Effect of γ-ray on metabolic enzyme CYP3A1 in rat liver on multiple levels / 中国药理学通报

Aim To explore the effect of γ-ray on the mRNA,protein expression levels and metabolic activity level of the key drug metabolic enzyme CYP3A1 in rat liver. Methods Wistar rats were randomly divided into control group, 24 h post-radiation group and 72 h post-radiation group. The experimental group was exposed to total body irradiation of single 6 Gy γ-ray. Blood was collected from the orbital venous plexus for blood routine examination and biochemical analysis 24 h and 72 h after irradiation, and liver tissue was prepared for quantifying expression of CYP3A1 mRNA and liver-specific microRNA (miR-122-5p) through RT-PCR. The expression level of CYP3A1 protein was analyzed by Western blot, and the metabolic activity level of CYP3A1 detected by the specific substrate midazolam combined with LC-MS method. Results Com¬pared with the control group, the weights of the rats in the radiation group significantly decreased, and the number of white blood cells was markedly reduced. Simultaneously, the activities of alanine aminotrans-ferase and alkaline phosphatase continuously descended, as well as the levels of total bilirubin and bile acid significantly increased, which indicated that the liver may be damaged after radiation. The relative expression of CYP3A1 mRNA continued to increase significantly 24 h and 72 h after irradiation. CYP3A1 protein expression and metabolic activity levels showed an obvious increasing trend 24 h after irradiation, and rose significantly 72 h after irradiation compared with the control group. At the same time, the expression of miR-122-5p in liver of rats in the 24 h and 72 h post-radiation group continued to decrease rapidly compared with the control group. Conclusions γ-ray radiation may arouse damage effect on liver, which leads to the continuous up-regulation of the mRNA and protein expression levels of the capital metabolic enzyme CYP3A1 in liver tissue, as well as the elevation of the metabolic activity level. The regulatory mechanism might be related to miR-122-5p.

Pharmacokinetics of two recombinant humanized monoclonal antibodies against ricin in rhesus monkeys / 药学学报

Recombinant humanized anti-ricin monoclonal antibody (MIL50) is a recombinant humanized monoclonal antibody targeting ricin. In this study, an ELISA method was used to establish a method for the determination of MIL50 in macaque serum, and a cross design method was used. Twelve rhesus monkeys were intravenously injected 1 mg·kg-1 test preparation (MIL50 freeze-died powder injection) and reference preparation (MIL50 liquid preparation) to determine the plasma concentration of MIL50 at different time points, and the pharmacokinetic parameters were analyzed to compare the pharmacokinetic characteristics of MIL50 liquid preparation and freeze-died powder injection in rhesus monkeys. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of the Chinese Academy of Medical Sciences and Use of Laboratory Animals and the regulations derived by the Animal Care and Welfare Committee of the Institute of Radiation Medicine, Academy of Military Medical Sciences (IACUC-DWZX-2020-503). The results showed that there was no significant difference between Cmax and AUC0-5d in the two groups. The liquid preparation was the reference preparation, with Cmax ratio of 101.6% and AUC0-5d ratio of 101.9%, the 90% confidence interval of Cmax was 79.42%-129.92%, and the 90% confidence interval of AUC0-5d was 85.72%-121.18%. These results suggested that different dosage forms of MIL50 had certain differences in the changes of blood drug concentration in rhesus monkeys.

Application of Self-assembling Peptides to Hemostasis / 中国实验血液学杂志

As a widespread phenomenon in living system, molecular self-assembly has become the meeting point of multidisciplinary research including chemistry, biology, materials science and medicine. In recent years, the rapid development in molecular self-assembly of peptide technology is showing a great potential in the application of tissue engineering, drug delivery, bionic medicine, cosmetology field, optical and electronic product development, etc. Especially, the remarkable hemostatic effect of self-assembling peptides (SAP) on organs, nerves and brain wounds successfully promoted its application to the material science and clinical medicine. This review focuses on the hemostatic effects and characteristics of SAP on different bleeding wound models, action mechanism, its benefits and limitations as well as its adrancing trends.

Determination of yogliptin and its metabolite in Wistar rat plasma by liquid chromatography-tandem mass spectrometry / 药学学报

A rapid, sensitive and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the simultaneous determination of yogliptin and its metabolite in Wistar rat plasma. Linagliptin and dexamethasone were chosen as the internal standards of yogliptin and its metabolite, (R)-8-(3-hydroxypiperidine- -yl)-7-(but-2-yn-1-yl)-1-((5-fluorobenzo[d]thiazol-2-yl)methyl)-3-methyl- H-purine-2, 6 (3H, 7H)-dione, respectively. After a simple protein precipitation using acetonitrile as the precipitating solvent, both analytes and ISs were separated on a Grace Altima HP C18 column (2.1 mm x 50 mm, 5 microm) with gradient elution using methanol (containing 0.1% formic acid, 4 mmol x L(-1) ammonium acetate)-0.1% formic acid (containing 4 mmol x L(-1) ammonium acetate) as the mobile phase. A chromatographic total run time of 4.4 min was achieved. Mass spectrometric detection was conducted with electrospray ionization under positive-ion and multiple-reaction monitoring modes. Linear calibration curves for yogliptin and its metabolite were over the concentration range of 0.5 to 500 ng x mL(-1) with a lower limit of quantification of 0.5 ng x mL(-1). The intra- and inter- assay precisions were all below 14%, the accuracies were all in standard ranges. The method was used to determine the concentration of yogliptin and M1 in Wistar rat plasma after a single oral administration of yogliptin (27 mg x kg(-1)). The method was proved to be selective, sensitive and suitable for pharmacokinetic study of yogliptin and M1 in Wistar rat plasma.

Pharmacodynamics and pharmacokinetics of batroxobin in Beagle dog / 药学学报

Healthy Beagle dogs were administrated with batroxobin by intravenous infusion at high, medium and low doses. The study of pharmacodynamics and pharmacokinetics was intended to clarify the relevance of them and provided strong evidence for clinical use of batroxobin. The blood samples were collected after injection based on the time schedule and samples were tested by ELISA method to get the concentration of batroxobin. At the same time, changes of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimmer were tested. The results showed that the concentration of D-D increased significantly after administration compared with that of before administration. The main pharmacokinetic parameters were as follows: t1/2 were (2.27 +/- 0.42) h, (10.65 +/- 2.19) h and (11.01 +/- 3.51) h; C(max) were (11.9 +/- 1.72) ng x mL(-1), (154.53 +/- 12.38) ng x mL(-1) and (172.14 +/- 47.33) ng x mL(-1); AUC(last) were (29.38 +/- 3.69) ng xh x mL(-1), (148.43 +/- 72.85) ng x h x mL(-1) and (599.22 +/- 359.61) ng x h x mL(-1). The elimination of batroxobin was found to be in accord with linear kinetics characteristics. The results of pharmacodynamics showed that D-dimmer level increased significantly after the administration of batroxobin, which was similar with the changes of batroxobin plasma concentration. Simultaneously, Fib concentrations in Beagle dog blood decreased significantly after the iv administration of batroxobin, while recovered to base level after 48 hours. PT, TT and APTT significantly became longer after administration, which returned to normal level after 48 hours. Especially, the D-dimmer levels and the batroxobin concentration in plasma after intravenous infusion of the drug were synchronized in Beagle dogs. Changes between PD/PK results had obvious correlation, and the D-dimmer levels in plasma can be one of the important monitoring indicators of batroxobin in thrombolytic medication.