Results in pharma sciences最新文献_第2页

In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex 聚谷氨酸包被脂质体靶向肝脏的体内siRNA递送系统

Results in pharma sciences Pub Date : 2014-01-01 DOI: 10.1016/j.rinphs.2014.01.001

Yoshiyuki Hattori, Ayako Nakamura, Shohei Arai, Mayu Nishigaki, Hiroyuki Ohkura, Kumi Kawano, Yoshie Maitani, Etsuo Yonemochi

{"title":"In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex","authors":"Yoshiyuki Hattori, Ayako Nakamura, Shohei Arai, Mayu Nishigaki, Hiroyuki Ohkura, Kumi Kawano, Yoshie Maitani, Etsuo Yonemochi","doi":"10.1016/j.rinphs.2014.01.001","DOIUrl":"10.1016/j.rinphs.2014.01.001","url":null,"abstract":"<div><p>In this study, we developed anionic polymer-coated liposome/siRNA complexes (lipoplexes) with chondroitin sulfate C (CS), poly-<span>l</span>-glutamic acid (PGA) and poly-aspartic acid (PAA) for siRNA delivery by intravenous injection, and evaluated the biodistribution and gene silencing effect in mice. The sizes of CS-, PGA- and PAA-coated lipoplexes were about 200 nm and their ζ-potentials were negative. CS-, PGA- and PAA-coated lipoplexes did not induce agglutination after mixing with erythrocytes. In terms of biodistribution, siRNAs after intravenous administration of cationic lipoplexes were largely observed in the lungs, but those of CS-, PGA- and PAA-coated lipoplexes were in both the liver and the kidneys, indicating that siRNA might be partially released from the anionic polymer-coated lipoplexes in the blood circulation and accumulate in the kidney, although the lipoplexes can prevent the agglutination with blood components. To increase the association between siRNA and cationic liposome, we used cholesterol-modified siRNA (siRNA-Chol) for preparation of the lipoplexes. When CS-, PGA- and PAA-coated lipoplexes of siRNA-Chol were injected into mice, siRNA-Chol was mainly observed in the liver, not in the kidneys. In terms of the suppression of gene expression <em>in vivo</em>, apolipoprotein B (ApoB) mRNA in the liver was significantly reduced 48 h after single intravenous injection of PGA-coated lipoplex of ApoB siRNA-Chol (2.5 mg siRNA/kg), but not cationic, CS- and PAA-coated lipoplexes. In terms of toxicity after intravenous injection, CS-, PGA- and PAA-coated lipoplexes did not increase GOT and GPT concentrations in blood. From these findings, PGA coatings for cationic lipoplex of siRNA-Chol might produce a systemic vector of siRNA to the liver.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"4 ","pages":"Pages 1-7"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2014.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33117039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Relationship between the usability and physicochemical properties of triamcinolone acetonide ointments 曲安奈德软膏的可用性与理化性质的关系

Results in pharma sciences Pub Date : 2013-01-01 DOI: 10.1016/j.rinphs.2013.10.002

Yutaka Inoue, Rikimaru Maeda, Kayoko Furuya, Murata Isamu, Kimura Masayuki, Ikuo Kanamoto

{"title":"Relationship between the usability and physicochemical properties of triamcinolone acetonide ointments","authors":"Yutaka Inoue, Rikimaru Maeda, Kayoko Furuya, Murata Isamu, Kimura Masayuki, Ikuo Kanamoto","doi":"10.1016/j.rinphs.2013.10.002","DOIUrl":"10.1016/j.rinphs.2013.10.002","url":null,"abstract":"<div><p>The purpose of this study was to examine the physicochemical properties of TA ointments and conduct a human sensory test to assess the properties of those ointments. Physicochemical assessment was done via near-infrared (NIR) absorption spectroscopy, measurement of water content, microscopy, and measurement of viscoelasticity. The human sensory test examined 5 aspects (texture, cohesiveness, spreadability, smell, and feel). Three TA ointments were used: TA-A, a brand-name preparation, and TA-B and TA-C, two generics. The sensory test revealed significant differences between TA-A and TA-B and TA-C in terms of cohesiveness and spreadability. Significant differences between TA-A and TA-C and between TA-B and TA-C in terms of feel were noted. Microscopic examination revealed that TA-C had good dispersibility while TA-A and TA-B produced crystallization. NIR spectroscopy revealed differences in absorption spectra attributed to oil and water content in TAA, TA-B, and TA-C. Measurement of water content indicated water content of 0.06 ± 0.02% for TA-A, 0.08 ± 0.08% for TA-B, and 36.7 ± 1.19% for TA-C. Assessment of viscoelasticity indicated that stress decreased for all 3 ointments at 35 °C compared to that at 25 °C. TA-A and TA-B were found to have a higher percent decrease in stress than was TA-C. These findings indicate that differences in the types and content of additives caused differences in the physicochemical properties of individual ointments. In addition, differences in physicochemical properties presumably resulted in the close correlation between cohesiveness and spreadability in the sensory test.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"3 ","pages":"Pages 15-19"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2013.10.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33117038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9

Advisory Board 咨询委员会

Results in pharma sciences Pub Date : 2013-01-01 DOI: 10.1016/S2211-2863(13)00006-7

引用次数: 0

Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract 胶囊壳材料影响绿茶提取物的体外崩解和溶出行为

Results in pharma sciences Pub Date : 2013-01-01 DOI: 10.1016/j.rinphs.2013.08.002

Natalie Glube , Lea von Moos , Guus Duchateau

{"title":"Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract","authors":"Natalie Glube , Lea von Moos , Guus Duchateau","doi":"10.1016/j.rinphs.2013.08.002","DOIUrl":"10.1016/j.rinphs.2013.08.002","url":null,"abstract":"<div><h3>Purpose</h3><p><em>In vitro</em> disintegration and dissolution are routine methods used to assess the performance and quality of oral dosage forms. The purpose of the current work was to determine the potential for interaction between capsule shell material and a green tea extract and the impact it can have on the release.</p></div><div><h3>Methods</h3><p>A green tea extract was formulated into simple powder-in-capsule formulations of which the capsule shell material was either of gelatin or HPMC origin. The disintegration times were determined together with the dissolution profiles in compendial and biorelevant media.</p></div><div><h3>Results</h3><p>All formulations disintegrated within 30 min, meeting the USP criteria for botanical formulations. An immediate release dissolution profile was achieved for gelatin capsules in all media but not for the specified HPMC formulations. Dissolution release was especially impaired for HPMC<sub>gell</sub> at pH 1.2 and for both HPMC formulations in FeSSIF media suggesting the potential for food interactions.</p></div><div><h3>Conclusions</h3><p>The delayed release from studied HPMC capsule materials is likely attributed to an interaction between the catechins, the major constituents of the green tea extract, and the capsule shell material. An assessment of <em>in vitro</em> dissolution is recommended prior to the release of a dietary supplement or clinical trial investigational product to ensure efficacy.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"3 ","pages":"Pages 1-6"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2013.08.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33116495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 27

Surfactants modify the release from tablets made of hydrophobically modified poly (acrylic acid) 表面活性剂对疏水改性聚丙烯酸片剂释放性能的影响

Results in pharma sciences Pub Date : 2013-01-01 DOI: 10.1016/j.rinphs.2013.08.001

Patrik Knöös , Sebla Onder , Lina Pedersen , Lennart Piculell , Stefan Ulvenlund , Marie Wahlgren

{"title":"Surfactants modify the release from tablets made of hydrophobically modified poly (acrylic acid)","authors":"Patrik Knöös , Sebla Onder , Lina Pedersen , Lennart Piculell , Stefan Ulvenlund , Marie Wahlgren","doi":"10.1016/j.rinphs.2013.08.001","DOIUrl":"10.1016/j.rinphs.2013.08.001","url":null,"abstract":"<div><p>Many novel pharmaceutically active substances are characterized by a high hydrophobicity and a low water solubility, which present challenges for their delivery as drugs. Tablets made from cross-linked hydrophobically modified poly (acrylic acid) (CLHMPAA), commercially available as Pemulen™, have previously shown promising abilities to control the release of hydrophobic model substances. This study further investigates the possibility to use CLHMPAA in tablet formulations using ibuprofen as a model substance. Furthermore, surfactants were added to the dissolution medium in order to simulate the presence of bile salts in the intestine.</p><p>The release of ibuprofen is strongly affected by the presence of surfactant and/or buffer in the dissolution medium, which affect both the behaviour of CLHMPAA and the swelling of the gel layer that surrounds the disintegrating tablets. Two mechanisms of tablet disintegration were observed under shear, namely conventional dissolution of a soluble tablet matrix and erosion of swollen insoluble gel particles from the tablet. The effects of surfactant in the surrounding medium can be circumvented by addition of surfactant to the tablet. With added surfactant, tablets that may be insusceptible to the differences in bile salt level between fasted or fed states have been produced, thus addressing a central problem in controlled delivery of hydrophobic drugs. In other words CLHMPAA is a potential candidate to be used in tablet formulations for controlled release with poorly soluble drugs.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"3 ","pages":"Pages 7-14"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2013.08.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33117037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Advisory Board 咨询委员会

Results in pharma sciences Pub Date : 2012-01-01 DOI: 10.1016/S2211-2863(12)00012-7

引用次数: 0

Anti-angiogenic poly-L-lysine dendrimer binds heparin and neutralizes its activity 抗血管生成聚l -赖氨酸树突状物结合肝素并中和其活性

Results in pharma sciences Pub Date : 2012-01-01 DOI: 10.1016/j.rinphs.2011.12.002

Khuloud T. Al-Jamal , Wafa T. Al-Jamal , Kostas Kostarelos , John A. Turton , Alexander T. Florence

{"title":"Anti-angiogenic poly-L-lysine dendrimer binds heparin and neutralizes its activity","authors":"Khuloud T. Al-Jamal , Wafa T. Al-Jamal , Kostas Kostarelos , John A. Turton , Alexander T. Florence","doi":"10.1016/j.rinphs.2011.12.002","DOIUrl":"10.1016/j.rinphs.2011.12.002","url":null,"abstract":"<div><p>The interaction between heparin, a polyanion, and a polycationic dendrimer with a glycine core and lysine branches Gly–Lys<sub>63</sub>(NH<sub>2</sub>)<sub>64</sub> has been investigated. Complexation was assessed by transmission electron microscopy, size and zeta potential measurements, methylene blue spectroscopy, and measuring the anti-coagulant activity of heparin <em>in vitro</em> and <em>in vivo</em>. Complete association between the heparin and the dendrimer occurred a 1:1 mass ratio (2:1 molar ratio or +/−charge ratio) with formation of quasi-spherical complexes in the size range of 99–147nm with a negative zeta potential (−47mV). Heparin–dendrimer (dendriplex) formation led to a concentration-dependent neutralization of the anticoagulant activity of heparin in human plasma <em>in vitro</em>, with complete loss of activity at a 1:1 mass ratio. The anticoagulant activity of the dendriplexes in Sprague-Dawley rats was also evaluated after subcutaneous administration with uncomplexed heparin as a comparator. The <em>in vivo</em> anticoagulant activity of heparin in plasma, evaluated using an antifactor Xa assay, was abolished after complexation. Measurement of [<sup>3</sup>H]-heparin showed that both free heparin and dendriplexes were present in plasma and in organs. Such data confirmed stably the formation of dendriplexes, which could be essential in developing novel dendrimer-based anti-angiogenic therapeutics suitable in combinatory therapeutics and theranostics.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"2 ","pages":"Pages 9-15"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2011.12.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32998629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 21

Development of oxaliplatin encapsulated in magnetic nanocarriers of pectin as a potential targeted drug delivery for cancer therapy 奥沙利铂包封在果胶磁性纳米载体中作为癌症治疗的潜在靶向药物递送

Results in pharma sciences Pub Date : 2012-01-01 DOI: 10.1016/j.rinphs.2012.05.001

Raj Kumar Dutta, Saurabh Sahu

{"title":"Development of oxaliplatin encapsulated in magnetic nanocarriers of pectin as a potential targeted drug delivery for cancer therapy","authors":"Raj Kumar Dutta, Saurabh Sahu","doi":"10.1016/j.rinphs.2012.05.001","DOIUrl":"10.1016/j.rinphs.2012.05.001","url":null,"abstract":"<div><p>Superparamagnetic iron oxide nanoparticles (SPIONs) and oxaliplatin (OHP) were in-situ encapsulated in pectin cross-linked with Ca<sup>2+</sup> forming 100–200nm sized magnetically functionalized pectin nanocarriers, referred here as MP-OHP nanocarriers. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies revealed formation of spherical nanostructures. The magnetic measurements by vibration sample magnetometer (VSM) revealed high saturation magnetization (<em>M</em><sub>s</sub>=45.65emu/g). The superparamagnetic property of MP-OHP was confirmed from the blocking temperature (<em>T</em><sub>B</sub>) determined from field cooled and zero field cooled magnetization, measured by superconducting quantum unit interference device (SQUID) magnetometry. The stability of the aqueous dispersion of MP-OHP nanocarriers was confirmed from its high zeta potential (−30.5mV). The drug encapsulation efficiency (55.2±4.8% w/w) and the drug loading content (0.10±0.04wt%) in MP-OHP nanocarriers were determined from corresponding platinum contents in OHP and MP-OHP batches measured by inductively coupled plasma mass spectrometry (ICPMS). These nanocarriers exhibited a sustained release of OHP in phosphate buffer solution maintained at pH 5.5 and 7.4, where the drug release profile satisfied a combination of diffusion and swelling controlled mechanism. The cytotoxicity effect of MP-OHP nanocarriers was studied on MIA-PaCa-2 (pancreas) cancer cell line, where the GI<sub>50</sub> values were more than 5mg/mL and it exhibited 10 folds higher cytoxicity than the equivalent concentration of free drug.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"2 ","pages":"Pages 38-45"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2012.05.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33116490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 53

Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes 胰高血糖素样肽1的酶单聚乙二醇化对2型糖尿病的持久治疗

Results in pharma sciences Pub Date : 2012-01-01 DOI: 10.1016/j.rinphs.2012.09.001

Fabio Selis , Rodolfo Schrepfer , Riccardo Sanna , Silvia Scaramuzza , Giancarlo Tonon , Simona Dedoni , Pierluigi Onali , Gaetano Orsini , Stefano Genovese

{"title":"Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes","authors":"Fabio Selis , Rodolfo Schrepfer , Riccardo Sanna , Silvia Scaramuzza , Giancarlo Tonon , Simona Dedoni , Pierluigi Onali , Gaetano Orsini , Stefano Genovese","doi":"10.1016/j.rinphs.2012.09.001","DOIUrl":"10.1016/j.rinphs.2012.09.001","url":null,"abstract":"<div><p>Human glucagon-like peptide-1 (GLP-1) is a physiological gastrointestinal peptide with glucose-dependent insulinotropic effects which is therefore considered an interesting antidiabetic agent. However, after <em>in vivo</em> administration, exogenous GLP-1 does not exert its physiological action due to the combination of rapid proteolytic degradation by ubiquitous dipeptidyldipeptidase IV (DPP IV) enzyme and renal clearance resulting in an extremely short circulating half-life. In this work we describe the conjugation of GLP-1-(7-36)-amide derivatives with polyethylene glycol (PEG) by enzymatic site-specific transglutamination reaction as an approach to reduce both the proteolysis and the renal clearance rates.</p><p>The compound GLP-1-(7-36)-amide-Q<sup>23</sup>-PEG 20kDa monopegylated on the single glutamine residue naturally present in position 23 maintained the ability to activate the GLP-1 receptor expressed in the rat β-cell line RIN-m5F with nanomolar potency along with an increased <em>in vitro</em> resistance to DDP IV and a circulating half-life of about 12h after subcutaneous administration in rats. These properties enabled GLP-(7-36)-amide-Q<sup>23</sup>-PEG 20kDa to exert a glucose-stabilizing effect for a period as long as 8h, as demonstrated by a single subcutaneous injection to diabetic mice concomitantly challenged with an oral glucose load.</p><p>The results reported in this work indicate that GLP-(7-36)-amide-Q<sup>23</sup>-PEG 20kDa could be a lead compound for the development of long-lasting anti-diabetic agents useful in the treatment of type 2 diabetes affected patients.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"2 ","pages":"Pages 58-65"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2012.09.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33116492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 16

Regenerated keratin membrane to match the in vitro drug diffusion through human epidermis 再生角蛋白膜匹配体外药物通过人表皮扩散

Results in pharma sciences Pub Date : 2012-01-01 DOI: 10.1016/j.rinphs.2012.10.001

Francesca Selmin , Francesco Cilurzo , Annalisa Aluigi , Silvia Franzè , Paola Minghetti

{"title":"Regenerated keratin membrane to match the in vitro drug diffusion through human epidermis","authors":"Francesca Selmin , Francesco Cilurzo , Annalisa Aluigi , Silvia Franzè , Paola Minghetti","doi":"10.1016/j.rinphs.2012.10.001","DOIUrl":"10.1016/j.rinphs.2012.10.001","url":null,"abstract":"<div><p>This work aimed to develop membranes made of regenerated keratin and ceramides (CERs) to match the barrier property of the human stratum corneum in <em>in vitro</em> percutaneous absorption studies. The membrane composition was optimized on the basis of the <em>in vitro</em> drug diffusion profiles of ibuprofen, propranolol and testosterone chosen as model drugs on the basis of their different diffusion and solubility properties. The data were compared to those obtained using human epidermis.</p><p>The ATR-FTIR and SEM analyses revealed that CERs were suspended into the regenerated keratin matrix, even if a partial solubilization occurred. It resulted in the membranes being physically stable after exposure to aqueous buffer and/or mineral oil and the fluxes of ibuprofen and propranolol from these vehicles through membranes and human skin were of the same order of magnitude. The best relationship with human epidermis data was obtained with 180μm-thick membrane containing 1% ceramide III and 1% ceramide VI. The data on the testosterone diffusion were affected by the exposure of the membrane to a water/ethanol solution over a prolonged period of time, indicating that such an organic solvent was able to modify the supermolecular organization of keratin and CERs.</p><p>The keratin/CER membranes can represent a simplified model to assay the <em>in vitro</em> skin permeability study of small molecules.</p></div>","PeriodicalId":89718,"journal":{"name":"Results in pharma sciences","volume":"2 ","pages":"Pages 72-78"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.rinphs.2012.10.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33116494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33