Objective Gamma amino butyric acid (GABA) signaling pathway related genes mRNA expression and promoter methylation of GABRB2 gene in peripheral blood were investigated to explore the mechanisms involved in schizophrenia (SZ) and antipsychotics treatment. Methods DNA was isolated from blood samples of 53 SZ patients and 53 gender-and age-matched healthy controls. 12 out of 25 SZ patients were followed 8 weeks antipsychotic treatment. The quantitative GABRB2 promoter methylation was analyzed using the high-throughput mass spectrometry on matrix-as?sisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array before and after treatment. Results The GA?BRB2 promoter methylation pattern of case and control group was not significantly different (P>0.05). However, signifi?cant differences of the methylation levels of CpG_28 in the GABRB2 promoter between two groups were found in males [(0.215±0.084) vs. (0.264±0.103), P<0.05]. After 8 weeks antipsychotics treatment, a significant decrease of GABRB2 pro?moter methylatin was detected in the patients [(0.088±0.037) vs. (0.121±0.063), P<0.01]. Conclusion A down regulation of GABRB2 promoter methylation in blood of SZ patients after-treatment supports that GABRB2 promoter methylation in blood may be associated with the mechanisms of antipsychotics treatment in SZ.

OBJECTIVETo evaluate efficacy and optimal cut-off-point through cerebral vascular hemodynamic indexes (CVHI) examination to predict stroke.

METHODSA number of 20,333 people at 35 years old and over were checked by CVHI and accumulative score was calculated according to the value of detected indexes. Risk factors of stroke were investigated simultaneously. One hundred and sixty-eight patients with stroke occurred during 4-year following up. Typical syndromes and signs stroke were used as golden standard to evaluate screening efficacy of CVHI.

RESULTSScore of optimal cut-off-point of cerebral vascular hemodynamic indexes was under 75 in ROC curve analyses. Sensitivity, specificity, accuracy, positive and negative predictive values, positive and negative likelihood ratios as well as Youden's index for predicting stroke within 4 years after examination were found to be 87.50%, 67.70%, 67.86%, 2.21%, 99.85%, 2.71, 0.18 and 0.55 respectively. Sensitivity and positive predict values for predicting cerebral vascular thrombosis were superior to predicting cerebral hemorrhage. Positive predicting value in risk exposure population was higher than that of overall population. Coefficiency of variation of cerebral vascular hemodynamic examination was 4.03%. The agreement rate of examination between two physicians was 97.62% and Kappa value was 0.94.

CONCLUSIONThe score of optimal cut-off-point of cerebral vascular hemodynamic indexes examination was 75. Both Efficacy and reliability for predicting stroke seemed to be good, especially for predicting cerebral vascular thrombosis.

Adult ; Aged ; Brain ; physiopathology ; Female ; Hemodynamics ; Humans ; Male ; Middle Aged ; Stroke ; diagnosis ; physiopathology

Objective·To develop physiologically based pharmacokinetic(PBPK)models specifically designed for the Chinese population by utilizing the combination of clozapine and fluvoxamine as a case,and predict the drug-drug interaction(DDI)associated with the combination medication of clozapine,ultimately optimizing the dosage of clozapine.Methods·By obtaining the physicochemical parameters,absorption,distribution,metabolism,excretion(ADME)-related parameters,and physiologically relevant parameters of the Chinese population through literature and pharmacology-related databases,PBPK models for the clozapine and fluvoxamine were constructed by using PK-Sim? software.The models' accuracy was evaluated by comparing predicted values of the area under the curve(AUC)and peak concentration(Cmax)to observed data,using the mean percentage error(MPE)and mean absolute percentage error(MAPE)as evaluation indicators.The models were validated against real-world plasma drug concentration data.Additionally,combining the inhibitory effect of fluvoxamine on clozapine,models for the combination therapy of clozapine and fluvoxamine were developed to predict the pharmacokinetic changes of clozapine.The presence of clinically significant DDI was determined by using the 90%confidence interval of the AUC ratio(AUCR)or Cmax ratio(CmaxR)as evaluation metrics,with a non-effect boundary set at 80%?125%.The pharmacokinetic changes of clozapine upon co-administration with fluvoxamine based on PBPK models were quantified,and a dosage optimization for clozapine was developed.Results·The constructed model of clozapine and fluvoxamine was considered accurate if the absolute value of the MPE was≤10%and the MAPE was<25%during validation,indicating that the predicted concentration-time curves were accurate.The PBPK model for the co-administration of clozapine and fluvoxamine was able to accurately predict pharmacokinetic parameters if the ratio of predicted AUC to observed AUC was within 1.25.The prediction of PBPK model for the co-administration showed that the 90%confidence intervals for AUCR and CmaxR of the combination therapy of clozapine and fluvoxamine were not entirely within the ineffective effect boundary,indicating a clinically significant DDI when these two drugs were used concomitantly.Moreover,the dose optimization according to the PBPK models indicated that when subjects were co-administered with clozapine and fluvoxamine,reducing the dose of clozapine to 50%of the original dose could maintain the exposure levels of clozapine consistent with monotherapy.Conclusion·The established PBPK model can effectively simulate the impact of combination therapy on pharmacokinetic changes of clozapine,providing valuable insights for predicting potential DDI and optimizing dosage regimens.If clozapine needs to be co-administered with fluvoxamine during the treatment,clinicians should remain vigilant for clinically significant DDI and contemplate optimizing the dosage of clozapine accordingly.