Physiologically based pharmacokinetic model (PBPK), a mechanistic mathematic model, which can simulate the absorption, distribution, metabolism and excretion of drugs, is being more widely used in pharmaceutical research and development areas. This article reviews primarily the recent advances in the procedure of establishing a PBPK model, including specifying of the PBPK model structure, specification of the tissue model, writing of equations, set of model parameters, simulation and evaluation. Application significance, major challenges and future developments of PBPK model in pharmaceutical areas are also discussed.
Animals ; Biological Transport ; Computer Simulation ; Humans ; Models, Biological ; Pharmaceutical Preparations ; chemistry ; metabolism ; Pharmacokinetics ; Software ; Tissue Distribution

Objective To explore changes of local renin-angiotensin system(RAS)in renal tissue of rat during short-and mid-term tail suspension,as well as their relations with humoral regulation and renal function induced by real or simulated weightlessness.Methods 1-and 4-week(wk)tail-suspended rat model were used to simulate short-and mid-term weightlessness,respectively.Reverse transcriptase polymerase chain reaction(RT-PCR)was carried out to examine the mRNA expression of components of local RAS in renal tissue.Results Except for angiotensin Ⅱ receptor type 2(AT2),all of the other components of local RAS,including angiotensinogen(AGT),renin,angiotensin converting enzyme(ACE),angiotensin Ⅱ receptor type 1a(AT1a)and angiotensin Ⅱ receptor type 1b(AT1b),were found their expression in renal tissue of Sprague-Dawley rats.After 1 wk of tail suspension,mRNA expression of renin in renal tissue increased significantly(P

BACKGROUND: Cell apoptosis and ventricle reconstitution following myocardial infarction are of mutual cause-effect, and they cause vicious cycle. How to reduce the apoptosis events following myocardial infarction is one of keys to saving heart function.OBJECTIVE: To observe the effect of umbilical cord blood mesenchymal stem cell (UCBSMC) transplantation on remaining myocardial tissue of dogs with acute myocardial infarction.DESIGN: A randomized controlled observation.SETTING: Department of Cardiothoracic Surgery, Xinhua Hospital.MATERIALS: This study was carried out in the Central Laboratory of Xinhua Hospital from October 2005 to May 2007.Thirty-six adult hybrid dogs, male and female in half, were provided by the Animal Experimental Center of Xinhua Hospital.METHODS: Thirty-six dogs were divided into cell transplantation group and control group, with 18 dogs in each according to table of random digit. Mesenchymal stem cells were isolated from the umbilical cord blood of full-term pregnant hybrid dogs, cultured and amplified. Then, they were labeled with Laz gene, in vitro induced with 5-azacytidine, and transplanted into the dogs with acute myocardial infarction in the cell transplantation group. Rats in the control group were injected with the same amount of normal saline. Each dog was euthanized by anesthesia for harvesting myocardial specimen 1,4 and 8 weeks after transplantation.MAIN OUTCOME MEASURES: ① Remaining and apoptosis index detected by TUNEL method. ② Myocardial cell volume and histomorphology detected by confocal microscopy. ③ Histological change of myocardial collagen network detected by haematoxylin-basic fuchsin-picric acid staining.RESULTS: Thirty-six involved experimental dogs all entered the stage of final analysis. ①The apoptosis index in the cell transplantation group was significantly lower than that in the control group 1, 4 and 8 weeks after cell transplantation (P ＜0.05). ② Myocardial cell volume in the cell transplantation group 1, 4 and 8 weeks after cell transplantation was significantly larger than that in the control group (P ＜ 0.05). ③ Collagen fiber in the myocardial tissue of dogs in the cell transplantation group was arranged in order and regularly, and in contrast that in the control group was not, and fibers in the control group fused partially.CONCLUSION: UCBSMC transplantation reduces the apoptosis of myocardial cells, promotes the hypertrophy of remaining myocardial cells, regulates myocardial collagen network and improves heart function.

Objective To evaluate the potential association of CD4+CD25+ T cells with alopecia areata.Methods Totally,this study enrolled 23 patients with progressive alopecia areata,25 patients with stable alopecia areata,and 25 healthy controls.Peripheral blood was isolated from these subjects followed by isolation of CD4+ CD25+ regulatory T cells,which were then cuhured with the presence of anti-CD3 and-CD28 monoclonal antibodies for four days.Subsequently,enzyme-linked immunosorbent assay was performed to measure the levels of interleukin (IL)-10 and transforming growth factor (TGF)-β1 in the culture supematant of these T cells.Results The levels of IL-10 and TGF-β1 were (31.68 ± 6.78) pg/ml and (32.29 ± 6.8) pg/ml respectively in the culture supernatant of CD4+CD25+ regulatory T cells from patients with progressive alopecia areata,significantly lower than those from the healthy controls ((57.34 ± 14.15) pg/ml and (57.43 ± 15.16) pg/ml,both P ＜ 0.05) and patients with stable alopecia areata ((52.56 ± 13.02) pg/ml and (61.75 ± 14.10) pg/ml,both P ＜ 0.05).However,no significant difference was observed in the supernatant levels of IL-10 or TGF-β1 between the healthy controls and patients with stable alopecia areata.Conclusions The secretion of IL-10 and TGF-β1 by CD4+CD25+ T cells is decreased in patients with progressive alopecia areata,which may contribute to the pathogenesis of alopecia areata.

Objective To determine the level of interleukin (IL)-10 in sera and culture supernatants of CD4+CD25+T cells from children with atopic dermatitis (AD),and to evaluate its relationship with clinical course and severity of AD.Methods Totally,46 children with AD and 31 healthy controls were included in the study.All the patients were divided into 3 groups,i.e.,mild (n =10),moderate (n =16) and severe (n =20) group,according to severity scoring of atopic dermatitis (SCORAD) score.Venous blood samples were obtained from the patients and healthy controls.CD4+CD25+ regulatory T cells were separated from the blood samples by magnetic cell sorting (MACS) system in two steps and cultured in vitro.Enzyme linked immunosorbent assay (ELISA) was conducted to quantify the level of IL-10 in sera and culture supernatants of CD4+CD25 + T cells from these subjects.Analysis of variance was carried out to compare the level of supematant and serum IL-10 between the patients and controls,and Pearson correlation analysis to assess the relationship between the level of IL-10 and SCORAD score.Results The patients with mild,moderate and severe AD showed a similar serum IL-10 level compared with the healthy controls ((43.10 ± 25.07) pg/ml,(68.40 ± 36.65) pg/ml and (55.55 ± 41.97) pg/ml vs.(58.27 ± 36.84) pg/ml,all P ＞ 0.05).The level of supernatant IL-10 secreted by CD4+CD25+ T cells from the controls was significantly higher than that from the patients with severe AD ((55.15 ± 11.15) pg/ml vs.(27.25 ± 7.01) pg/ml,P ＜ 0.05),but similar to that from the patients with mild and moderate AD ((52.96 ± 11.69) pg/ml and (49.86 ± 9.18) pg/ml,respectively,both P ＞ 0.05).The level of secreted IL-10 was negatively correlated with SCORAD score (r =－0.757,P ＜ 0.01),whereas the serum level of IL-10 showed no statistical correlation with SCORAD score.Conclusion CD4+CD25+ T cells and IL-10 may be implicated in the development of AD.

Objective To understand the current situation and the main influencing factors of hospital staffs' scientific research work in a affiliated hospital of Xinjiang,so as to provide the basis for improving awareness and level of scientific research of hospital staffs.Methods Survey using stratified random sampling method,using self-questionnaire research capacity factors questionnaire, to investigate the status of project leaders' research capacity in a affiliated hospital of Xinjiang.Using frequencies and relative number described ability to research,using x2 to compare research level among the various metrics.Scientific research levels' multivariate analysis using Ordinal Logistic Regression Analysis.Results regarding of scientific research,low level of 14 people,accounting for 4.9％,the middle level of 158 people,accounting for 55％,a high level of 115 people,accounting for 40.1％.Univariate analysis showed that age,length of service,education level,job title,whether master instructor it is,the research team,the situation of foreign training and learning opportunities,foreign academic session (times),support from leadership and family,non-working time for research,the total research funding (ten thousands yuan),discipline level have impact on the level of scientific research work.Ordinal Logistic regression analysis showed that age,length of service,educational level,whether master instructor it is,the total research funding (ten thousands yuan),discipline level are the main factors on level of scientific research work.Conclusions The scientific research level needs to be further improved,the level of scientific research is affected by many factors.

OBJECTIVETo analyze the clinical characteristics of elderly patients with spinal tuberculosis and explore its clinical effects with anti-TB drugs alone.

METHODSFrom January 2008 to July 2010, the data of 36 patients with spinal tuberculosis underwent conservative treatment of anti-TB drugs alone were analyzed. There were 19 males and 17 females with an average age of 73.5 years (ranged, 60 to 85). All patients were in the active phase with high ESR and CRP levels and were treated with 3HRZE/6-9HRE (course from 9 to 12 months). According to clinical symptoms, chemical examination, radiological image to adjust drug and depending on VAS score to evaluate pain.

RESULTSAll the patients were followed up from 8 to 24 months with an average of 15 months. Tuberculose of 31 patients healed after chemotherapy from 9 to 12 months and ESR and CRP recovered normally. Levofloxacin and para-amino salicylic acid were used in 4 cases because of 4 cases occurred drug fast for RFP or INH, after 15 months, their obtained healing. Symptom of 1 case got worse during chemotherapy, and surgical treatment were performed, after 3 months, ESR and CRP recovered normally, X-ray and CT showed spinal osteosclerosis and fusion without significant kyphosis and internal fixation loosening. Cobb angle was respectively(17.6+/-2.3) degrees, (18.1+/-2.7) degrees before treatment and last follow-up (P>0.05). MRI showed abscess was absorbed and spinal inflammation subsidised. VAS score was respectively 6.5+/-1.7, 1.4+/-0.5 before treatment and last follow-up (P<0.05). Seven patients had complications relating with drug adverse reaction,after discontinuation and treated with clinical symptom,the patients recovered normally.

CONCLUSIONAnti-TB drugs alone can obtain satisfactory effects in treating early senile spinal tuberculosis, but strict supervision and individual administration should not be disregardful.

Aged ; Aged, 80 and over ; Antitubercular Agents ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Tuberculosis, Spinal ; diagnosis ; drug therapy

Objective To compare the efficacy of weight loss,metformin and rosiglitazone in women with polycystic ovary syndrome(PCOS).Methods A randomized controlled trial(RCT)was carried out in Peking Union Medical College Hospital(PUMCH),one hundred and six women with PCOS were assigned to three intervention groups:weight loss,weight loss and metformin,weight loss and rosiglitazone group.Patients were treated with weight loss(diet and exercise),weight loss and mefformin (500 mg three times daily),weight loss and rosiglitazone(4 mg once daily)for three months.Sixty patients completed treatments.Basal body temperature(BBT),total testosterone as well as fasting serum insulin levels and lipid were measured and compared in all patients before and after weight loss.Results No significant differences were found in the baseline characteristics among three groups.In weight loss group 51%(22/43)patients completed treatment,and 23%(5/22)patients resumed ovulation.In weight loss and mefformin group 58%(21/36)patients completed treatment,and 43%(9/21)patients resumed ovulation.In weight loss and rosiglitazone group 63%(17/27)patients completed treatment,and 59% (10/17)patients resumed ovulation.Ovulation rate was significantly higher in weight loss and rosiglitazone group than in weight loss group.There was no significant difference among three groups in body mass index (BMI),waist circumference,waist-hip ratio(WHR),sex hormone,serum fasting insulin and lipid level after treatment.Conclusion Weight loss,metformin and rosiglitazone all can improve ovulation each.

Objective To report a case of Majocchi's granuloma induced by var. raubitschekii of Trichophyton rubrum, and to evaluate the relationship between deep and superficial fungal infection with genotyping technique. Methods The patient underwent physical, pathological and mycologic examination,which included microscopic observation, fungal culture, and urease reaction. The sequence of intertranscribed spacer (ITS) of rDNA was analysed by PCR and sequencing. Isolates from affected toes and tissue as well as one reference strain and six clinical strains of T. rubrum, were subjected to analysis of the tandem repeat subelement(TRS-1) in nontranscribed spacer(NTS)of rDNA by PCR. Results A 48-year-old female patient presented with a 2-month history of red papules and nodular lesions on the back, buttock and thigh,as well as a 3-year history of onychomycosis which had become more severe after a liver transplantation 9 months before. Pathological and mycologic examinations confirmed the diagnosis of Majocchi's granuloma. The pathogen was identified as var. raubitschekii of T. rubrum by microscopic examination, fungal culture, positive urease reaction and the sequence of ITS. As shown by the amplications of TRS-1 of NTS, the genotypes of strains from affected nails and tissue were identical, but differed from those of other clinical strains of T.rubrum. Conclusions There is a polymorphism in TRS-1 of rDNA NTS of T. rubrum, with the genotypes of isolates from affected nails and tissue being identical, which suggests they are of the same origin.

To state the importance of scientific research capability and general practitioners training for the poor scientific innovation conditions of general practitioner standardization training by the analysis of several ways to improve the scientific research capacity and the probe of the impact on strengthening the consciousness of scientific research to help general practitioner to better work in the areas of primary care and public health.