The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.
Algorithms ; Bayes Theorem ; Carbamazepine ; analogs & derivatives ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; pharmacokinetics ; Models, Biological ; Monte Carlo Method ; Nonlinear Dynamics ; Regression Analysis ; Tacrolimus ; pharmacokinetics

The tuberous roots of Aconitum carmichaeli are largely used in traditional Chinese medicine and widely grown in Jiangyou, Sichuan, China. During the growth process, this medicinal plant releases a large amount of allelochemicals into soil, which retard the growth and development of near and late crops. Therefore, a pure culture experiment was thus carried out by seed soaking to study the allelopathic effects of extracts from tuberous roots of A. carmichaeli (ETR) on the seed germination and young seedling growth of Lolium perenne, Trifolium repens, and Medicago sativa, the late pasture grasses after cultivation of A. carmichaeli. The results showed that three pasture grasses varied significantly in seed germination and young seedling growth in response to ETR concentrations. Seed germination of M. sativa was stimulated by low ERT concentration (0.01 x g(-1)), while all of pasture grass seeds germinated poorly in solution with 1.00 g x L(-1). Seed soaking with 1.00 g x L(-1) also inhibited significantly the growth of pasture young seedlings, with M. sativa showing the highest seedling height reduction of 42.05% in seeding height, followed by T. repens (40.21%) and L. perenne with about 11%. Cultivation of L. perenne could thus be beneficial to increase whole land productivity in A. carmichaeli-pasture grass cropping systems. In addition, hydrolysis of protein, starch, and inositol phosphates was blocked and free amino acids, soluble sugars and phosphorus were decreased in seeds by seed soaking with ETR, which could be one of the reason for the inhibition of seed germination. There was a significant reduction in root vigor, nitrate reductase, and chlorophyll after the seed treatment with ETR, indicating the suppression of nutrient uptake, nitrate assimilation, and photosynthesis by allelopathic chemicals in ETR, which could lead to the slow growth rate of pasture grass seedlings.
Aconitum ; chemistry ; metabolism ; Allelopathy ; China ; Pheromones ; metabolism ; pharmacology ; Plant Extracts ; metabolism ; pharmacology ; Plant Roots ; chemistry ; metabolism ; Poaceae ; drug effects ; growth & development

Objective To study the therapeutic effects of intermittent hypoxia therapy(IHT)in isolated systolic hypertension(ISH)patients with elevated cerebral blood flow velocity(Vp),and to explore the mechanisms involved.Methods Seventy-six ISH patients with increasing Vp and normal pulsatility index(PI)of the middle ce- rebral artery(MCA)were randomly divided into a therapy group and a control group.IHT was administrated in the therapy group,and air in the control group.The Vp and PI of the MCA and blood pressure(BP)were observed be- fore and after treatment.Results Vp and systolic blood pressure(SBP)were significantly reduced after IHT(P＜0.01)compared with the therapy group's scores betore treatment,but PI and diastolic blood pressure showed no sig- nificant difference.There was no significant change in BP,Vp or PI in the control group before or after treatment. Conclusion IHT has therapeutic effects on ISH by reducing Vp and moderating SBP.

Objective To evaluate the radiation protection of occupational hazards in a hospital Clinac 23EX medical electronic accelerator construction project so as to ensure the health and safety of the relevant people involved.Methods According to the relevant laws,regulations and standards of China,combined with the relevant materials provided by the construction unit,the radiation protection tests and comprehensive assessment of this project were carried out.Results The performance test results of the medical electron accelerator met the requinements of GB/T 19046-2013 The ambient dose equivalent rate in the workplace was between the background dose rate (0.10 μ,Sv/h) and 11.5 μSv/h,which suggested the computer room shielding met the requirements of radiation protection.The total body effective dose,the for 7 radiation workers were 0.85,1.19,1.64 mSv,respectively,which were lower than the dose management control values of the construction unit and the national standards.Radiation protection supplies and the management system of the construction unit met the national requirements.Conclusions The construction project can effectively control the radioactive occupational hazard factors in normal operation,and the radiation protection facilities have reached the completion requirements.

Objective To study the clinical value of short term variation(STV)of fetal heart rate. Methods Three hundred thirty-eight pregnant women who delivered at our hospital during June 2002 and Dee 2005 were studied.All the eases were examined by non-stress test(NST)and vibratory acoustic stimulation test(VAST).Meanwhile,they were also analyzed by Sonieaid system 8002.One hundred fifty cases with STV≥5.0 ms as control group,and 188 cases with STV

This study was aimed to systematically appraise the effectiveness and safety of traditional Chinese medicine (TCM) decoction in combination with bisphosphonates in treatment of bone metastasis of malignant tumors. Related literatures were searched in the PubMed, Embase, CBM, CNKI and Cochrane Databases. The endpoints included cancer pain, activity of daily living, sclerotin reparation, KPS and adverse events. The Stata 11.0 software was used in the statistical analysis. The results showed that a total of 19 articles involving 1080 patients were included. It showed that TCM in combination with bisphosphonates can significantly relieve pain (RR=0.8079,95%CI =0.754-0.85,P <0.001), improve the activity of daily living (RR =0.787,95%CI =0.69-0.897,P <0.001), promote sclerotin reparation (RR =0.71,95%CI =0.52-0.96,P =0.026), and improve KPS (RR=0.7268,95%CI =0.61-0.85,0.58-0.81,P <0.001). It was concluded that TCM decoction in combination with bisphosphonates can significantly improve its therapeutic effect as well as improve the patients’ quality of life.

Objective To evaluate and follow-up the effection of vertebral artery origin stenting (VAOS) by color Doppler flow imaging(CDFI) and assess the rate of restenosis after stenting. Methods One hundred and thirty-five patients with stenosis of vertebral artery origin segment underwent stent input,135 pieces of stent was input in vertebral artery origin segment with moderate or severe stenosis,in which 70 bare metal stent(BMS) and 65 drug-eluting stent(DES). The diameter of VAOS, peak systolic velocity (PSV),end diastolic velocity (EDV) and resistence index(RI) of segment at origin and cervical vertebral were evaluated before and every 1,3,6, 12 month after VAOS by CDFI. The incidence of restenosis were calculated,and the factors of restenosis were analysed by COX regression. Results The diameter of VAOS was improved from (1.20±0.38) mm to (2.61±0.49) mm after stent procedure ( P = 0. 000), PSV and EDV also decreased from (296.02 ± 113.86)cm/s to ( 113.47 ± 36.35 )cm/s and (90.08 ± 47. 59)cm/s to (32. 21 ± 12. 69)cm/s respectively(P=0.000). The PSV and RI in cervical segment were increased from (46. 88 ± 17.46)cm/s to (67.79 ± 24.31 ) cm/s and 0. 54 ± 0. 10 to 0.62 ± 0.09 respectively( P = 0. 000).Over a median 7 months follow up(range 1 to 12 months) ,the cumulative restenosis rate at 3,6,12 month were 7.9% ,16. 9% and 25.0% respectively. DES was the only one negtive predictor of restenosis(OR=0. 388,95% CI:0.162-0.931, P = 0.034),and the factor of residual stenosis contributed to the occurance of restenosis after stenting(OR = 3.758,95% CI:1.498-9.427, P=0.005). Conclusions CDFI is a sensitive and noninvasive examination to follow-up VAOS and detect in-stent restenosis immediately. VAOS has a high rate of restenosis. DES is effective to prevent in-stent restenosis.

BACKGROUND: Osteoporosis is a genetic disease associated with many enes. To date, the genes that regulate bone mass are incompletely defined.OBJECTIVE: To investigate the relationship between polymorphisms of steoprotegerin (OPG) gene promoter with bone mineral density (BMD) in remenopausal and postmenopausal women.DESIGN: Prospective study.SETTING: Peking Union Medical College Hospital.PARTICIPANTS: In July 2002, 495 Han nationality women selected from Peking Union Medical College Hospital were non-related volunteers and gave their informed consent prior to the study, which included 306 premenopausal women aged 20-39 years, 189 postmenopausal women aged 50-84 years.METHODS: ① BMD measurement: BMD was measured at the Lumbar Spine and Femoral Neck, trochanter, Ward's triangle by dual-energy X-ray absorptiometry. ② Genotyping: Whole blood genome DNA was extracted by QIAGEN DNA extraction kit. The PCR product and the result of endonuclease digest were confirmed by sequencing (Bioasia Biotechnology,Shanghai, China). The impact of the polymorphisms on BMD was also investigated using multiple Logistic regression.MAIN OUTCOME MEASURES: ① Distribution of OPG genotypes and the relationship with BMD. ② Association between OPG polymorphisms and osteoporosis.RESULTS: All 495 subjects were involved in the final analysis. ① These polymorphisms were in Hardy-Weinberg equilibrium (χ2= 0.056 -0.222, P＞ 0.05). The frequencies of genotypes of these subjects were as follows: AA (70.1%), AG (26.9 %), GG (3.0 %) for 163A→G polymorphism; TT (71.3 %), TG (25.9 %), GG (2.8 %) for 245T→G polymorphism. BMD was lower in premenopausal women with GG +AG genotype than AA genotype for 163A→G polymorphism, so did GG+TG genotype than TT genotype for 245T→G polymorphism. But there was no significant difference. BMD was lower in postmenopausal women with AG+GG genotype than AA genotype for 163A→G polymorphism at Lumbar Spine 2-4, Femoral Neck, Ward's triangle and Trochanter (P ＜ 0.05). For 245T→G polymorphism, BMD of postmenopausal women with TG+GG genotype was lower at Femoral Neck,Ward's triangle and Trochanter than TT genotype (P ＜ 0.05). For 245T→G polymorphism, BMD of postmenopausal women with TG+GG genotype was lower at Femoral Neck, Ward's triangle, and Trochanter than TT genotype (P ＜ 0.05). ② Age, weight, height, years since menopause, and 163A→G/245T→G genotypes were sewed as covariates. AG+GG genotype was contributed to low BMD at Lumbar Spine 2-4 and Ward's triangle (OR =2.045, OR=2.956, P ＜ 0.05, 95% CI 1.05-6.7). TG+GG genotype was risk factor for osteoporosis at Lumbar Spine 2-4, Ward's triangle,and Trochanter (OR=2.059, OR=2.859, OR=2.123, P ＜ 0.05, 95% CI 1.04-6.5).CONCLUSION: BMD was lower in postmenopausal women with the variant G allele for 163A→G and 245T→G polymorphisms at Femoral Neck,Ward's triangle, and Trochanter. The variant allele G may associate with lower BMD in postmenopausal women.

OBJECTIVETo study the effect of Feiji Recipe (FR) intervening indoleamine 2,3-dioxygenase (IDO) induced immune escape on the murine model of Lewis lung carcinoma. Methods Totally 48 C57BL/6 mice inoculated with Lewis lung cancer cells transfected with human (enhanced green fluorescent protein,EGFP)-IDO gene were divided into four groups according to radom digit table, i.e., the model group (administered with normal saline by gastrogavage) , the Chinese medicine group (treated with FR Decoction at the daily dose of 100 mg/g by gastrogavage), the 1-methyl-D-trytaphan (1-MT) group (administered with 1-MT mixed liquor at the daily dose of 100 mg/kg by gastrogavage), and the Paclitaxel group (treated with Paclitaxel at the daily dose of 15 mg/kg by peritoneal injection), 12 in each group. The intervention was started from the 2nd day of modeling. The survival time was observed in 24 of them. Ratios of CD4+ CD25+ FoxP3+ regulatory T cells (Treg) in the spleen were detected in the rest 24 mice by flow cytometry respectively.

RESULTSCompared with the model group, the survival time was significantly prolonged in the Chinese medicine group and the 1-MT group (P < 0.01); ratios of Treg cells remarkably decreased in the Chinese medicine group, the 1-MT group, and the Paclitaxel group (P < 0. 01). Compared with the Paclitaxel group, the survival time was significantly prolonged in the Chinese medicine group and the 1-MT group (P < 0.01); ratios of Treg cells decreased significantly in the 1-MT group (P < 0.05).

CONCLUSIONFR could inhibit the proliferation of lung cancer cells and immune eseape, improve the immune function, and prolong the survival of tumor-bearing mice.

Animals ; Antineoplastic Agents ; pharmacology ; therapeutic use ; Carcinoma, Lewis Lung ; drug therapy ; immunology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Lung Neoplasms ; Mice ; Mice, Inbred C57BL ; Paclitaxel ; T-Lymphocytes, Regulatory

To investigate the effects of lipopolysaccharide (LPS) on autophagy in rat hepatic stellate cells (HSC-T6) and involvement of NF-κB pathway in it.Methods 1)HSC-T6 cells were treated with LPS at the concentraction of 0, 0.01, 0.1, 1, and 10 mg/L for 0, 3, 6, 12, 18, and 24 h respectively, Microtubule-associated protein light chain Ⅱ (LC3Ⅱ) and Beclin1 levels were detected by Western blot; 2)HSC-T6 cells were randomized into groups of control group, LPS group, PDTC group, LPS+PDTC group, PMA group and LPS+PMA group, Western blot assay was used to measure the levels of LC 3Ⅱand Beclin1, immunofluoresence was used to measure NF-κB P65 intracellular distribution.The levels of hydroxyproline (Hyp) were determined by the method of colorimetry and the levels of laminin (LN) and hyaluronic acid (HA) were determined by ELISA in the culture supernatants after corresponding processing .Results The levels of LC3Ⅱand Beclin1 were significantly increased after HSC-T6 cells were treated with LPS at the concentraction of 0.1 mg/L for 6 h and the levels of Hyp, LN, and HA in the culture supernatants increased remarkably as well (P<0.05).PDTC pretreatment increased the levels of LC3Ⅱand Beclin1 in the LPS-treated HSC-T6 cells while decreased the levels of Hyp , LN, and HA significantly (P<0.05).PMA pretreatmen decreased the levels of LC 3Ⅱand Beclin1 in the LPS-treated HSC-T6 cells while increased the levels of Hyp, LN, and HA (P<0.05).Conclusions LPS can promote autophagy and activation of NF -κB pathway in HSC-T6 cells.Activation of NF-κB pathway may inhibit the LPS-induced autophagy of HSC-T6 cells.