With the advance of drug development and research techniques, the drug metabolic processes and mechanism can be more deeply achieved. As the drug metabolism and pharmacokinetics process are mediated by drug metabolizing enzymes and transporters, study of drug metabolizing enzymes and transporters has become an important part for drug development. The traditional immunoassays with low sensitivity and poor specificity can not reflect the accurate expression level of drug metabolizing enzymes and transporters. We now give a brief review on the quantitative study of drug metabolizing enzymes and transporters by mass spectrometry-based proteomic approach.
Enzymes ; chemistry ; Humans ; Inactivation, Metabolic ; Mass Spectrometry ; Membrane Transport Proteins ; chemistry ; Pharmacokinetics ; Proteomics

Adolescent ; Adult ; Child ; Female ; Fracture Fixation, Intramedullary ; methods ; Humans ; Male ; Radius Fractures ; surgery

Adolescent ; Adult ; Arteries ; injuries ; pathology ; surgery ; Child ; Child, Preschool ; Extremities ; blood supply ; pathology ; physiopathology ; Female ; Follow-Up Studies ; Humans ; Male ; Microsurgery ; methods ; Middle Aged ; Recovery of Function

OBJECTIVETo investigate the effects of alpha-keto acid on the expression of neuropeptide Y in malnutrition rats with chronic renal failure.

METHODSSD rats received 5/6 nephrectomy and were fed with 4% casein to establish models of malnutrition with chronic renal failure. Serum albumin, urea nitrogen, serum creatinine, type-1 insulin like growth factor and body weight of the rats were measured. The rat models were randomized into chronic renal failure group, alpha-keto acid group and normal control group, and after a 4-week treatment as indicated, neuropeptide Y mRNA levels in the hypothalamus were measured by RT-PCR in rats with surgically induced renal failure (two-stage subtotal nephrectomy). The blood neuropeptide Y of the rats were analyzed by radioimmunoassay.

RESULTSMalnutrition occurred in chronic renal failure rats at the end of 10 weeks. Compared with those in the chronic renal failure group, the plasma neuropeptide Y concentrations in alpha-keto acid group were significantly lowered with substantially elevated neuropeptide Y mRNA expression in the hypothalamus.

CONCLUSIONalpha-keto acid capsule can improve malnutrition in rats with renal insufficiency possibly by up-regulating neuropeptide Y mRNA expression in the hypothalamus and reducing the level of blood neuropeptide Y.

Animals ; Hypothalamus ; metabolism ; Keto Acids ; pharmacology ; therapeutic use ; Kidney Failure, Chronic ; blood ; Male ; Malnutrition ; blood ; drug therapy ; Neuropeptide Y ; blood ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo examine the influence of vascular endothelial growth factors (VEGF) in controlling the growth of an experimental osteosarcoma in mice by performing retrovirus-mediated sFlt-1 gene modification.

METHODSFrom March to October 2010 human osteosarcoma G-292 cells were in vitro infected with retroviral vectors encoding soluble Flt-1 or LacZ gene before transplanted into proximal tibiae of immune deficient SCID mice to establish experimental orthotopic osteosarcoma. Daily observation and biweekly microCT were performed to monitor tumor development and progression till sacrifice at 8 weeks after tumor cell inoculation for histological and molecular analyses.

RESULTSSuccessful transgene expression was confirmed in the culture media of sFlt-1 transduced G-292 cells using ELISA, and with positive X-gal staining of the LacZ transduced cells. Noteworthy tumors were grown in all mice on the tibiae receiving G-292 cell inoculation, with clear detection on microCT images starting 2 weeks after inoculation. Over the time period, tumors derived from sFlt-1 transduced G-292 cells were distinctively smaller in size compared to the ones from wide-type G-292 and G-292-LacZ cells. Histology showed typical osteosarcoma characteristics including severe cellular pleomorphism, bone erosions, and neo-vascularization. Real-time polymerase chain reaction indicated significantly higher sFlt-1 expression in sFlt-1 transduced groups than the wild-type G-292 or LacZ treated groups. Strong expression of oncogenes c-myc and c-fos were also obvious, along with the expression of VEGF in the primary tumor tissue.

CONCLUSIONRetrovirus-mediated sFLT-1 gene modification decelerates the osteosarcoma tumor growth in this murine model.

Animals ; Bone Neoplasms ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Female ; Genetic Vectors ; Humans ; Lac Operon ; Mice ; Mice, SCID ; Neovascularization, Pathologic ; metabolism ; pathology ; Osteosarcoma ; genetics ; metabolism ; pathology ; Retroviridae ; genetics ; Transgenes ; Vascular Endothelial Growth Factor A ; metabolism ; Vascular Endothelial Growth Factor Receptor-1 ; metabolism

OBJECTIVETo investigate the effects of different reference point on intra-abdominal pressure (IAP) measurement.

METHODSNine critically ill patients with risk of intra-abdominal hypertension (IAH) were studied from July 2008 to June 2010, all of the patients were equipped with abdominal cavity drain and urinary drainage tube. By which IAP was measured using direct and indirect methods respectively. The symphysis pubis, phlebostatic axis and the midaxillary line at the level of the iliac crest were defined as reference points. According to the different reference point, three sets of IAP measurements were obtained in the supine position with each method and kept as IAP(S), IAP(P), IAP(I). Bland-Altman method analysis and Pearson's correlation were performed to evaluate the relationships between results from different reference points with direct and indirect methods. Paired t-test was performed to evaluate the differences among different reference points.

RESULTSSixty measurements of IAP(S), IAP(P) and IAP(I) were obtained. In direct measurement through abdominal cavity drain, IAP(I) (13.8 ± 3.9) mmHg (1 mmHg = 0.133 kPa) was significantly higher than IAP(P) (12.8 ± 3.6) mmHg and IAP(S) (9.1 ± 3.6) mmHg, P < 0.05; while in indirect measurement through urinary drainage tube, IAP(I) (12.7 ± 3.2) mmHg was significantly higher than IAP(P) (11.7 ± 2.9) mmHg and IAP(S) (7.9 ± 3.0) mmHg too, P < 0.05. In either direct or indirect method, IAP(P) was higher than IAP(S), P < 0.05. And good correlations were found among IAP(S), IAP(P) and IAP(I).

CONCLUSIONSIn the supine position, pressure obtained via the bladder could reflect authentic IAP. But selection of reference point has great impact on IAP measurement.

Abdominal Cavity ; physiopathology ; Aged ; Critical Illness ; Female ; Humans ; Male ; Manometry ; methods ; Middle Aged ; Pressure

Objective To compare the clinical effect of aripiprazole and risperidone in patients with schizophrenia and metabolic syndrome.Methods A retrospective analysis was performed on the case data of schizophrenia and metabolic syndrome.According to different treatment methods,they were divided into risperidone group(oral risperidone,2 mg once,twice a day)and aripiprazole group(oral aripiprazole,5 mg once,once a day).All were treated for 24 weeks and given lifestyle intervention.The clinical effect,scores of positive and negative symptom scale(PANSS),metabolic syndrome-related indexes[systolic blood pressure(SBP),diastolic blood pressure(DBP),body mass index(BMI),fasting blood glucose(FPG),triglyceride(TG)],cognitive function[MATRICS consensus cognitive battery(MCCB)],levels of serum brain-derived neurotrophic factor(BDNF),tyrosine kinase receptor B(TrkB)and glial cell line-derived neurotrophic factor(GDNF)were compared between the two groups.The adverse drug reactions were statistically analyzed in two groups.Results There were 60 cases in risperidone group and 60 cases in aripiprazole group.The total response rates of aripiprazole group and risperidone group were 91.67％and 76.67％,with significant difference(P＜0.05).After treatment,scores of positive symptoms in PANSS in aripiprazole group and risperidone group were(10.04±1.55)and(11.52±1.62)points;negative symptom scores were(12.74±2.38)and(14.38±2.25)points;general psychopathology scores were(16.53±4.39)and(19.76±4.10)points;total scores of PANSS were(39.31±6.25)and(45.66±6.71)points;total scores of MCCB were(43.61±8.50)and(40.55±8.16)points;BMI were(24.05±2.52)and(25.73±2.86)kg·m-2;SBP were(123.61±7.64)and(128.75±8.59)mmHg;FPG were(5.69±0.60)and(6.38±0.62)mmol·L-1;TG levels were(1.76±0.20)and(2.01±0.22)mmol·L-1;levels of serum BDNF were(32.41±5.81)and(28.65±4.87)pg·mL-1;TrkB levels were(43.88±5.92)and(41.73±5.63)ng·mL-1;GDNF levels were(587.47±36.12)and(468.23±35.68)pg·mL-1,the differences between the two groups were all statistically significant(all P＜0.05).There was no significant difference in the incidence of adverse drug reactions between aripiprazole group and risperidone group(15.00％vs.6.67％,P＞0.05).Conclusion Compared with risperidone,clinical effect of aripiprazole is better in patients with schizophrenia and metabolic syndrome,which has fewer effects on body weight,blood pressure and glycolipid metabolism,and it may improve cognitive function by increasing levels of serum BDNF,TrkB and GDNF.

OBJECTIVETo cultivate human umbilical vein endothelial cells (HUVECs) in the serum of overfatigue rats with the intervention of Tongxinluo superfine powder (TXLSP). By examining the variation of the activity of JNK/c-Jun/HO-1 pathway, the possible mechanisms of vascular endothelial dysfunction under overfatigue conditions and the intervening effect of TXLSP were explored.

METHODSThe HUVECs were randomly divided into the normal control group, the model group, the SP600125 (a specific antagonist of JNK) group, the TXLSP group and the TXLSP + SP600125 group. The content of carboyhemoglobin (COHb) and the leak rate of lactic dehydrogenase (LDH) in different groups were measured. The mRNA and protein expression of JNK, c-Jun, HO-1 and the phosphorylation level of c-Jun (P-c-Jun) were detected using Western blot and PCR methods.

RESULTSCompared with the normal control group, the COHb level in supernatant was increased significantly in the model group, and the expression of HO-1, JNK, c-Jun mRNA and corresponding proteins and P-c-Jun were also increased remarkably. The increases in these parameters were significantly decreased by SP600125. TXLSP showed remarkable up-regulation on the expression of JNK, c-Jun, P-c-Jun and HO-1 mRNA and their protein expression. Compared with the SP600125 group, the expressions of JNK, c-Jun, P-c-Jun and HO-1 mRNA and its protein in the TXLSP+SP600125 group were significantly increased at different time points (P<0.05, P<0.01).

CONCLUSIONSThe vascular endothelial dysfunction under overfatigue conditions is related to the activity of the JNK/c-Jun/HO-1 pathway. One of the mechanisms of TXLSP in improving the vascular endothelial function is to adjust the activity of the JNK/c-Jun/HO-1 pathway at gene and protein levels.

Animals ; Blood Proteins ; pharmacology ; Cells, Cultured ; Cytoprotection ; drug effects ; genetics ; Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Endothelial Cells ; drug effects ; metabolism ; Fatigue ; blood ; metabolism ; Heme Oxygenase (Decyclizing) ; genetics ; metabolism ; physiology ; Humans ; JNK Mitogen-Activated Protein Kinases ; genetics ; metabolism ; physiology ; Male ; Particle Size ; Powders ; administration & dosage ; pharmacology ; Proto-Oncogene Proteins c-jun ; genetics ; metabolism ; physiology ; Rats ; Rats, Wistar ; Serum ; metabolism ; physiology ; Signal Transduction ; drug effects ; genetics ; physiology ; Umbilical Veins ; cytology ; drug effects ; metabolism

AIMTo observe the effect of homocysteine (HCY) on the function of endothelium cell, and to discuss the possible mechanisms that Tongxinluo super powder affected.

METHODSHealthy male Wistar rats were divided into randomly the control group, the model group, the Tongxinluo group. The effect of Ach on isolated rat thoracic aorta in vitro was examined, the microcirculation was observed by microcirculation meter, the activity of SOD and GSH-PX and content of NO, MDA, ET, Ang II, TXA2, PGI2 was detected.

RESULTSCompared with control group, the effect of Ach on isolated rat thoracic aorta in vitro weakened markablely (P < 0.01), the format and percentage that capillary dilated declined significantly (P < 0.05), after treatment with Tongxinluo powder, the effect of Ach on isolated rat thoracic aorta in vitro was improved obviously (p < 0.01), and the format and percentage that capillary dilated were increased compared with model group; comparing with the control group, the level of Ang II and ET, TXA2 in plasm increased obviously (P < 0.05, P < 0.01), while the content of PGI2 depressed manifestly (P < 0.05), at the same time, both content of NO and activity of SOD, (GSH-PX declined obviously (P < 0.001, P < 0.05). After treatment with Tongxinluo powder, the level of ET, AngII and TXA2 reduced significantly in different degree (P < 0.01), while the content of PGI2 appeared stepping up notably (P < 0.01), and both activity of SOD and NO level increased obviously (P < 0.01, P < 0.05).

CONCLUSION(1) The high homocystein might cause the contracted and dilated function decreased, it might get involved in endothelium disfunction as a result of the massive free radicals production and diastolic-contract factors balance disorder induced by high homocystein. (2) Tongxinluo powder could improve the function of endothelium-dependment dilation induced by high homocystein, that associated with inhibitting the excessive production of free radicals, and improved function of endothelium.

Animals ; Aorta ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Endothelium, Vascular ; drug effects ; pathology ; physiopathology ; Homocysteine ; antagonists & inhibitors ; pharmacology ; Male ; Protective Agents ; pharmacology ; Random Allocation ; Rats ; Rats, Wistar

OBJECTIVETo evaluate the correlation between the lactate in artery blood and lactate clearance rate and prognosis in patients with septic shock in intensive care unit (ICU).

METHODSProspectively studied 221 consecutive patients with septic shock from December 2005 to December 2007, the diagnosis of septic shock was made based on the criteria of 2001 ACCP/SCCM. For inclusion in the study, we required admission of the patients within 24 h of septic shock diagnosed. The criteria for exclusion from the study were an age of less than 18 years, pregnancy, serious inadequacy of liver and renal, needing blood purification, or acidosis result of biguanides drugs, or do-not-resuscitate. The eligible patients assigned to early goal-directed therapy. The 6-, 24- and 72-hour lactate clearance rate were calculated, the relationship between the level of lactate, lactate clearance rate, the APACHE II score, the number of failed organ and the 28-day mortality were evaluated.

RESULTSOne hundred and five patients with septic shock were admitted, 74 male and 31 female, the mean age was 70 +/- 12 years. The 28-day mortality was 54.3%. The average APACHE II score at baseline was 20 +/- 8, the number of failed organs was 3.0 +/- 1.1 and the average concentration of lactate in artery blood at baseline was (3.8 +/- 3.6) mmol/L. Significant differences of the lactate at 0-, 6-, 24- and 72-hour were found between death group and survival group. There were 69 patients whose lactate in artery blood at baseline was > 2 mmol/L, 24 survived. The lactate clearance rate of 6- and 24-hour in survival group were significantly higher than death group (P < 0.01, P < 0.05, respectively), but the lactate clearance rate of 72-hour was not (P > 0.05). By using a multivariate logistic regression analysis, it showed that the lactate clearance rate of 6-hour was the independent predictive factor of survival. The area under the receiver operating characteristic curve (ROC) was 0.564, 0.649, 0.754, 0.784, respectively according to the level of the lactate at 0-, 6-, 24-hour and the 6-hour lactate clearance rate. The cutoff of 6-hour lactate clearance rate was >or= 30.0%, resulting in a sensitivity of 60.0% and a specificity of 77.3%.

CONCLUSIONSDynamic observation of lactate level is very important for the survival in the patients with septic shock. Patients with elevated lactate and not decreased rapidly have a worse outcome. The 6-hour lactate clearance rate might be the indicator for predicting the prognosis of patients with septic shock.

Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Lactic Acid ; blood ; Male ; Middle Aged ; Monitoring, Ambulatory ; Prognosis ; Prospective Studies ; Shock, Septic ; blood ; Young Adult