RESUMO
@#The aim of this study was to develop a multi-target pharmacokinetic-pharmacodynamic(PK-PD)model for the evaluation of the protective effect of salvianolic acid A(Sal A)on ischemic heart failure based on a metabolic balance model. The rats were assigned to 3 groups: sham-operated group(saline), ischemic heart failure group(saline)and Sal A-treated group(Sal A, 1 mg/(kg ·d), ip). The concentrations of brain natriuretic peptide(BNP), angiotensin II(Ang II), malondialdehyde(MDA), asymmetric dimethylarginine(ADMA)and the activity of glutathione peroxidase(GSH-Px)in rat plasma were determined before and at 1, 2, 3, and 4 weeks after ligation in all the groups. A multi-target PK-PD model was developed based on the change rate of metabolic disruption parameter k and was eventually used to integrally evaluate the protective effect of Sal A on ischemic heart failure. Sal A showed improvement effects on multiple biomarkers and the correlation study demonstrated a good relationship between dynamic parameter k and left ventricular ejection fraction(LVEF). More importantly, the multi-target model well fitted the relationship between AUC and the change rate. The multi-target PK-PD model provides a novel method to integrally evaluate the protective effect of Sal A, which might offer a new strategy for the establishment of a PK-PD model that embodies the characteristics of traditional Chinese medicine.
RESUMO
@#The study developed a metabolic balance model to evaluated the cardiotoxicity of doxorubicin. The rats were divided into 3 groups, control group(saline), low dose group(8 mg/kg of cumulative doxorubicin)and high dose group(15 mg/kg of cumulative doxorubicin). Doxorubicin or saline was intraperitoneally injected and blood sample was collected at day 1, 4, 7 and 10. The concentrations of nitric oxide(NO), B-type natriuretic peptide(BNP)and the activity of glutathion peroxidase(GSH-Px), xanthine oxidase(XOD)in rat plasma were determined. A metabolic balance model based on the four biomarkers was developed to evaluate the doxorubicin cardiotoxicity in rat. Doxorubicin leaded to significant changes of multiple biomarkers, resulting in metabolic balance disruption according to the metabolic balance maps and dynamic parameters of metabolic balance disruption. Moreover, the correlation study showed a good relationship between metabolic balance disruption and ejection fraction(EF). The metabolic balance model provide a novel method to integrally evaluate the doxorubicin-induced cardiotoxicity.