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

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.

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

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.

Objective To investigate the effects of sevoflurane pretreatment on renal ischemia-reperfusion (I/R)-induced apoptosis in kidney in rats. Methods Thirty pathogen-free male SD rats weighing 220-260 g were randomized into 3 groups (n=10 each):group control (group C);group I/R and group sevoflurane(group S). Renal I/R was induced by clamping the left renal pedicle for 45 min in I/R and S groups. In group S inhalation of 2.2% sevoflurane in O2 was started at 30 min before operation and maintained throughout the experiment.Venous blood samples were taken at 3 h of reperfusion for determination of serum BUN and Cr concentrations. The animals were then sacrificed and the left kidneys were removed for microscopic examination, detection of apoptosis(by TUNEL)and determination of heme oxygenase-1(HO-1) mRNA and protein expression (by RT-PCR and Western blot).Results Renal I/R significantly increased serum BUN and Cr concentrations, apoptotic index(percentage of apoptotic cells) and the severity of necrosis of renal proximal convoluted tubules (0=normal,4=necrosis of whole segment of proximal convoluted tubules).Sevoflurane inhalation attenuated the I/R-induced changes mentioned above.HO-1 mRNA and protein expression was up-regulated by I/R and HO-1 mRNA expression was further up-regulated by sevoflurane inhalation.Conclusion Sevoflurane pretreatment can protect kidney against I/R injury by attenuating cell apoptosis.Up-regulation of HO-1 mRNA expression may be involved in the mechanism.

Aim To explore the behavior and CBS /H2 S levels of hippocampus in post traumatic stress dis-order (PTSD)rats and study the effect of exogenous H2 S on PTSD rats.Methods Single prolonged stress paradigm was adopted to prepare PTSD animal model. Morris water maze test was adopted to test space learn-ing and memory ability.CBS /H2 S content in hippo-campus tissue sample was measured using Western blot and methylene blue method.In vivo extracellular single unit recording was used to examine the frequency of spontaneous discharges of hippocampus neurons.Re-sults ① Escape latency increased and quadrant time (%)and platform crossing times decreased in Morris water maze test of PTSD group compared with normal group(P <0.01 ).CBS /H2 S level in hippocampus tis-sue of PTSD group also decreased compared with nor-mal group (P <0.01 ,P <0.05 ).② Escape latency decreased and quadrant time(%)and platform cross-ing times increased in Morris water maze test of NaHS+PTSD group compared with PTSD group(P <0.01 ).③ L-cysteine increased the frequency of spontaneous discharges of hippocampus neurons(P < 0.01 ).Con-clusions Learning and memory ability decrease in PTSD model rats owing to the inhibition of CBS /H2 S content in hippocampus tissue.The mechanism of be-havior improvement of H2 S on PTSD model rat is possi-bly related to the excitation of H2 S on frequency of spontaneous discharges of hippocampus neurons.

Objective To prepare 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) hydrogel suppositories and to evaluate their photosensitizer transfer efficiencies in rectal tumor tissue.Methods The BALB/c mice implanted SW837 rectal cancer cells subcutaneously were randomly divided into four groups:intrarectal suppository administration group,cutaneous administration group,intratumoral injection group and intravenous injection group.Fluorescence spectrophotometry was used to measure the concentration of protoporphyrin Ⅸ (PpⅨ) and HMME in rectal wall,skin and tumor tissue.The distribution of photosensitizer was determined by a fluorescence spectroscopy system.Results The concentration of PpⅨ in the ALA suppository administration group was 9.76 times (1 h) and 5.80 times (3 h) higher than that in the cutaneous administration group,and the differences were statistically significant (all P＜0.05).The maximal penetration depth of ALA in tumor tissue was about 3-6 mm at 2 h after the cutaneous administration.After the HMME suppository administration,the concentration of HMME in the rectal wall was very low.The maximal penetration depth of HMME in tumor tissue was less than 2 mm after the cutaneous administration.Conclusions ALA is more likely to penetrate mucosal barrier compared to skin tissue.The hydrogel suppository based rectal administration is expected to be a new administration method for the rectal cancer photodynamic therapy using ALA.