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

Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Animals ; Benzimidazoles ; therapeutic use ; Hypertension ; blood ; drug therapy ; Male ; Nitric Oxide ; blood ; Nitric Oxide Synthase Type III ; blood ; Random Allocation ; Rats ; Rats, Inbred SHR ; Tetrazoles ; therapeutic use ; Urotensins ; blood

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

OBJECTIVETo explore clinical efficacy of double Endobutto reconstituting coracoclavicular ligament combined with repairing acromioclavicular ligament in stage I in treating acromioclavicular dislocation with Rockwood type III - V .

METHODSFrom January 2010 to September 2013, 56 patients with Rockwood type III - V acromioclavicular dislocation were treated by operation, including 20 males and 36 femlaes, aged from 32 to 52 years old with an average of 38.5 years old. Twenty-five patients were on the left side and 31 cases on the right side. The time from injury to operation was from 3 to 14 days, averaged 7 days. All patients were diagnosed as acromioclavicular dislocation with Rockwood type III - V, and double Endobutto were used to reconstituting coracoclavicular ligament, line metal anchors were applied for repairing acromioclavicular ligament. Postoperative complications were observed, Karlsson and Constant-Murley evaluation standard were used to evaluate clinical effects.

RESULTSAll patients were followed up from 8 to 24 months with average of 11 months. According to Karlsson evaluation standard at 6 months after operation,42 cases were grade A, 13 were grade B and 1 was grade C. Constant-Murley score were improved from (42.80±5.43) before operation to (91.75±4.27) at 6 months after operation. All items at 6 months after operation were better than that of preoperative items. Forty-eight patients got excellent results, 7 were moderate and only 1 with bad result. No shoulder joint adhesion, screw loosening or breakage were occurred during following up.

CONCLUSIONDouble Endobutto reconstituting coracoclavicular ligament combined with repairing acromioclavicular ligament in stage I for the treatment of acromioclavicular dislocation with Rockwood type III - V could obtain early staisfied clinical effects, and benefit for early recovery of shoulder joint function.

Acromioclavicular Joint ; injuries ; surgery ; Adult ; Bone Plates ; Bone Screws ; Female ; Humans ; Ligaments, Articular ; injuries ; surgery ; Male ; Middle Aged ; Reconstructive Surgical Procedures ; Shoulder Dislocation ; surgery ; Treatment Outcome

A PCR method was used to amplify the sequence encoding the mature peptide of?-mannanase of Bacillus subtilis. The gene was inserted into the Pichia pastoris vector pPIC9K, downstream of?-factor signal peptide sequence. The resultant recombinant plasmid pPIC9K-MAN was lineared by BglII digestion and introduced into the host Pichia pastoris GS115 by PEG method. After screen, the recombinant P. pastoris strain MAN22 was obtained and fermented in large scale 5L fermenter. The recombinant mannanase activity could reach to 1102IU/ml. The properties of the recombinant mannanase were characterized.

OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid (AA) epoxygenase, and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and 14,15-EET). Human CYP2J2 is one of the main CYP isoforms expressed in brain, but CYP2C8 was present at a low level. The aim of this study is to investigate the roles of brain CYP2J in Parkinson disease. METHODS Rats received the right-unilaterally injection with concentrated LV-CYP2J3 or LV-EGFP in the substantia nigra (SN) at 3 d before LPS or 6-OHDA treatment. The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 14 and 21 d after LPS injection. The influence of CYP2J-dependent derivative, 14,15-EET, on the genes related with oxidative stress was assayed in SH-SY5Y cells. RESULTS CYP2J overexpression or 14,15-EET treatment significantly increased the levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in neurons. TLR4- MyD88 signaling pathway was involved the down- regulation of CYP2J by LPS. The binding of p-CREB with the promoter of CYP2J was inhibited by the LPS treatment. The loss of dopami?nergic neurons in the right SN induced by LPS or 6- OHDA was significantly decreased by CYP2J3 transfection at 21 d after LPS injection. Compared with LPS or 6-OHDA group, the number of the rotation of rats was decreased by 42.6% and 60.7% by CYP2J3 transfection at 14 d after LPS or 6-OHDA injection;meanwhile, the rotation number was decreased by 12.7% and 21.3% at 21 d. The accumulation of alpha synuclein induced by LPS was significantly decreased by CYP2J3 transfection. The mRNA levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in SN were decreased by LPS, which was attenuated by the injection of LV-CYP2J3. CONCLUSION Brain CYP2J can play a protective role in the damage of the inflammation and oxidative stress to the dopaminergic neurons. Brain CYP2J- dependent derivatives from AA may have therapeutic effects in Parkinson disease via the up- regulation of the antioxidant system in neurons.

Objective To observe the variation of enzymatic activity and areas and bulk of focus of heart injuries by using controllable catheter to ablate epicardial tmsue of rabbits and focus underneath atrioventrieular ring narcosis with 20% urethane(4 ml/kg)and divided into three groups.Each group included 7 rabbits.Anterior wallepieardium of left ventricle was ablated thirty seconds in each group(10,20 and 30 W)with self-made ablationspheroid microwave antenna,refilling with high pressure normal saline at same time.Then all of the rabbits were sacrificed respectively and their ventricular myocardium were taken out to undergo immunohistochemistry in order to display suceinate dehydrogenase(SDH).Also amplitude Wag measured in order to calculate areas of heart injuries.(8F)wag delivered to the pre-selected sites around atrioventricular ring of thirty-two healthy dogs,which had beenin intravenous narcosis with pentobarbital sodium(30 mg/kg).The dogs were divided into four groups(40,50,60 and 80 w) and two time points(60 and 120 s),by the combined method of X-ray and endocardial electrocardiograph,the microwave antenna could be confirmed to be located at the accurate position between anterior and posterior wall close to septum of left/right ventricle.After ventricular myocardium had been taken out,amplitude were measuredin order to calculate bulk of heart injuries by 1/6×3.14 x long×wide×deep.In addition.the histological changesand transmural injury were examined by optic microscope.Results In each group,the centre of injuries wagenzyme deficiency locus.The diameter and areag of heart injuries enlarged significantly(3.99.±0.41),(5.20±0.25),(6.31±0.37)mm and(12.53±2.56),(21.19±3.14),(30.96±3.76)mm2 with the increased microwave power level(10、20、30 W).Group comparison had statisficM significance(F＝76.8,58.5;P＜0.01 or ＜0.05).A total of 116points were ablated.The myocardial lesion showed ellipse in shape,and continuous symmetrical coagulationnecrosis under microscopic examination.There was a clear demarcated line around tlle myocardial tissue and fewparietal thmmbus.There were 16 transmura]injuries and five-with lung damage.The bulk of lesion aroundatrioventrieular ring hag been significantly enlarged(46.7±2.5),(51.1±2.7),(133.2±3.4),(141.8±3.9),(248.5±6.2),(260.3±6.5),(313.7±9.5),(327.4±10.5)with the increased microwave power level(40,50,60and 80 W)and/or distance of microwave ablation(60 and 120 s).Groups comparison had statistical significance(F＝31.16,27.85;all P＜0.01).In each time point,the lesion bulks had conspicuous distinction of statistics.In the same microwave power,the time wag longer,the bulk was larger(P＜0.01).Conclusions The more the microwave power level and time,the severe the heart injuries is.It is possible to use the microwave energy to ablate the deep focus under endocardium around atrioventricular ring.

Objective To evaluate the effect of health education on endemic diseases in Henan province in 2010.Methods According to the requirements of The Education Program for Endemic Diseases Control in 2009 Henan Province,50 counties (districts) of 18 cities with endemic diseases were selected.Referring to the health education questionnaire in the program,knowledge of endemic diseases were asked of pupils and housewives.Intervention effects were evaluated two months after teaching pupils and housewives in counties,towns,villages and schools with the knowledge of endemic diseases and the questionnaire was used.Results Among 50 counties investigated,5523 pupils and 3206 housewives were surveyed in the baseline according to the requirement,and 5417 pupils and 2891 housewives were surveyed for outcome evaluation.The results showed that after this education,pupils' knowledge about endemic diseases increased from 66.31％(10 987/16 569) in the baseline survey to 93.84％(15 250/16 251),the difference have statistical significant(x2 =3877.78,P ＜ 0.01) ; housewives from 67.56％(6133/9078)to 92.67％(8037/8673),the difference have statistical significant(x2 =1736.33,P ＜ 0.01).After the education,the pupils' knowledge about the iodine deficiency disorders,drinking-water-borne fluorosis and arsenic poisning,coal-burning-borne fluorosis increased from 70.15％ (6263/8928),62.29％(4423/7101),42.96％ (185/270),68.52％ (116/270) to 94.19％ (8344/8859),93.05％ (6376/6852),99.63％ (261/270),96.67％ (269/270),the difference have statistical significant (x2 =1749.85,1939.26,211.83,74.43,all P ＜ 0.01),housewives' knowledge about the iodine shortage diseases,drinking-water-borne fluorosis,the endemic fluorine,the arsenic poisoning increased from 73.27％ (3330/4545),62.79％ (2677/4263,30.37％ (85/135),62.96％(41/135) to 93.96％(4228/4500),91.08％(3555/3903),97.04％(123/135),91.11％(131/135),the difference have statistical significant (x2 =751.03,924.65,129.75,30.23,all P ＜ 0.01).Conclusions Health education intervention has a marked effect in increasing the peoples' knowledge of endemic diseases.Therefore health education should be enhanced in the future.

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 explore the influence of obstructive sleep apnea hypopnea syndrome (OSAHS) in children on the secretion of antidiuretic hormone (ADH).

METHODSThirty pediatric patients with OSAHS were examined with polysomnography (PSG) and urinary volume was recorded during sleep, and vein blood was sampled in deep sleep to detect the level of ADH in serum using radioimmunoassay technique, which were performed before and after adenotonsillectomy. Among twenty heath children were also detected the secretion of ADH as normal controls.

RESULTSAfter surgery, apnea-hypopnea index (AHI) decreased (from 17.4 +/- 2.6 to 3.3 +/- 1.4, t = 27.68, P < 0.001), lowest SaO2 increased (from 0.783 +/- 0.134 to 0.954 +/- 0.062, t = 6.45, P < 0.001). The level of ADH in OSAHS patients (63.1 +/- 35.2) ng/L was much lower than that in health children (85.1 +/- 22.2) ng/L (t = 2.75, P < 0.01). The serum ADH level in postoperative patients (83.1 +/- 21.2) ng/L was increased significantly compared with that of preoperative (t = 2.56, P < 0.05), and no statistical difference versus that of health children (t = 0.17, P > 0.05). Nycturia volume of preoperative OSAHS children (492 +/- 90) ml was significant higher than that of postoperative (332 +/- 56) ml or normal controls (346 +/- 62) ml (t was 7.85 and 6.43, both P < 0.001). There was no significance in nycturia volume between postoperative group and control group (t = 0.77, P > 0.05).

CONCLUSIONSAfter adenotonsillectomy in children with OSAHS caused by adenotonsillar hypertrophy, the sleep pattern and ADH secretion could become normal.

Adenoidectomy ; Case-Control Studies ; Child ; Female ; Humans ; Male ; Polysomnography ; Polyuria ; etiology ; Sleep Apnea, Obstructive ; blood ; physiopathology ; surgery ; urine ; Tonsillectomy ; Vasopressins ; blood