphilic poly(2-Oxazoline)s","authors":"Shubhashis Datta ,&nbsp;Juraj Kronek ,&nbsp;Zuzana Nadova ,&nbsp;Ludmila Timulakova ,&nbsp;Alzbeta Minarcikova ,&nbsp;Pavol Miskovsky","doi":"10.1016/j.ejpb.2025.114635","DOIUrl":"10.1016/j.ejpb.2025.114635","url":null,"abstract":"<div><div>Due to the straightforward single-step synthesis, amphiphilic gradient copoly(2-oxazoline)s are becoming more popular alternative to their block analogue for the development of next-generation drug delivery systems. Here, we investigated the influence of polymer architecture on the physiochemical and biological assessment of nanoformulations formed by the self-assembly of gradient copoly(2-oxazoline)s. Two different architectures were synthesized: hydrophilic-grad-hydrophobic (mono-gradient) and hydrophobic-grad-hydrophilic-grad-hydrophobic (di-gradient) which contained a hydrophilic monomer, 2-ethyl-2-oxazoline (EtOx) and a hydrophobic monomer, 2-phenyl-2-oxazoline (PhOx). Di-gradient copolymers self-assembled in the presence of a hydrophobic model drug, curcumin and formed monodispersed or slightly polydispersed nanoparticle solution. On the other hand, mono-gradient copolymers formed polydispersed nanoparticle solutions. Di-gradient copolymer was slightly more efficient to solubilize curcumin. Mono-gradient copolymer nanoparticle showed faster monomer chain exchange kinetics and comparatively less stability in the presence of serum albumin. At longer incubation times, faster drug release was observed from the mono-gradient copolymer nanoformulations. Cytotoxicity of free curcumin and curcumin loaded nanoparticles in cancer cell of U87 MG (human glioblastoma cell) was dose and time-dependent, whereby the significant cell death occurred after 48 h. Curcumin-loaded mono-gradient copolymer nanoparticles inhibited U87MG cancel cell growth to a large extent compared to the di-gradient copolymer nanoparticles.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114635"},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037654","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}