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Acta Pharmacologica Sinica 2007年第9期28卷 1422-1428页

作者： Gary D STONER Robeena M AZIZ Division of Hematology and Oncology and Comprehensive Cancer center Division of Environmental Health Sciences College of Public HealthThe Ohio State UniversityColumbusOH 43210USAUS Food and Drug AdministrationCenter for Drug Evaluation and ResearchSilver SpringMD 20903USA

Aim:This study was conducted to determine if short-term treatment of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus withdietary freeze-dried black raspberries (FBR) would result in tumor regression andenhanced survival of the ***:Four-week-old male Fisher-344 ratswere administered an AIN-76A control diet and injected subcutaneously with 0.5mg/kg NMBA once per week for 15 *** 19 weeks,when rats had an averageof 5-6 tumors (papillomas) per esophagus,they were given a control diet contain-ing either 5%,10%,or 20% *** 7 weeks of berry treatment,all survivingrats were killed and tumor incidence,number and volume were ***:Esophageal tumor incidences,numbers and volumes in NMBA-treated rats werenot influenced by any of the berry *** were progressive increasesin the survival of NMBA-treated rats fed 5%-20% FBR diets;however,theseincreases were not ***:FBR at 5%,10%,and 20% of the diethad no effect on the development of NMBA-induced tumors in the rat esophagusor on animal survival when administered for 7 weeks beginning at the papillomastage of tumor ***,FBR appear to have no therapeutic value inthe treatment of esophageal *** contrast,dietary FBR are highly effectivein preventing the development of NMBA-induced esophageal tumors in rats whenadministered before and during NMBA treatment or shortly after NMBA treat-ment when the esophagi contain preneoplastic (dysplastic) lesions of varyingdegrees of severity.

关键词： chemoprevention therapy esophagus squamous cell carcinoma rodent black raspberries

Dose optimization of piperacillin/tazobactam in patients with renal dysfunction based on population pharmacokinetic and pharmacodynamic simulations

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Journal of Chinese Pharmaceutical Sciences 2018年第12期27卷 824-831页

作者： Chao Zhang Ruohan Xie Chuhui Wang Chenchen Xi Mengjia Ge Department of pharmacy Peking University Third Hospital Beijing 100191 China center for drug evaluation China Food and Drug Administration Beijing 100053 China

In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.

关键词： Piperacillin/tazobactam Renal dysfunction Dose optimization

The Role of Toxicology in Evaluating Marketing Applications for Prescription drug Products in the United states

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The Role of Toxicology in Evaluating Marketing Applications ...

Influence and related mechanism of Retn gene expression on glucose uptake in 3T3-L1 cells

中国毒理学会第四届全国学术会议

作者： Kenneth L Hastings Associate Director Office of New drugs center for drug evaluation and Research US food and drug administration

＜正＞In the United states, in order to market a prescription drug product studies need to be conducted to demonstrate safety and efficacy. The toxicologist’s responsibility is to ensure that adequate studies have been conducted to demonstrate that the drug can be safely administered to humans in clinical trials and that the drug does not produce toxicities that would preclude marketing. There are three general principles that the toxicologist relies on in evaluating what are generally referred to as nonclinical studies: （1） humans are animals;therefore, studies conducted in animals are relevant to assessing the safety of

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Frontiers of Medicine 2007年第3期1卷 269-273页

作者： LI Yahui LI Huaixing DONG Shiyuan YU Chao JIANG Yu SUN Shuhan Institute for Nutritional Science Shanghai Institute for Biological SciencesChinese Academy of ScienceShanghai 200031China center for Healthy food evaluation State Food and Drug AdministrationBeijing 100061China Department of Medical Genetics College of Basic Medical ScienceSecond Military Medical UniversityShanghai 200433China

The aim of this article was to investigate the influence and the related mechanism of the Retn gene on glucose uptake and insulin resistance in 3T3-L1 *** was used to determine glucose uptake in 3T3-L1 cells with different Retn gene expression levels,whether cells were stimulated by insulin or ***-PCR and real-time RT-PCR analysis were used to determine the mRNA levels of several glucose transport proteins in 3T3-L1 cells with different Retn gene expression levels,including insulin receptor substrate-1(IRS-1),phosphatidylinositol 3-kinase(PI-3K),AKT-2,glucose transporter-4(GLUT-4),p38 mitogen-activated protein kinase(p38MAPK)and glycogen synthase kinase-3b(GSK-3b).The glucose uptake decreased with the increase in Retn gene expression in 3T3-L1 cells,which was independent of whether the cells were stimulated by insulin or *** mRNA expression of two signal proteins PI-3K and AKT-2 decreased and the other two signal proteins,GSK-3b and p38MAPK,increased with Retn overexpression in 3T3-L1 *** could induce insulin resistance in adipocytes,which might be related to the changes of some proteins in PI-3K and Ras pathways.

关键词： Resistin Retn gene insulin glucose uptake 3T3-L1 cells

Optimized functional and structural design of dual-target LMRAP,a bifunctional fusion protein with a 25-amino-acid antitumor peptide and GnRH Fc fragment

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Acta Pharmaceutica Sinica B 2020年第2期10卷 262-275页

作者： Meng Li Hanmei Xu Junzhi Wang Shenyang Pharmaceutical University Shenyang 110016China Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products National Institutes for Food and Drug ControlBeijing 102629China state Key Laboratory of Natural Medicines Ministry of Educationthe Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu ProvinceDepartment of Marine PharmacyChina Pharmaceutical UniversityNanjing 211198China

To develop fusion protein of a GnRH Fc fragment and the integrin targeting AP25 antitumor peptide for GnRH receptor-expressing cancer *** LMRAP fusion protein was constructed.A transwell invasion assay was *** gene mRNA and protein levels of GnRHR-I,α5β1,andαvβ3 in different cancer cell lines were *** proliferation was measured using a cell counting *** antagonist assay was performed on GnRH ***-tumor activity was evaluated with a mouse xenograft tumor ***(IHC)was applied to detect CD31 and CD34 *** characteristics were determined with an indirect competition *** developed bifunctional fusion protein LMRAP not only inhibited HUVEC invasion,but also inhibited proliferation of GnRHR-I,α5β1,and high expression cancer *** IC50 for LMRAP in the GnRH receptor was 6.235 x 10-4 mol/*** significantly inhibited human prostate cancer cell line22 RV1 proliferation in vivo and in *** significantly inhibited CD31 and CD34 *** elimination half-life of the fusion protein LMRAP was 33 h in *** fusion protein made of a GnRH Fc fragment and the integrin targeting AP25 peptide retained the bifunctional biological activity of GnRHR blocking,angiogenesis inhibition,prolonged half-life and good tolerance.

关键词： Fusion protein GnRH Integrin Angiogenesis Prostate cancer

Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3444-3453页

作者： Shiwen Song Dong Sun Hong Wang Jinliang Wang Huijing Yan Xuan Zhao John Paul Fawcett Xin Xu Deqi Cai Jingkai Gu Research center for drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China center for food and drug Inspection of NMPA Changchun 130012China Jen Kem Technology Co. Ltd.Tianjin 300450China state Key Laboratory of Supramolecular Structure and Materials College of ChemistryJilin UniversityChangchun 130012China Beijing Institute of drug Metabolism Beijing 102209China

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,***,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting *** address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of *** results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to *** compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and *** a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by *** summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than *** supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.

关键词： Irinotecan SN-38 Trivalent PEGylated irinotecan Prodrug Full-profile pharmacokinetics

Development and Application of a Validated UHPLC Method for the Determination of Atropine and Its Major Impurities in Antidote Treatment Nerve Agent Auto-Injectors (ATNAA) Stored in the Strategic National Stockpiles

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Pharmacology & Pharmacy 2017年第1期8卷 15-31页

作者： Cheng H.Yen Adil Mohammad Miah Schneider Salwa K.Poole Bryan Lowry Brenda W.Mc Curdy Patrick J.Faustino Saeed R.Khan Office of Regulatory Affairs Detroit LaboratoryFood and Drug AdministrationDetroitMIUSA Division of Product Quality Research Office of Testing and ResearchOffice of Pharmaceutical QualityCenter for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringMDUSA

The development and implementation of advanced analytical technologies is essential for extending the expiry for complex drug products stored in the Strategic National Stockpiles. Consequently, a novel Ultra High-Performance Liquid Chromatographic (UHPLC) method has been developed for the analysis of atropine and its respective impurities to support the analytical research platform for auto-injectors. This study is part of a larger research effort to improve the efficiency and broaden the applicability of advanced analytical methods for medical counter-measure medications. The current HPLC compendial methodology for atropine sulfate injection requires an analysis time of 40 minutes for atropine. In comparison, the novel gradient UHPLC method required only 8 minutes to evaluate both atropine and its major pharmaceutical impurities. Improved separation was achieved on a Waters Acquity UHPLC BEH C18 1.7 μm, 2.1 × 100 mm column employing gradient elution of mobile phase solvent A (0.1% H3PO4) and solvent B (0.1% H3PO4, 90% ACN, and 10% H2O). The method was validated according to USP Category I requirements for assay. The daily standard calibration curves were linear over a concentration range from 50 μg/mL to 250 μg/mL with a correlation coefficient of >0.999. The detection limit (LOD) and quantitation limit (LOQ) were 3.9 μg/ml and 13.1 μg/ml, respectively. Resolution results indicate that atropine and the following impurities, degradants and a preservative can also be separated and analyzed using this proposed method: noratropine, 4,4’-di-hy-droxydiphenyl ether, 2,4’-dihydroxydiphenyl ether, 4-bromophenol, 4-hydro-xyatropine, tropic acid, apoatropine HCl, atropic acid, hydroquinone, nitroethane, phenol and catechol. The UHPLC method demonstrated enhanced selectivity and significantly reduced the analysis time when compared with the traditional USP compendial HPLC method. The method was successfully applied to the evaluation of atropine in ATNAA auto-injectors lots fro

关键词： Atropine Sulfate Atropine ATNAA SLEP UHPLC Impurities

Short-term Effect of Combined Therapy with Jinlong Capsule(金龙胶囊)and Transcatheter Arterial Chemoembolization on Patients with Primary Hepatic Carcinoma and Its Influence on Serum Osteopontin Expression

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Chinese Journal of Integrative Medicine 2010年第2期16卷 109-113页

作者：吴国琳张力李天一陈玖余国友李剑平 The First Affiliated Hospital College of MedicineZhejiang University center for drug Reevaluation State Food and Drug Administration Zhejiang Chinese Medical University

Objective：To observe the clinical combination effect of Jinlong Capsule（金龙胶囊,JLC） and transcatheter arterial chemoembolization（TACE） on the patients with primary hepatic carcinoma（PHC） and JLC＇s influence on serum osteopontin（OPN） expression and elucidate the correlation between the serum OPN level and curative effect of JLC and ***：A total of 98 patients with PHC were observed in a randomized controlled trial（RCT）.They were assigned to the Chinese medicine（CM） group（53 patients who were treated with TACE and JLC） and the intervention group（45 patients who were treated with TACE only）.The serum OPN levels were measured before and after treatment by quantitative sandwich enzyme-linked immunosorbent assay（ELISA）.Forty healthy people were assigned to the control *** clinical efficacy was observed and Karnofsky score（KPS） was ***：The clinical efficacy of the CM group（60.38%） was better than that of the intervention group（40.00%）,and the KPS（84.35±12.19） was higher than the intervention group（69.86±11.58）（P〈0.05）.The serum OPN levels before and after treatment in the patients with PHC were significantly elevated compared with those in the control group（P〈0.01）.After treatment,the OPN levels in CM group（117.69±78.50） were significantly lower compared with those in intervention group（151.09±83.90,P〈0.05）.The OPN levels of responders were remarkably lowered than the non-responders after treatment,and the level of OPN in the CM group was lower than the intervention group（P〈0.05）.Conclusions：The short-term clinical efficacy and the quality of life of patients with PHC can be improved by combining JLC with *** serum OPN levels in PHC patients can reflect the curative effect of treatment and the prognosis of the disease.

关键词： Jinlong Capsule transcatheter arterial chemoembolization primary hepatic carcinoma osteopontin clinical efficacy

Structural characteristics of the hydrophobic patch of azurin and its interaction with p53: a site-directed spin labeling study

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Science China(Life Sciences) 2010年第10期53卷 1181-1188页

作者： XU Chao YIN JunJie ZHAO BaoLu state Key Laboratory of Brain and Cognitive Science Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Graduate University of the Chinese Academy of Sciences Beijing 100049China center for food Safety and Applied Nutrition Food and Drug AdministrationCollege ParkMD 20740USA

Site-directed spin labeling (SDSL) is a powerful tool for monitoring protein structure, dynamics and conformational changes. In this study, the domain-specific properties of azurin and its interaction with p53 were studied using this technique. Mutations of six residues, that are located in the hydrophobic patch of azurin, were prepared and spin labeled. Spectra of the six azurin mutants in solution showed that spin labeled residues 45 and 63 are in a very restricted environment, residues 59 and 65 are in a spacious environment and have free movement, and residues 49 and 51 are located in a relatively closed pocket. Polarity experiments confirmed these results. The changes observed in the spectra of spin labeled azurin upon interaction with p53 indicate that the hydrophobic patch is involved in this interaction. Our results provide valuable insight into the topographic structure of the hydrophobic domain of azurin, as well as direct evidence of its interaction with p53 in solution via the hydrophobic patch. Cytotoxicity studies of azurin mutants showed that residues along the hydrophobic patch are important for its cytotoxicity.

关键词： azurin p53 spin label protein-protein interaction anticancer ESR