Journal of pharmaceutical sciences最新文献

{"title":"Characterization of oral drug absorption from jelly formulations: Effects of membrane permeability and intestinal fluid volume","authors":"Junko Nakamura ,&nbsp;Yukari Kakino ,&nbsp;Makoto Kataoka ,&nbsp;Shinji Yamashita ,&nbsp;Yoshihiro Hishikawa ,&nbsp;Keiko Minami","doi":"10.1016/j.xphs.2024.07.016","DOIUrl":"10.1016/j.xphs.2024.07.016","url":null,"abstract":"<div><div>This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for <em>in vitro</em> drug release and <em>in vivo</em> drug absorption in rats. All drugs showed similar release profiles <em>in vitro</em> from both jelly formulations, except for the faster release from pectin jelly at neutral pH. In contrast, <em>in vivo</em> absorption of ATE but not of ANT from jelly formulations was significantly lower than from solution. Absorption of ATE and MET was low from agar jelly after oral administration, whereas additional water intake significantly increased the absorption. The process of drug absorption was described by the compartmental model consisting of jelly, intestinal fluid, and blood compartments. Drugs in the jelly diffuse into the intestinal fluid and then permeate the intestinal membrane. By considering the rate-limiting process, membrane permeability-dependent drug absorption from agar jelly and the effects of water intake were identified. In conclusion, jelly formulations may potentially decrease and delay drug oral absorption, especially of poorly permeable drugs. Intestinal fluid volume is one of the important factors to control the drug absorption.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3206-3215"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing the dosing regimen of roxadustat in kidney transplant recipients with early post-transplant anemia","authors":"Zhuo-Wei Shen ,&nbsp;Xiu-Yan Yang ,&nbsp;Lu Han ,&nbsp;Xi Yang ,&nbsp;Jiao Xie ,&nbsp;Xiao-Qin Liu ,&nbsp;Jue-Hui Mao ,&nbsp;Hao-Ran Dai ,&nbsp;Wei-Wei Kong ,&nbsp;Xiao-Ying Wu ,&nbsp;Yun-Qing Qiu ,&nbsp;Hong-Feng Huang ,&nbsp;Yan Lou","doi":"10.1016/j.xphs.2024.09.004","DOIUrl":"10.1016/j.xphs.2024.09.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Roxadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase domain enzymes, has been approved for the treatment of renal anemia. However, there is a lack of study on its pharmacokinetics in kidney transplant recipients (KTRs) with early posttransplant anemia (PTA). Therefore, the aim of this study is to elucidate the pharmacokinetic characteristics of roxadustat in KTRs with early PTA and optimize the dosing regimen.</div></div><div><h3>Methods</h3><div>A population pharmacokinetic (PopPK) analysis was performed based on 72-hour full concentration-time profiles collected from 52 Chinese KTRs. Covariates influencing exposure were assessed using stepwise covariate modelling. Monte Carlo simulations were conducted to recommend the dosing regimen for patients with different levels of covariates.</div></div><div><h3>Results</h3><div>PopPK analysis showed that the concentration-time data can be fully described by a two-compartment model. Body weight (BW) and direct bilirubin (DBIL) levels significant affected the apparent clearance of roxadustat. Based on the established model and the estimated exposures of roxadustat by Monte Carlo simulations, a recommended dosing regimen for KTRs with early PTA at varying BW and DBIL levels were developed. Roxadustat at 100 mg three times weekly were suitable for the majority of KTRs with a DBIL level around 3 μmol/L and BW between 50 and 75 kg. The required dose may need to be increased with higher BW and lower DBIL levels, while decreased with lower BW and higher DBIL levels.</div></div><div><h3>Conclusions</h3><div>It was the first PopPK analysis of roxadustat in KTRs with early PTA, which provide a research basis for optimizing the dosing regimen.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3344-3353"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of differential scanning calorimetry as a rapid, effective in-process check method for impurity quantitation of an early clinical batch of Giredestrant (GDC-9545)","authors":"Paroma Chakravarty,&nbsp;Karthik Nagapudi","doi":"10.1016/j.xphs.2024.09.003","DOIUrl":"10.1016/j.xphs.2024.09.003","url":null,"abstract":"<div><div>Giredestrant (GDC-9545) is a selective estrogen receptor degrader (SERD) that was developed for treatment of ER+/HER2− metastatic breast cancer. An anhydrous crystalline tartrate salt was identified as the solid form suitable for clinical development. An early clinical batch of the active pharmaceutical ingredient (API)/drug substance failed to pass the GMP purity specifications owing to the presence of a substantial amount of high molecular weight impurities (oligomers), as determined by size exclusion chromatography. Several trial rework batches were manufactured using various re-slurry and recrystallization conditions to purge impurities in the drug substance to adhere to purity specifications. Based on the melting point depression of the API in presence of oligomers in these rework batches, a differential scanning calorimetry method was developed to quantify impurity content as a function of melting point onset of the API. This thermal analysis method was used as a surrogate for chromatography as a rapid, effective in-process check method for impurity quantitation to enable the timely release of the final reworked clinical batch. Post release, the % w/w oligomer value determined by calorimetry was in excellent agreement to that obtained by size exclusion chromatography.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3191-3195"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in nano-based drug delivery systems for treatment of liver cancer","authors":"Amr Hefnawy ,&nbsp;Ahmed S. Abdelhamid ,&nbsp;Moustafa M. Abdelaziz ,&nbsp;Ahmed O. Elzoghby ,&nbsp;Islam A. Khalil","doi":"10.1016/j.xphs.2024.08.012","DOIUrl":"10.1016/j.xphs.2024.08.012","url":null,"abstract":"<div><div>Liver cancer is one of the aggressive primary tumors as evident by high rate of incidence and mortality. Conventional treatments (e.g. chemotherapy) suffer from various drawbacks including wide drug distribution, low localized drug concentration, and severe off-site toxicity. Therefore, they cannot satisfy the mounting need for safe and efficient cancer therapeutics, and alternative novel strategies are needed. Nano-based drug delivery systems (NDDSs) are among these novel approaches that can improve the overall therapeutic outcomes. NDDSs are designed to encapsulate drug molecules and target them specifically to liver cancer. Thus, NDDSs can selectively deliver therapeutic agents to the tumor cells and avoid distribution to off-target sites which should improve the safety profile of the active agents. Nonetheless, NDDSs should be well designed, in terms of the preparing materials, nanocarriers structure, and the targeting strategy, in order to accomplish these objectives. This review discusses the latest advances of NDDSs for cancer therapy with emphasis on the aforementioned essential design components. The review also entails the challenges associated with the clinical translation of NDDSs, and the future perspectives towards next-generation NDDSs.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3145-3172"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-dimensional culture of human proximal tubular epithelial cells for an in vitro evaluation of drug-induced kidney injury","authors":"Hiroshi Arakawa ,&nbsp;Daichi Higuchi ,&nbsp;Etsushi Takahashi ,&nbsp;Kohei Matsushita ,&nbsp;Shiho Nedachi ,&nbsp;Hanwei Peng ,&nbsp;Moeno Kadoguchi ,&nbsp;Kaoru Morimura ,&nbsp;Ayano Araki ,&nbsp;Masayuki Kondo ,&nbsp;Naoki Ishiguro ,&nbsp;Yoichi Jimbo ,&nbsp;Ikumi Tamai","doi":"10.1016/j.xphs.2024.08.009","DOIUrl":"10.1016/j.xphs.2024.08.009","url":null,"abstract":"<div><div>Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (<em>EC₂₀</em>) was obtained, and the ratio of EC₂₀ values and clinical maximum concentration (C_max) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for <em>in vitro</em> evaluation of RPTEC injury by measuring intracellular ATP levels.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3255-3264"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995937","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":"Oral viscous budesonide solution for enhanced localized treatment of eosinophilic esophagitis through improved mucoadhesion and permeation","authors":"Dongyu Wu ,&nbsp;Tiantian Zhang ,&nbsp;Yuzhen Kang ,&nbsp;Yan Zhong ,&nbsp;Shiqi Chen ,&nbsp;Yue Zhang ,&nbsp;Xuyu Chai","doi":"10.1016/j.xphs.2024.09.016","DOIUrl":"10.1016/j.xphs.2024.09.016","url":null,"abstract":"<div><div>Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and <em>in vitro</em> elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. &gt;80 % of the budesonide was released after 24 h, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7 % HEC could be stored for &gt;6 months at a temperature of 5 °C ± 3 °C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3384-3392"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progressive Amyloid-β Accumulation in the Brain leads to Altered Protein Expressions in the Liver and Kidneys of APP knock-in Mice.","authors":"Shingo Ito, Yumi Iwata, Mitsumi Otsuka, Yui Kaneko, Seiryo Ogata, Ryotaro Yagi, Tatsuki Uemura, Takeshi Masuda, Takashi Saito, Takaomi Saido, Sumio Ohtsuki","doi":"10.1016/j.xphs.2024.10.051","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.051","url":null,"abstract":"<p><p>Impaired hepatic and renal function influence Alzheimer's disease (AD) progression; however, whether AD progression affects these important organ functions remains unclear. Here, we investigated the impact of AD progression, characterized by brain amyloid-beta (Aβ) accumulation, on liver and kidney function of App^{NL-G-F/NL-G-F} (APP-KI) mice using quantitative proteomics. SWATH-based quantitative proteomics revealed changes in mitochondrial, drug metabolism, and pharmacokinetic-related proteins in mouse liver and kidneys during the early (2-month-old) and intermediate (5-month-old) stages of Aβ accumulation. Notably, in 5-month-old APP-KI mouse liver, 25 phase I/II metabolizing enzymes (8 CYPs, 7 UGTs, 7 CESs, and 3 SLCs) and five transporters (2 ABCs and 3 SLCs) were significantly altered; specifically, Ugt1a9 and Slc33a1 protein abundances increased, whereas Ugt1a1 and Abcc3 protein abundances decreased. In the kidneys, 13 phase I/II metabolizing enzymes and 10 ABC-SLC transporters were altered, including Ugt1a6, Ugt1a7, Slc22a7, and Abcb1a. Additionally, plasma proteins, such as albumin and alpha-1-acid glycoprotein, which are critical for drug binding and distribution, were also altered. These results underscore the significant role of progressive brain Aβ accumulation in modifying hepatic and renal protein abundances, potentially influencing drug metabolism and disposition in AD. Our findings provide novel insights into the complex relationship between AD progression and organ dysfunction.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reactivity of N terminal histidine of peptides towards excipients/impurity of excipients: A case study of liraglutide excipient compatibility study","authors":"Azahar R. Sheikh ,&nbsp;Jyotsna G. Vitore ,&nbsp;Vijay S. Bhalekar ,&nbsp;Sonali Jain ,&nbsp;Divya Kukreja ,&nbsp;Tushar Giri ,&nbsp;Nitish Sharma ,&nbsp;Derajram Benival ,&nbsp;Ravi P. Shah","doi":"10.1016/j.xphs.2024.08.007","DOIUrl":"10.1016/j.xphs.2024.08.007","url":null,"abstract":"<div><div>The selection of quality excipients is a crucial step in peptide formulation development. Apart from excipient incompatibility, process-related impurities or degradants of an excipient can interact with peptide-active pharmaceutical ingredients, forming the interaction products. The formaldehyde has been reported as an impurity of excipient in polyethylene glycol, glycerol, magnesium stearate, microcrystalline cellulose, mannitol, etc. The peptide contains various amino acids such as histidine, lysine, and arginine having free amine groups. These amine groups act as strong nucleophile and can increase the reactivity of peptides. PLGA is the most widely used biodegradable polymer in sustained-release formulations. The hydrolysis of PLGA generates glycolic acid and lactic acid impurities, which can form the interaction product with the amines of peptides. During the formulation development of Liraglutide, we have found few interaction products. The systematic characterization and mechanistic understanding of these interaction products lead us to imidazopyrimidine, glycolyl, and lactolyl moieties. These interaction products have been characterized thoroughly with the use of LC-HRMS, MS/MS, and hydrogen-deuterium exchange mass studies. The study revealed that the reactivity of N-terminal histidine must be considered for formulation development. Moreover, the quality of excipients with respect to presence of impurities must be considered as critical material attributes.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3246-3254"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S0022-3549(24)00461-1","DOIUrl":"10.1016/S0022-3549(24)00461-1","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages A2-A4"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142656639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quality risk management and data integrity in R&D laboratories supporting CMC lifecycle of biological products","authors":"Brent S. Kendrick ,&nbsp;John P. Gabrielson ,&nbsp;Deanna Hunt ,&nbsp;Merry Christie ,&nbsp;Steven Bowen ,&nbsp;Christina Vessely ,&nbsp;Richard S. Rogers ,&nbsp;Chad Cleveland ,&nbsp;Karl Maluf ,&nbsp;Shawn Roach ,&nbsp;Nadine Ritter","doi":"10.1016/j.xphs.2024.09.013","DOIUrl":"10.1016/j.xphs.2024.09.013","url":null,"abstract":"<div><div>The development of pharmaceutical products is the critical bridge that moves a potential new medicine from academic discovery to applied treatment of patients. It translates an idea for a new drug to bench-level research on how it can be manufactured, formulated, characterized and controlled for use in non-clinical and early clinical trials.</div><div>From pre-clinical R&amp;D discovery work through the commercial launch, substantial R&amp;D CMC data is generated to develop and optimize cGMP manufacturing and testing operations, while also supporting product comparability, elucidating product / impurity structures, assessing critical quality attributes, developing the drug delivery mode, and developing the product formulation for long-term stability. Significant R&amp;D CMC work continues post-approval to support continuous improvement and market expansion of the commercial product. These activities are crucial elements of Product Lifecycle Management, and taken together, they comprise Pharmaceutical Quality or Chemistry, Manufacturing and Controls (CMC). The objective of this paper is to mitigate the regulatory ambiguity of R&amp;D quality systems with practical, risk-based examples and recommendations when conducting supportive CMC studies for biological products.</div><div>Making sound strategic CMC decisions under any circumstances assumes data from R&amp;D studies are reliable, traceable, and complete. While there are specific regulatory guidelines on phase-appropriate cGMP activities, none exist for quality practices in R&amp;D CMC laboratories conducting non-cGMP studies. Hindsight is not the time to discover that R&amp;D studies lack key elements that would otherwise have allowed the data to be directly presented to regulators, if needed. There is a strong prospective business interest in protecting considerable investments made for CMC R&amp;D studies. Therefore, establishment of a robust and stage-appropriate R&amp;D laboratory quality system is essential for companies seeking to capitalize on prior knowledge, protect investments, and be prepared for accelerated approval pathways.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3123-3136"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}