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

Cone-Beam Computed Tomography ; methods ; Humans ; Nasopharyngeal Neoplasms ; diagnostic imaging ; radiotherapy ; Radiotherapy Planning, Computer-Assisted ; Radiotherapy, Intensity-Modulated ; methods

Alimentary tract duplications are rare congenital anomalies that usually present in childhood and occasionally in adults. They are most common in the ileum, but can occur anywhere along the alimentary tract from the mouth to the anus. We report a 24-year-old woman who presented with a giant chylous ileum cyst duplication. To our knowledge, there is only one other report of a patient with a giant chylous cyst in the literature.
Abdominal Pain ; Adult ; Cysts ; diagnosis ; pathology ; surgery ; Female ; Humans ; Ileum ; surgery ; Magnetic Resonance Imaging ; Tomography, X-Ray Computed

Objective To explore the diagnostic value of prothrombin time(PT),activated partial thromboplastin time(APTT),fibrinogen(FIB),D-Dimer(DD),antithrombin Ⅲ(ATⅢ),platelet(PLT)in activity and severity assessment of ulcerative colitis(UC),and to analyze whether they could evaluate the degree of activity UC in children.Methods The data of UC patients in the Department of Gastroenterology,Children's Hospital of Nanjing Medical University from January 2012 to September 2016 were analyzed,25 cases of remission and 36 cases of active UC patients were selected as the study subjects.Thirty healthy children were selected as healthy control group,combined with the coagulation function indicators for analysis.Results Receiver operating characteristic area under the curve(AUC)of PT,APTT,FIB,DD,ATⅢ and PLT in UC patients was 0.659,0.840,0.744,0.776,0.599 and 0.792,the activity of UC patients was 0.849,0.889,0.836,0.912,0.964 and 0.966,respectively.The results of PT,APTT,FIB,DD and PLT in children with active UC were significantly higher than those in the healthy control group,and ATⅢ was significantly lower than that in the healthy control group.Compared with the healthy controls,the levels in remission UC patients were not significantly different(P>0.05).The 3 subgroups of activity UC had no significant differences among PT and APTT(F=0.652,1.755,all P>0.05),However,there were significant differences among FIB,DD,ATⅢ and PLT(F=66.495,32.817,88.284,22.892,all P<0.05).FIB,DD and PLT were moderately positively correlated with severity of activity UC patients(r=0.857,0.648,0.654,all P<0.05),and ATⅢ had moderately negative correlation(r=-0.789,P<0.05).Progressive regression analysis showed that the severity of UC was associated with FIB,DD and ATⅢ(R2=0.830,F=39.962,P<0.05).Conclusion FIB,DD and ATⅢ can be used as index for the activity and evaluation of UC.

Objective To explore the relationship between peripheral Th17 cell number and chronic gastritis in Helicobacter pylori(H.pylori)-infected children.Methods Children were diagnosed as chronic gastritis by endoscopy.The degree and activity of inflammation were graded by histopathology examinations.The patients with both 13C urea breath test and urease test positive were diagnosed as H.pylori infection.The peripheral Th17 cell number was measured by flow cytometry and expressed as a ratio to total T cell.Results The Th17 cell number in HP group (chronic gastritis with H.pylori infection,n =33),non-HP group (chronic gastritis without H.pylori infection,n =24) and normal controls (n =15) were (1.55 ±0.30)％,(1.06 ±0.33)％,and (1.04 ±0.35)％,respectively.HP group included a statistically higher Th17 cell number than the other groups (all P ＜ 0.05),while no obvious difference was found between non-HP group and controls (P ＞ 0.05).According to the degree of inflammation,the chronic gastritis with H.pylori infection was categorized into non-apparent (n =10),mild (n =8),moderate (n =9) and severe (n =6) subgroups.The Th17 cell number in each subgroup was (1.64 ± 0.21)％ (non-apparent),(1.61 ± 0.23)％(mild),(1.25 ± 0.29) ％ (moderate) and (1.75 ± 0.20) ％ (severe),respectively.The moderate group had a lowest Th17 cell number among 4 groups (P ＜ 0.05).And significant differences did not exit in the other 3 groups (P ＞ 0.05).The HP group patients with different inflammatory activity had a Th17 cell number of (1.23 ±0.25)％ in nonapparent (n=15),(1.53 ±0.15)％ in mild (n=6),(1.55 ±0.32)％ in moderate (n=6) and (1.71 ±0.35)％ in severe (n =6) subgroup,respectively.However,there were no significant differences among 4 subgroups (P ＞ 0.05).Conclusions In the progress of chronic gastritis with H.pylori infection,Th17 cells may play a role as a double-edged sword by protecting and fighting against H.pylori infection and immunopathologic insults.This would provide more insights into the treatment of H.pylori infection.

Brain Neoplasms ; diagnostic imaging ; radiotherapy ; Cranial Irradiation ; Dose Fractionation ; Glioblastoma ; diagnostic imaging ; radiotherapy ; Humans ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Radiotherapy Dosage ; Radiotherapy, Conformal ; methods ; Tomography, X-Ray Computed

Objective To find the effective therapeutic arrangement through investigating the clinical characteristics of chronic cardiac insufficiency with anaemia. Methods A total of 46 cases of anemia from 315patients who had been admitted to department of cardiology, the First Affiliated Hospital, Harbin Medical University for chronic cardiac insufficiency with anaemia were selected. They were divided into two groups. There were 22 patients in the first group who only accepted treatment to improve cardiac function (normal cardiac, diuretic,vasodilator therapy, etc.), and 24 patients in the second group who accepted treatment to improve cardiac function while receiving anti-anemia therapy treatment, oral ferrous sulfate tablets(0.3 g/tablet), 1 tablet each time, 3 times a day and(or) 2 times per week subcutaneous erythropoietin 3000 U. The hemoglobin(Hb), red blood cell(RBC) ,hematocrit (HCT), left ventricular ejection fraction (LVEF), fractional shortening (FS), stroke volume (SV) , cardiac output(CO) and E peak and A peak ratio(E/A) were observed before and after treatment. By logistic regression, grade grade Ⅱ , Ⅲ , Ⅳ, the incidence of anaemia were 7.9% (10/126), 19.2% (23/120) and 24.6% (17/69),respectively. Grade Ⅱ compared with grades Ⅲ, Ⅳ, the difference was statistically significant (x2 = 4.08, 3.12, all (3.49 ± 0.17) × 1012/L, (0.36 ± 0.08)%, (48.9 ± 3.11)%, (15.6 ± 1.8)%, (38.9 ± 3.7)%, (4.4 ± 1.6)% and (130.7 ±5.75)g/L, (4.12 ± 0.25) × 1012/L, (0.43 ± 0.02)%, (58.5 ± 2.65)%, (18.0 ± 2.5)%, (49.1 ± 7.7)%, (5.1 ± 1.2)%in the first and second groups, respectively. The difference between the two groups was statistically significant(t =value of Hb, RBC, HCT, LVEF, FS,SV, CO were (102.7 ± 6.93)g/L, (3.41 ± 0.12) × 1012/L, (0.35 ± 0.07)%,(47.5 ± 2.86)%, (16.0 ± 2.4)%, (38.2 ± 7.9)%, (3.7 ± 1.4)%, respectively. Compared with those after treatment,the difference was statistically significant (t = 15.632, 13.325, 5.569, 17.182, 3.186, 2.999, 3.074, all P ＜ 0.05);Ⅳ-level relative risk were 1.62, 3.14(P ＜ 0.05 or ＜ 0.01) . Conclusions Based on the standard treatment with treatment of anemia, cardiac contractile function can be improved.

OBJECTIVETo investigate the migration of fluorescent dye PKH26-labeled BM-MSC in the Alzheimer's model rats.

METHODSNormal human bone marrow extracted for isolation of BM-MSC was cultured in vitro. The 5th passaged BM-MSC was labeled with PKH26, and observed under a fluorescence microscope for PKH26 labeling efficiency, and using flow cytometry BM-MSC surface markers was checked. The PKH26 labeled BM-MSC injected into the tail vein of the normal control group and AD animal model group, 14 days after finding the PKH26-labeled BM-MSC cells in the rat hippocampus using fluorescence microscopy. Using the Morris water maze experiment comparison of AD model and BM-MSC transplantation group of spatial learning and memory ability.

RESULTSTFlow cytometry showed BM-MSC surface markers CD73 and CD105 were positive. In vitro, PKH26-labeled rate of BM-MSC was 100 %. The Morris water maze experiment comparison of BM-MSC transplantation group and AD group of animals, BM-MSC transplantation group at 13, 14 days of spatial learning and memory ability than AD animal group had significantly improved. 14 days after BM-MSCs in rat hippocampus could be found which were PKH26-positive, consistent with DAPI staining. PKH26-positive cells in animal models of AD were significantly more than those in the normal control group.

CONCLUSIONBM-MSC in AD rats not only migrates through the blood-brain barrier, but also mainly survives in the hippocampus of AD rats, and it can improve AD rat model of learning disabilities.

Alzheimer Disease ; pathology ; Animals ; Bone Marrow Cells ; cytology ; Cell Movement ; Cells, Cultured ; Disease Models, Animal ; Humans ; Injections, Intravenous ; Male ; Mesenchymal Stromal Cells ; cytology ; Organic Chemicals ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the effects of navel-warming therapy on clinical efficacy in patients with yang-deficiency tympanites based on regular treatment of western medication.

METHODSOne hundred and twenty cases of yang-deficiency tympanites were randomly divided into a navel-warming therapy group and a western medication group, sixty cases in each one. The regular treatment of western medicine was applied in the western medication group, including oral administration of antiviral drug and diuretics as well as intravenous drip of hepatic protector. Based on western medicine treatment, the navel-warming therapy was applied in the navel-warming group. A medical cake was laid on Shenque (CV 8), and then a medical cylinder was placed above the medical cake and ignited. The treatment was given once daily. One month was considered as a treatment session in both groups and totally one session was required. The TCM symptom score, B-ultrasound ascites and temporary use of diuretics before and after treatment were observed in both groups; also the efficacy was evaluated.

RESULTSThe total effective rate was 81.7% (49/60) in the navel-warming therapy group, which was superior to 56.7% (34/60) in the western medication group (P < 0.05). After the treatment, the TCM symptom score and ascites were improved in both groups (all P < 0.05), which was more significant in the navel-warming therapy group (all P < 0.05). The temporary use of diuretics was statistically different between the two groups (P < 0.05), indicating the navel-warming therapy group could obviously reduce or stop the use of diuretics.

CONCLUSIONBased on regular treatment of western medication, the navel-warming therapy could significantly improve therapeutic efficacy, effectively relieve clinical symptoms and ease ascites.

Acupuncture Points ; Adult ; Aged ; Diuretics ; administration & dosage ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Female ; Humans ; Male ; Middle Aged ; Moxibustion ; Yang Deficiency ; drug therapy ; Young Adult

OBJECTIVETo study the effects of Citalopram on the mRNA expression of bax and bel-2 in frontal cortical neurons and on cell apoptosis of rats after stress.

METHODSTwenty-four healthy male SD rats were randomly divided into three groups (n = 8). The control group did no receive any treatment, the stress group was subject to stress and given normal saline and experimental group was given Citalopram irrigation stomach after stress. Rats were forced to swim to establish chronic stress model (15 min/d, 4 weeks), bax, bcl-2 mRNA expression were tested by in situ hybridization technique (ISH), TUNEL assay was used to determine cell apoptosis, Nikon image analysis software were used to measure the number of positive cells in each index.

RESULTSCompared with the control group, the stress group showed a larger number of bax mRNA expressing cells( P < 0.01), a smaller number of bcl-2 mRNA expressing cells (P < 0.01), and the staining intensity of positive cells was significantly reduced( P < 0.01). Compared with the stress group, the experiment group showed more reduced number of bax mRNA positive cells( P < 0.01) and significantly increased bcl-2 mRNA positive cells( P < 0.05), a small amount of positive cells were found, compared with that in the stress group, nuclear condensation in the experimental group was reduced significantly and the staining was obviously weaker( P < 0.01).

CONCLUSIONCitalopram significantly antagonizes bax mRNA and potentiatesbcl-2 mRNA protein expression and inhibits apoptosis of rat prefrontal cortical neurons caused by chronic stress, which might be one possible mechanism of Citalopram for prevention and treatment of psychosis caused by chronic stress.

Animals ; Apoptosis ; Citalopram ; pharmacology ; Male ; Neurons ; drug effects ; metabolism ; Prefrontal Cortex ; cytology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Stress, Physiological ; bcl-2-Associated X Protein ; metabolism