The metabolism study of radiolabeled drugs plays an important role in the development of new drugs. It provides information on drug absorption, metabolism, tissue distribution and excretion, and plays an irreplaceable role in the metabolite safety evaluation and mass balance of new drugs. The new guidance draft on clinical trials of radiolabeled drugs recently released by the US FDA puts forward higher standards and has been widely concerned by the industry. In recent years, in the research and development of new drugs in China, ¹⁴C labeled drugs have been used to carry out clinical metabolism studies, which has overcome key technical bottlenecks and accumulated experience. This paper summarizes the above research progress, analyzes the existing problems, and preliminarily looks forward to the future technological development and application.

Adult ; Female ; Graft vs Host Disease ; diagnosis ; Hepatitis, Autoimmune ; diagnosis ; Humans

Objective To analyze comparatively the outcome of modified Manipal and DeVega tricuspid annuloplaaty.Methods From Oct.2001 to Aug.2004,the consecutive 123 patients operated with modified Manipal tricuspid annuloplasty for tricuspid re- gurgitation at the time of left cardiac valve replacement(group A)were elected in this study.The other 174 patients operated with De Vega tricuspid annuloplasty at the time of left cardiac valve replacement were elected randomly for control(group B).There were no significant differences of the patient data before surgery between two groups.Results There were overall 11 early deaths(4 in group A,7 in group B),The overall in-hospital mortality rate was 3.7 %.215 of the 286 surviving patients were followed;the overall follow up was 75.2 %.Mean follow-up was(28.4?9.1)months(range from 13 to 49 months).There were ten late deaths and the late mortality rate was 4.7%.There was no significant differences in the patients with 3+～4+ tricuspid regurgitation at follow-up 18,30 and 42 months in group A;but there was an increase of the patients with 3+～4+ tricuspid regurgitation with an incremental follow up term in group B(P

Acute Disease ; Adult ; Chromatography, Gas ; Female ; Humans ; Lung ; chemistry ; Phosphines ; analysis ; blood ; poisoning

Objective To establish a RP-HPLC method for determining indigo and indirubin in Baphicacanthus cusia from different producing areas and medicinal parts. Methods The separation was achieved by an Agilent TC-C18 Column (4.6 mm×250 mm, 5 μm) at 25 ℃ using methanol-water (75??25) as mobile phase at a flow rate of 1 mL??min-1.The detection wavelength was 290 nm. Results Indigo had a good linear relationship with peak area at range of 0. 051 3-0.820 8 μg (r=0.999 3).The recovery rate was 99.00% and RSD was 1.30% (n=6).Indirubin had a good linear relationship with peak area at range of 0.049 5-0.792 0 μg (r=0.999 9).The recovery rate was 98.88% and RSD was 1.51% (n=6). Conclusion The contents of the two components are obviously different in Baphicacanthus cusia because of different places or medicinal parts. The proposed method is simple, rapid and reliable. This method for determination of indigo and indirubin in Baphicacanthus cusia by RP-HPLC provides a basis for quality control of Baphicacanthus cusia.

BACKGROUND: Because of complicated physiological environment and difficulty to control experimental conditions, it is difficult to get satisfactory results from in vivo studies of cell mechanics.OBJECTIVE: To study the action and mechanism of p38MAPK signaling pathways on myoblast apoptosis based on successful construction of in vitro mechanical stimulation models.METHODS: The C2C12 cells cultured in vitro were divided into control group and SB203580 treatment group. Cyclic tensile stress was applied on the C2C12 myoblast cells for 0, 6, 12 and 24 hours in each group. The Flexcell Strain Unit-5000T was used to expose C2C12 myoblast cell to an equiaxial cyclic of 15% magnitude and a frequency of 10 cycles/min, each cycle including the 3 s stretch and 3 s relaxation. Hoechst 33258 fluorescent staining and optical microscope were used to detect cell apoptosis. RT-PCR, flow cytometric analysis were used to observe the apoptosis of C2C12 myoblast cells and Western blotting were used to detect the activity of p38MAPK and p-p38MAPK. RESULTS AND CONCLUSION: The optical microscope tested the change in the morphology. Hoechst 33258 staining showed that after treatment with cyclic stress, the cell took the typical appearance of apoptosis with chromatin condensation and apoptotic bodies. RT-PCR and flow cytometry showed that with the extension of time the rate of the apoptosis of C2C12 myoblast cell increased. And cells imposed SB203580 before imposing cyclical tensile stress, the results showed that the apoptosis was markedly affected, and the p-p38MAPK expression declined apparently. These findings demonstrate that p38MAPK signaling pathways in stress mediated into C2C12 myoblast cell apoptosis plays an important role.

This study aims to develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of ivabradine and N-demethylivabradine in human plasma, and investigate effects of stable isotope labeled (SIL) internal standard (IS) on ivabradine. The analytes and IS were extracted from plasma by protein precipitation with acetonitrile, and chromatographied on a Capcell PAK C18 (100 mm x 4.6 mm, 5 μm) column using a mobile phase of methanol and 5 mmol x L(-1) ammonium acetate. Multiple reaction monitoring with electrospray ionization (ESI) was used in the positive mode for mass spectrometric detection. The effect of ivabradine isotope peak [M+H+3] + on IS and the effect of SIL IS purity on ivabradine were evaluated. An appropriate concentration of SIL IS was chosen to permit method selectivity and linearity of the assay over the required range. The standard curves were demonstrated to be linear in the range of 0.100 to 60.0 ng x mL(-1) for ivabradine, and 0.050 0 to 20.0 ng x mL(-1) for N-demethylivabradine. The intra and inter day precision and accuracy were within the acceptable limits for all concentrations. Besides, the interaction between IS and ivabradine did not impact the determination of analytes. This method was successfully applied to a pharmacokinetic study of hydrogen sulfate ivabradine sustained release tablets on Chinese healthy volunteers.
Benzazepines ; blood ; Chromatography, High Pressure Liquid ; Delayed-Action Preparations ; Humans ; Isotope Labeling ; standards ; Reference Standards ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tablets ; Tandem Mass Spectrometry

OBJECTIVETo study the effects of Huoxue Jiedu Recipe (HJR) on the hemodynamics of central retinal artery (CRA) and central retinal vena, as well as the morphology of blood vessels of diabetic rats.

METHODSSixty SD rats were selected and fasted for 12 h. Streptozotocin (STZ, 65 mg/kg) was intraperitoneally injected to induce diabetic rat models. The modeled rats were randomly divided into the model group, the high dose HJR group (15.4 g/kg), the middle dose HJR group (7.70 g/kg), the low dose HJR group (3.85 g/kg), and the Doxium Capsule group (the Western medicine group, 0. 167 g/kg), 10 in each group. Another 10 rats were recruited as the normal control group. Equal volume of distilled water was given to rats in the normal control group. The intervention was carried out once daily in each group, totally for 20 weeks. The peak systolic velocity (PSV), the end diastolic velocity (EDV), the mean velocity (MV), the pulsatile index (PI), the resistive index (RI), and the central retinal vena velocity (CRV) were detected in each group. The retinal vascular morphologies were observed and compared using trypsin digestion.

RESULTSCompared with the normal control group, the PSV, EDV, MV, and CRV decreased, PI, RI, and capillary density increased in the model group with statistical difference (P<0.01). The retinal capillaries rowed disorderly. The calibers of capillaries were not even. The hyperplasia of endothelial cells and less pericytes could be seen. Compared with the model group, PSV, EDV, MV, and CRV all increased, PI and RI decreased in the high and middle dose HJR groups with statistical difference (P<0.01). There was no statistical difference among all the medication groups (P>0.05). The distributions of capillaries in the 3 HJR groups were even. The vascular morphous was comparatively regular, without obvious twisting and dilation. The hyperplasia of endothelial cells was not obvious. Compared with the model group, the capillary density significantly decreased (P<0.01). There was no statistical difference among the 3 HJR groups. Compared with the model group, the capillary density significantly decreased in the Western medicine group (P<0.01).

CONCLUSIONHJR could obviously improve the retinal hemodynamics parameters of diabetic rats, increase the retinal capillary blood flow and reperfusion, and restrain the hyperplasia of endothelial cells in the capillary.

Animals ; Diabetes Mellitus, Experimental ; drug therapy ; pathology ; physiopathology ; Diabetic Retinopathy ; drug therapy ; pathology ; physiopathology ; Drugs, Chinese Herbal ; therapeutic use ; Hemodynamics ; Male ; Phytotherapy ; Rats ; Rats, Sprague-Dawley

A sensitive, rapid and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with pre-column derivatization was developed for the simultaneous determination of erdosteine and its thiol-containing active metabolite in human plasma. Paracetamol and captopril were chosen as the internal standard of erdosteine and its active metabolite, respectively. Aliquots of 100 microL plasma sample were derivatized by 2-bromine-3'-methoxy acetophenone, then separated on an Agilent XDB-C18 (50 mm x 4.6 mm ID, 1.8 microm) column using 0.1% formic acid methanol--0.1% formic acid 5 mmol x L(-1) ammonium acetate as mobile phase, in a gradient mode. Detection of erdosteine and its active metabolite were achieved by ESI MS/MS in the positive ion mode. The linear calibration curves for erdosteine and its active metabolite were obtained in the concentration ranges of 5-3 000 ng x mL(-1) and 5-10 000 ng x mL(-1), respectively. The lower limit of quantification of erdosteine and its active metabolite were both 5.00 ng x mL(-1). The pharmacokinetic results of erdosteine and its thiol-containing active metabolite showed that the area under curve (AUC) of the thiol-containing active metabolite was 6.2 times of that of erdosteine after a single oral dose of 600 mg erdosteine tables in 32 healthy volunteers, The mean residence time (MRT) of the thiol-containing active metabolite was (7.51 +/- 0.788) h, which provided a pharmacokinetic basis for the rational dosage regimen.
Administration, Oral ; Area Under Curve ; Chromatography, Liquid ; Female ; Humans ; Male ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry ; Thioglycolates ; administration & dosage ; blood ; metabolism ; pharmacokinetics ; Thiophenes ; administration & dosage ; blood ; metabolism ; pharmacokinetics

Objective To explore the relationship between physical activity(PA) and the risk of colon cancer. Methods Cohort studies on physical activity and risk of colon cancer were identified by searching MEDLINE, EMBASE, Chinese Bio-medicine and Chinese Wanfang databases from January 1979 to December 2009. Results from the individual studies were synthetically combined in our study. Inverse variance weighting was used in fixed effects model and the random effects estimate was based on the DerSimonian-Laird method. Variance-weighted least squares method was used for trend test of summarized dose-response data. Results A total of 28 studies were included in our analysis. An inverse association between physical activities and the risk of colon cancer was observed with the relative risks (RR) as 0.75 [95% confidence interval (CI): 0.66-0.86] in males and 0.85(95%CI: 0.76-0.95)in females, respectively. However, the findings from those documents with high quality showed significant and borderline significant associations between PA and colon cancer in both males (RR=0.74, 95% CI: 0.61-0.90) and females (RR=0.99, 95% CI: 0.95-1.02). Meanwhile, the dose-response trend was not observed either in males (P=0.142) or in females (P=0.417). For men, the pooled RRs differed by subsites were 0.62(95%CI:0.45-0.85) and 0.74 (95%CI:0.56-0.99)for highest level PA, compared with lowest level PA in proximal colon and distal colon cancer,respectively. For women, the pooled RRs were 0.84 (95%CI: 0.69-1.01 ) in proximal colon and 0.75(95%CI: 0.53-1.05)in distal colon cancer, respectively. Conclusion These results added to the evidence for the protective effects in colon cancer among men and women.