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Zhou X.-B.,National Institutes for Food and Drug Control | Sun L.,National Institutes for Food and Drug Control | Chen Y.-H.,Hangzhou Jiuyuan Gene Engineering Co. | Qu Z.,National Institutes for Food and Drug Control | And 11 more authors.
Chinese Journal of New Drugs

Objective: To evaluate the safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) following repeated dosing in rhesus monkey. Methods: Rhesus monkeys were randomly divided into four groups (0, 100, 300 and 1000 μg·kg -1). All animals were subcutaneously injected with vehicle or PEG-G-CSF weekly for 3 months followed by 1-month recovery. Results: There were no obvious abnormalities in clinical symptoms, weight, food consumption, temperature, electrocardiogram and urine analysis in all groups. In PEG-G-CSF groups, the amounts of white cells and percentages of classified white cells showed marked changes related with pharmacology of PEG-G-CSF. The microscopic results of bone marrow were consistent with the changes in hematology. Four weeks later, serum GGT and ALP levels were significantly increased (P<0.01) in the high-dose group while serum K + levels were significantly decreased in all PEG-G-CSF groups (P<0.01). The changes in hematology and clinical chemistry showed a trend to restore 4 weeks after dosing. There were no significant differences in hematology and clinical chemistry during recovery period. Histopathological results showed that the target organs included liver, spleen and sternum (bone marrow). Three months later, the ratios of antibody-positive animals in PEG-G-CSF groups were 6/6, 5/6 and 5/6. Conclusion: PEG-G-CSF at 300 μg·kg -1 can be regarded as the no-observed-adverse-effect level and 100 μg·kg -1 can be considered to be safe dose. Source

Guo W.,Zhejiang University | Guo W.,Hangzhou Jiuyuan Gene Engineering Co. | Zhu X.,Zhejiang University | Cai J.,Zhejiang University | And 3 more authors.
Process Biochemistry

To renature the inactive rhBMP-2 which overexpressed in Escherichia coli, post-expression treatments including inclusion bodies solubilization and in vitro refolding were systematically investigated. An optimized refolding process was established from screening and successfully scaled up with yield greater than 70%. Then, hydrophobic interaction chromatography (HIC) was adopted as two consecutive stages to separate the active rhBMP-2 homodimer from refolding mixture. Aiding additive N,N-dimethylformamide (DMF) was found to enhance the resolution of rhBMP-2 homodimer most effectively. The rhBMP-2 homodimer was purified to homogeneity through two HIC separations at different salt contents, the purified rhBMP-2 homodimer was fully bioactive and had equivalent biological activity to rhBMP-2 produced from Chinese hamster ovary cell (CHO). Under the optimal refolding and purification conditions, 80 mg rhBMP-2 homodimer with high purity could be obtained from 1 g wet weight of inclusion bodies. Finally, this efficient refolding and purification procedure was successfully scaled up in the pilot pharmaceutical plant. © 2012 Elsevier Ltd. Source

Zhou S.,Hangzhou Jiuyuan Gene Engineering Co. | Huang H.,Xiamen University | Huang R.,Xiamen University | Harrison W.T.A.,University of Aberdeen
Acta Crystallographica Section E: Structure Reports Online

In the title compound, C26H33NO2 [systematic name: (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,-4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phen-anthren-3-yl acetate], the steroid A, B, C and D rings adopt chair, half-chair, chair and envelope conformations, respectively. The flap atom of the envelope is the methine C atom fused with the C ring. In the crystal, adjacent molecules, generated by a 21 screw axis, are linked by weak C - H⋯O hydrogen bonds, forming a C(16) helical chain running along the c - axis direction. Source

Guo W.-M.,Zhejiang University | Guo W.-M.,Hangzhou Jiuyuan Gene Engineering Co. | Cai J.,Zhejiang University | Huang L.,Zhejiang University | And 2 more authors.
Gao Xiao Hua Xue Gong Cheng Xue Bao/Journal of Chemical Engineering of Chinese Universities

The recombinant human granulocyte colony stimulating factor (rhG-CSF) is an important recombinant protein drug; however the rhG-CSF is liable to be oxidized. The reversed-phase chromatography was used to measure the purity of rhG-CSF in 37°C accelerated stability and 4°C long-term stability assays. The oxidant and reductant with different concentrations were added to the rhG-CSF products to evaluate their short-term and long-term effects on the stability of rhG-CSF. It was found that all oxidants including hydrogen peroxide and nitrite sodium have a strong concentration effect on the oxidation process, and the reducing agents have strong pH dependence. The protein oxidation is obvious when the concentration of nitrite is higher than 0.1 ppm. The effects of different types of package material and transition metal ions on protein stability were evaluated. The results show that trace amounts of transition metal ions would be released during the sealing of ampoule with flame fusion, and the ferrous ions (Fe 2+) released have the strongest catalytic activity, and even if the released Fe 2+ concentration is 0.05 ppm, the rhG-CSF oxidation is obvious. It was also found that the addition of EDTA (Edetate disodium) and L-Met can inhibit rhG-CSF oxidation to a certain degree during its long-term preservation. The experiments show that adding EDTA would improve the stability of rhG-CSF more significantly. Source

Zhou S.,Hangzhou Jiuyuan Gene Engineering Co. | Huang H.,Xiamen University | Zhang T.,Xiamen University | Wang D.,Xiamen University | Huang R.,Xiamen University
Acta Crystallographica Section E: Crystallographic Communications

The title compound, C22H29F3O5S [systematic name: (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(trifluoromethyl-sulfonyloxy)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate], contains a fused fourring steroidal system. Rings A and C adopt a chair conformation, while rings B and D adopt half-chair and envelope (with the fused CH atom as the flap) conformations, respectively. In the crystal, weak intermolecular C-H⋯O interactions link the molecules into layers parallel to the ab plane. © 2015, International Union of Crystallography. All rights reserved. Source

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