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

Adolescent ; Diagnosis, Differential ; Diverticulum, Stomach ; complications ; diagnosis ; pathology ; Gastrointestinal Hemorrhage ; diagnosis ; etiology ; pathology ; Gastroscopy ; Humans ; Male

Objeetlve To evaluate the role of IL-1β and TNF-α in the spinal cord in a murine model of bone cancer pain(BCP)induced by activation of glial cells.Methods Three hundred and sixty male 8-10 weeks old C3H/He mice weighing 18-22 g were randomly divided into 6 groups(n=60 each):group I nomal control (group N);group Ⅱ sham operation (group S);group Ⅲ BCP+aCSF(group aCSF);group Ⅳ BCP+FC (group FC);group V BCP+MI(group MI) and group Ⅵ BCP+FC+MI (group FC-MI).BCP was produced by inieeting fibrosarcoma cells of bone into the medullary cavity of left ealcaneus bone.Intrathecal catheter was placed in the 4 BCP groups(group Ⅲ-Ⅳ).FC 0.5 nmol/5 μl or/and MI 16 μg/5 μl were injected IT once a day for 21 consecutive days after operation.The mechanical threshold to von Frey filaments was measured at 0.5 h(T0)before injection of fibrosarcoma cells and at 3,5,7,10,14,21 d(T1-6)after injection of fibrosarcoma cells.Twelve animals of each group were killed and L4.5 segment of the spinal cord was removed at T0,1,3,5,6 for determination of IL-1β and TNF-α content (by ELISA) and expression (by immuno-flurorescence) in the spinal cord. Results The mechanical threshold was significantly decreased at T1-6, while IL-1β content at T1,3,5,6 and TNF-α content at T5,6 was significantly increased in group BCP, FC, MI and FC + MI compared with those at T0 and group C (P < 0.05). Compared with group BCP, the mechanical threshold was significantly increased at T1-6 in group MI and FC + MI and at T4-6 in group FC, IL-1β content was significantly decreased at Ts,3,5,6 in group MI and FC + MI and at T5,6 in group FC and TNF-α content was significantly decreased at T5,6 in group FC, MI and FC + MI ( P < 0.05). Conclusion IL-1β and TNF-α in the spinal cord is involved in the process of glial cell activation-induced BCP.

Objective To study the effect of allicin on the growth and radiosensitivity of human pancreatic carcinoma BXPC3 cells.Methods BXPC3 cells were exposed to X-rays in the presence or absence of allicin.Cell proliferation was measured by MTT assay.Cell cycle distribution and apoptosis were detected by flow cytometry assay.Cell radiosensitivity and the influence of allicin on it was evaluated by colony formation assay.The expressions of Bax and Bcl-2 proteins were assayed by RT-PCR and Western blot.Results IC50 values of allicin on cell growth were 76.24,58.34 and 43.58 μmol/L under 12,24 and 48 h treatment,respectively.Treatment of cells with allicin obviously inhibited cell growth after irradiation and hence increased radiosensitivity (t =2.74,P ＜ 0.05).This treament also enhanced radiation-induced cell cycle arrest at G2/M phase (t =11.41,P ＜0.05),apoptosis induction (t =12.36,P ＜ 0.05),and Bax expression (t =4.83,P ＜ 0.05),but it decreased Bcl-2 expression (t =3.69,P ＜ 0.05).Conclusions Allicin could inhibit cell growth,induce cell cycle arrest and apoptosis via Bax/Bcl-2 pathway and hence increases radiosensitivity of BXPC3 cells.

Objective To investigate the usage of antiepileptic drugs (AEDs),epileptic seizures,pregnancy outcomes and infant feeding practices among pregnant women with epilepsy,and provide scientific evidence for eugenics.Methods The clinical characteristics of 350 pregnant women with epilepsy from Shaanxi Provincial Epilepsy & Pregnancy Register from October 2012 to July 2016 were analyzed retrospectively.Results A total of 350 patients with 376 pregnancies were included in the final analysis.Among 376 pregnancies,272 pregnancies (72.3％) were under the treatment of AEDs.Of them,246 pregnancies (90.4％) were on monotherapy,26 (9.6％) on polytherapy.Only patients during 179 pregnancies (47.6％) took folic acid in the first trimester.Seizure frequency increased in patients during 123 pregnancies (32.7％),of whom patients during 43 pregnancies (35.0％) did not use AEDs.Although other patients during 80 pregnancies (65.0％) took AEDs,regular pharmacokinetic monitoring was absent.A total of 170 pregnancies (45.2％) attained seizure-free.Seizure frequency decreased in 42 pregnancies (11.2％) and remained unchanged in 24 pregnancies (6.4％).The rates of cesarean section and natural delivery were 43.8％ (158/361) and 56.2％ (203/361),respectively.Totally 4.5％ (17/376) pregnancies had adverse pregnancy outcome,and 1.9％ (7/376) had fetal malformations.The most common congenital malformation was heart malformation,which was observed in two offspring.One offspring developed dysostosis,one developed chromosome abnormality,and another developed cerebellum deformity.In addition,one twin developed conjoined deformities.Breastfeeding rate was 52.6％ (190/361).Conclusions In Shaanxi province,AEDs compliance,pharmacokinetic monitoring and usage rate of folic acid still need to be improved in pregnant women with epilepsy.Clinical trial registration Chinese Clinical Trial Registry,ChiCTR-OOC-16009277

Toad venom is the Bufo bufo gargarizans or B. melanostictus after the ears of the gland secretion, used in the treatment of various cancers in recent years. Research shows that the main anti-tumor components in bufadienolide. Bufadienolide have free type structure and conjunct type structure. To identify and clarify the difference between bufogenin and bufotoxin contained in Bufonis Venenum, which was from B. bufo gargarizans, an UPLC-TQ-MS method has been established. UPLC-TQ-MS method was used to identify and quantify the major bufadienolides in Bufonis Venenum. UPLC-TQ-MS assay with positive ion mode was performed on a Waters ACQUITY UPLC BEH C, (2.1 mm x 100 mm, 1.7 µm) with the mobile phase consisting of 0. 1% aqueous formic and acidacetonitrile in gradient elution at a flow rate of 0.4 mL · min⁻¹ and the column temperature was set at 35 °C. By comparing their retention time and high resolution mass data of Bufonis Venenum extracts, 37 effective components were primarily identified by MS/MS analysis in positive ion mode. Twenty-six of them were free-type bufadienolides (bufogenin), 11 of them were conjugated bufadienolides. There were significant differences in the main composition between fresh and processed Bufonis Venenum. The study found that the chemical composition of toad venom through great changes after processing, conjunct type content is much less, free type content as well change.
Amphibian Venoms ; chemistry ; metabolism ; Animals ; Bufonidae ; classification ; metabolism ; Chromatography, High Pressure Liquid ; methods ; Molecular Structure ; Tandem Mass Spectrometry ; methods

ObjectiveTo explore the effects of gabapentin on mechanical allodynia in rats with tibial bone cancer pain (BCP).MethodsForty-two female SD rats were randomized into 7 groups ( n=6):naive group (group N ),sham operation + NS control group (group SN),sham operation + GBP200mg/( kg · d) group (group SG200),BCP + NS control group (group BN),BCP + GBP50mg/( kg · d) group ( group BGS0),BCP +GBP100mg/(kg · d) group (group BG100),and BCP + GBP200mg/(kg · d) group (group BG200).The rats in group N,SN and BN received 5 ml normal saline and the rats in group SG200,BG50,BG100 and BG200 received 200,50,100 and 200 mg/( kg · d) dose of GBP via feeding from day 7 to 13 after operation,respectively.Mechanical withdrawal threshold(MWT) of the right paw and behavioral assays for ambulatory pain were measured just before operation and on days 1,3,5,7,8,10,12 and 14 after operation.ResultsMWT( (3.78 ± 0.38)g) in rats with BCP decreased and behavioral assays for ambulatory pain (0.76 ± 0.44) increased on day 7 after operation,as compared with those in group N ( ( 14.50 ± 1.38 ) g,(0.00 ± 0.00 ) ) and group sham ( ( 10.21 ± 0.88 ) g,( 0.00 ±0.00) ) (P ＜ 0.05 ).There was no apparent praxiological difference between group SN and group SG200 in a week of continuous application of gabapentin(P＞ 0.05 ).Compared with those in group BN,there was no change on MWT in group BG50 (P ＞ 0.05 ),and however,behavioral assays for ambulatory pain decreased (P ＜ 0.05 ).MWT in group BG100( (5.35 ±0.85)g) and BG200( (5.71 ±0.72) g) increased in day 10 after operation,as compared with those in group BN ( ( 2.61 ± 0.40) g) and group BG50 ( ( 3.28 ± 1.15 ) g) (P ＜ 0.05 ),and the difference was still statistically significant until day 14 (P ＜ 0.05 ).Behavioral assays for ambulatory pain in group BG100 and BG200 decreased from day 8 after operation,as compared with those in group BN and group BG50 (P ＜ 0.05 ).ConclusionGabapentin,in medium to large dosage,can inhibit pain reaction of rats with bone cancer pain.Nevertheless,with the development of cancer,the effect of gabapentin decreases.

Objective To study the current incidence of Keshan disease in Yunnan Province,and provide scientific basis for Keshan disease(KD) prevention and control. Methods Based on the Scheme of KD Surveillance, 16 villages in 11 counties were chosen as surveillance sites by the historical data. An survey was made to the residents in the 16 surveillance sites by filling in the questionnaire, inquiry medical history, clinical examination, electrocardiogram and 2 meters post-anterior chest X-ray for suspected cases. KD cases were diagnosed according to the Diagnostic Criteria for Keshan Disease(GB 17021-1997). The prevalence data of KD in the whole province were collected from the KD case report in 2007 and the trace surveys. Results There were 6877 residents in 16 surveillance sites of 11 surveillance counties and totally 39 KD cases were diagnosed with a detection ratio of 0.57% (39/6877). The detection ratio of latent and chronic KD were 0.41%(28/6877) and 0.16%(11/6877), respectively and no acute or subacute cases were found. The cases aged 5 to 14 years old accounting for 66.67% (26/39). Electrocardiogram examination of 6877 residents were made and 5.25% (361/6877) abnormal electrocardiograms were detected in the 16 surveillance sites. Fifty-five people were checked by chest X-ray and there were 31 cases with heart-chest ratio ≤0.50, 16 cases with heart-chest ratio from 0.51 to 0.55 and 8 cases with heart-chest ratio from 0.56 to 0.60. The prevalence rate and incidence rate of chronic KD were 4.24 per 100 000 and 0.50 per 100 000 in Yunnan. No acute or subacute cases were found and the latent cases were listed. The prevalence rate and incidence rate were 7.76 per 100 000 and 1.18 per 100 000 in the 16 surveillance sites. Conclusions The incidence of KD is low incidence in Yunnan Province. Higher ineidence of chronic KD was detected in the some areas and the corresponding control measures need to be adopted.

Objective In order to master the current situation of Keshan disease in Yunnan province and to provide scientific basis for Keshan disease control and prevention. Methods Eighteen villages were selected as the investigation sites in 6 counties across all the Keshan disease wards in Yunnan province,where the residents were investigated. Then,the villages census data was collected,clinical examination aiming mainly on cardiovascular system was carried out,including electrocardiography and X-ray to the suspected patients. Correct diagnose of Keshan disease was made by the Diagnostic Standard of Keshan Disease(GB 17021-1997). At the same time,10 food samples and 10 hair samples for detecting selenium content in every investigation site. Results There were 9818 residents investigated in the 18 investigation sites in 6 counties,and 34 eases of Keshan disease were found,the total incidence rate was 0.35%(34/9818). Among the 34 Keshan disease eases,32 cases were latent Keshan disease,the incidence rate was 0.33%(32/9818); 2 cases were chronic Keshan disease,the incidence rate was 0.02%(2/9818). There was no any acute and sub acute cases be found. Most Keshan disease cases aged from 5 to 14,67.65% (23/34). Abnormal ECG rate was 6.90% (677/9818). Among 56 X-ray films,47 cases had a cardiothoracic ratio less than or equal to 0.50,83.93%(47/56),5 cases from 0.51 to 0.55,8.93%(5/56),4 cases from 0.56 to 0.60,7.14%(4/56). Selenium content was detected in 180 food samples and 180 hair samples. The average food selenium content (mg/kg) was 0.013±0.010,the lowest content in Yongsheng county (0.006± 0.001),the highest content in Tonghai county(0.027±0.009). The average hair selenium eontentwas(0.252± 0.078)mg/kg,with the lowest(0.145±0.043)mg/kg in Yoagsbeng county,the highest (0.297±0.062)mg/kg in Tonghai county. Conclusions The detected ratio of Keshan disease is low in Yunnan province. Most of Keshan disease patients age from 5 to 14. It was presented that the Keshan disease infectious agents were still strong and active. The foodstuffs and hair Selenium content is low in food and hair sample,and varies in different investigation site. It is necessary to supply selenium for prevent Keshan disease in the severe areas.

Objective:Osteoprotegerin (OPG) is a key molecule negatively regulating osteoclast differentiation and activation; and the conserved mycobacterial heat shock 70 (HSP70) peptide p111-125 has also been found to inhibit inflammation reactions in chronic arthritis. BaculoDirectTM baculovirus expression system was selected to express recombinant OPG-HSP70 in insect cells.Methods:The human functional fragment (p22-194) of OPG and functional fragment (p111-125) of mycobacterial HSP70 gene were cloned into the transfer vector pENTRTM/SD/D-TOPO. The recombinant plasmid was performed an LR reaction with the BaculoDirectTM Linear DNA to generate recombinant baculovirus DNA. The cultured Sf9 insect cells were directly transferred with the recombinant baculovirus DNA,and the pure recombinant baculovirus was obtained. Then recombinant baculovirus was infected Sf9 insect cells again to express the OPG-HSP70 gene.Results:The target protein was detected at the time of 48h post infection,reached at highest yield at the time of 72h post-infection. A 28kDa protein immunostaining band was detected by Western blotting from lysate of those cells.And the purified protein was obtained by using Ni-NTA system. Functional stuies on the fusion protein showed it significantly reduce osteoclast cell number[(3.10?0.640) cells under each microscope field in treatment group by comparing to (10.70?0.817)cells in the control group] in the osteoclast inhibition test,and reduce the inflammation reaction in a delayed type hypersensitivity (DTH) mice model (P