Kana Koinuma, Kenji Noto, Tokio Morita, Yoshinori Uekusa, Haruhisa Kikuchi, Miyuki Shimoji, Hiroyuki Seki, Hiroshi Yamazaki, F Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Ayuko Imaoka, Takeshi Akiyoshi, Hisakazu Ohtani
{"title":"Kinetics of the Inhibition of CYP3A4 and CYP2C19 Activity by Jabara Juice and Identification of the Responsible Inhibitory Components.","authors":"Kana Koinuma, Kenji Noto, Tokio Morita, Yoshinori Uekusa, Haruhisa Kikuchi, Miyuki Shimoji, Hiroyuki Seki, Hiroshi Yamazaki, F Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Ayuko Imaoka, Takeshi Akiyoshi, Hisakazu Ohtani","doi":"10.1016/j.xphs.2024.10.037","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.037","url":null,"abstract":"<p><p>Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6',7'-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3',4',5,6,7,8-heptamethoxyflavone (HpMF) and 3,3',4',5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (K<sub>I</sub>) of 10.0 and 7.90 µM and maximal inactivation rate constants (k<sub>inact,max</sub>) of 0.00856 and 0.0134 min<sup>-1</sup>, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558085","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":"Application of Atomic Force Microscopy in the Development of Amorphous Solid Dispersion.","authors":"Soumalya Chakraborty, Arvind K Bansal","doi":"10.1016/j.xphs.2024.10.036","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.036","url":null,"abstract":"<p><p>Development of Amorphous Solid Dispersion (ASD) requires an in-depth characterization at different stages due to its structural and functional complexity. Various tools are conventionally used to investigate the processing, stability, and functionality of ASDs. However, many subtle features remain poorly understood due to lack of nano-scale characterization tools in routine practice. Atomic force microscopy (AFM) is a type of scanning probe microscopy, used for high resolution imaging and measuring features at the nano-scale. In recent years AFM has been used increasingly as a characterization tool in different areas of the development of ASD, including drug-polymer miscibility, localized characterization of the phase separated domains, lateral molecular diffusivity on ASD surface, crystallinity and crystallization kinetics in ASD, phase behavior of ASD during dissolution, and conformation of polymer during dissolution. In this review, we have highlighted the current applications of AFM in capturing critical aspects of stability and dissolution behavior of ASD. Potential areas of future development in this domain have been discussed.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558083","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}
Thai T H Nguyen, Cai Y Ma, Ioanna D Styliari, Parmesh Gajjar, Robert B Hammond, Philip J Withers, Darragh Murnane, Kevin J Roberts
{"title":"Structure, Morphology and Surface Properties of α-Lactose Monohydrate in Relation to its Powder Properties.","authors":"Thai T H Nguyen, Cai Y Ma, Ioanna D Styliari, Parmesh Gajjar, Robert B Hammond, Philip J Withers, Darragh Murnane, Kevin J Roberts","doi":"10.1016/j.xphs.2024.10.031","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.031","url":null,"abstract":"<p><p>The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction contrast tomography. Interestingly, from aqueous solution fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to their slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558087","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}
Dipy M Vasa, Shih-Wen Wang, Matthew F Dunn, Erica Long, Suman A Luthra
{"title":"Molecular-properties based formulation guidance tree for amorphous and supersaturable mesoporous silica preparations of poorly soluble compounds.","authors":"Dipy M Vasa, Shih-Wen Wang, Matthew F Dunn, Erica Long, Suman A Luthra","doi":"10.1016/j.xphs.2024.10.040","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.040","url":null,"abstract":"<p><p>A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558086","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}
Airton G Salles, Manoel T Rodrigues, Bruno B Guidotti, Paulo C P Rosa
{"title":"Comprehensive Analysis of Deflazacort Oxidative Degradation: Insights into Novel Degradation Products and Mechanisms.","authors":"Airton G Salles, Manoel T Rodrigues, Bruno B Guidotti, Paulo C P Rosa","doi":"10.1016/j.xphs.2024.10.048","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.048","url":null,"abstract":"<p><p>The oxidative degradation pathways of deflazacort (DFL) were investigated to address the gap in understanding its degradation products, focusing on reactions with oxidative stressors such as hydrogen peroxide and 4,4'-azobis (4-cyanovaleric acid) (ACVA). Using HPLC-PDA, high-resolution mass spectrometry (HRMS), NMR and IR spectroscopy, four novel degradation products were identified and structurally characterized. Two of these products were isolated using preparative HPLC before characterization. Hydrogen peroxide led to the formation of three novel products (DP-1, DP-2, and DP-3), while ACVA resulted in a single novel product (DP-4). Mechanistic and kinetic experiments supported the proposed degradation pathways under the various oxidative stress conditions studied, revealing distinct rates of formation for the degradation products during the time-course study. The identification and detailed structural elucidation of these degradation products provide critical insights into the chemical stability and potential reactivity of DFL under oxidative stress. These findings underscore the importance of comprehensive stability testing for ensuring drug safety and efficacy, and offer valuable data for future research on the toxicity and pharmacological impact of DFL degradation products.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546080","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":"Cocrystal Screening in Minutes by Solution-Mediated Phase Transformation (SMPT): Preparation and Characterization of Ketoconazole Cocrystals with Nine Aliphatic Dicarboxylic Acids.","authors":"Junguang Yu, Rodger F Henry, Geoff G Z Zhang","doi":"10.1016/j.xphs.2024.10.046","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.046","url":null,"abstract":"<p><p>The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546079","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}
Alexander E Yarawsky, Carlo Ciatto, Peter Slade, Natalya Figueroa, John W Burgner, Michael DeLion, Lake N Paul
{"title":"Quantitation of AAV in a dual-vector system using SV-AUC.","authors":"Alexander E Yarawsky, Carlo Ciatto, Peter Slade, Natalya Figueroa, John W Burgner, Michael DeLion, Lake N Paul","doi":"10.1016/j.xphs.2024.10.049","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.049","url":null,"abstract":"<p><p>Sedimentation velocity analytical ultracentrifugation (SV-AUC) has become the \"gold standard\" for characterization of the empty, partial, and full capsids of gene therapy products (e.g., AAV and Adenovirus vectors). Other techniques, such SEC-MALS, TEM, and mass photometry, are commonly used for capsid quantitation, however, the resolving power of these techniques is lacking. In this body of work, SV-AUC was implemented in the characterization of a dual-vector AAV system where the difference in packaged genomes was ∼400 nucleotides. SV-AUC instrument parameters and analysis were optimized to accurately quantitate both AAV vectors with less than 8% error and highly correlated linearity (R<sup>2</sup> > 0.99) as compared to ddPCR. The results of this work highlight the resolution and accuracy of dual-vector capsid quantitation by SV-AUC and demonstrate the use of the powerful Bayesian analysis implemented in the SEDFIT analysis software.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546081","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}
Jayant Iyer, Matilde Barbosa, João F Pinto, Amrit Paudel
{"title":"Implications of crystal disorder on the solid-state stability of Olanzapine.","authors":"Jayant Iyer, Matilde Barbosa, João F Pinto, Amrit Paudel","doi":"10.1016/j.xphs.2024.10.047","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.047","url":null,"abstract":"<p><p>Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569091","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}
Joseph R Cohen, Marisa K Joubert, Syeda Tabassum, Allyson Capili, Julia Carreon, Cathie Xiang, Siddharth Prabhu, Anthony Merlo, Dan Mytych, David G Dolan, Ram Kouda
{"title":"Experimental Validation of a Parenteral Permitted Daily Exposure Value for Cleaning-Induced Degradants from Recombinant Therapeutic Proteins with In Vitro Immunogenicity Assays.","authors":"Joseph R Cohen, Marisa K Joubert, Syeda Tabassum, Allyson Capili, Julia Carreon, Cathie Xiang, Siddharth Prabhu, Anthony Merlo, Dan Mytych, David G Dolan, Ram Kouda","doi":"10.1016/j.xphs.2024.10.041","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.041","url":null,"abstract":"<p><p>Multiproduct manufacturing of biotherapeutic proteins generate cleaning-induced protein degradants because of extreme pH and temperature conditions during the cleaning process. Cleaning Acceptance limits are calculated based on the maximum allowable carryover (MAC) assessment of the previously manufactured active pharmaceutical ingredient (API) - or drug product - based on the permitted daily exposure (PDE) of the previously manufactured API into the dose of subsequent product. In this study, we tested a previously determined PDE value for cleaning-induced protein degradants of 650 µg/dose. A bench-scale cleaning method was used to generate cleaning induced degradants from both a half-life extension (HLE) BiTE® molecule and a mAb product. For this investigation degradants of HLE BiTE®-A and mAb-1 were characterized either alone or degradants of HLE BiTE®-A and mAb-1 spiked into mAb-1 at 650 µg. These samples were characterized by endotoxin testing, size exclusion chromatography (SEC), light obscuration by HIAC, and micro-fluidic imaging (MFI). These results suggest that significant degradation of the molecule occurs because of the cleaning procedure, and it is no longer in the intact form or active state. The biological impact was assessed using a cell line assay to assess immune activation, and a human Peripheral Blood Mononuclear Cell (PBMC) assay to assess T cell activation, T cell proliferation, and cytokine release after 20 hours and 7 days. Findings from the various in vitro cell-based assays suggest that the presence of 650 µg of carryover of degradants either alone or spiked into the same or a cross-product do not increase immunogenicity risk in cell-based assays - suggesting that the current PDE of 650 µg/dose for cleaning-induced degradant carryover does not have a risk of immunogenicity in patients.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569074","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}
Alexandru Deac, Chailu Que, Michelle L Cousineau, Anura S Indulkar, Yi Gao, Geoff G Z Zhang, Lynne S Taylor
{"title":"Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Polymer Molecular Weight and Identification of a New Failure Mode.","authors":"Alexandru Deac, Chailu Que, Michelle L Cousineau, Anura S Indulkar, Yi Gao, Geoff G Z Zhang, Lynne S Taylor","doi":"10.1016/j.xphs.2024.10.026","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.026","url":null,"abstract":"<p><p>The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of PVP were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502573","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}