RESUMEN
BACKGROUND: To investigate the suppressing effects of vascular endothelial growth factor (VEGF)-mediated angiogenesis at different treatment schedules by applying apatinib combined with transarterial embolization (TAE). METHODS: Forty ideal liver cancer rat models were randomly divided into four groups based on different administration methods of apatinib [control group (CG): TAE only; Combined Group 1 (CG1): apatinib administration 3 days pre-TAE; Combined Group 2 (CG2): apatinib administration simultaneously with TAE; Combined Group 3 (CG3): apatinib administration 3 days post-TAE]. The characteristics of liver cancer, the expression of VEGF and microvascular density (MVD) as determined by CD34, and the overall survival (OS) were compared among the groups. RESULTS: The tumor sizes of the liver on the 10th day after treatment were significantly larger when compared to the baseline sizes (P<0.05), and tumor growth in the combined groups was significantly slower than that of CG (P<0.05). The OS of rats was significantly different between the combined groups and control group (P<0.05), which were 19.9±3.21, 31.2±6.48, 27.1±5.59, and 25.9±6.06 days in groups CG, CG1, CG2 and CG3, respectively. Significant differences were observed between groups CG1 and CG3. The expression levels of VEGF in groups CG1, CG2 and CG3 were 45.6±9.88, 70.8±14.11 and 75.3±9.82, and were significantly lower than that in control groups (85.8±11.26). The MVD in CG (109.7±10.32) reached the peak value when compared to those in the three combined groups (46.4±19.22, 75.7±15.97, and 90.5±12.71, all P<0.05). Furthermore, overexpression of VEGF and MVD showed significant positive correlation with poor OS. CONCLUSIONS: These findings demonstrated that apatinib treatment enhanced anti-tumor effects of TAE via reducing tumor angiogenesis, suppressing tumor growth, and prolonging the OS of rats with liver tumors. Early administration of apatinib showed better therapeutic effects.
RESUMEN
AIMS: Considering the potential oral administration sequences and role of microbiota for metformin (MET) and berberine (BBR) during anti-diabetic treatments, the current study aimed to investigate the pharmacokinetic interactions between MET and BBR in rats after oral administration at different sequences and impacts of microbiota on such interactions. MAIN METHODS: Sprague-Dawley rats were divided into five groups as per what was orally administered to them: MET (G1)/BBR (G2) at 200â¯mg/kg, BBR 2-hour (h) after dosing MET (G3), MET 2-h after dosing BBR (G4) or MET with BBR at the same time (G5) followed by monitoring their pharmacokinetic profiles. Further in vitro incubations mimicking the above five treatments in rat intestinal content (G1R-G5R), human fecalase (G1H-G5H) and selected bacteria (G1B-G5B) were conducted for both MET and BBR (10⯵g/ml for G1R/H-G5R/H and 50⯵M for G1B-G5B) up to 24-h. Concentrations of MET and BBR were analyzed by LC/MS/MS. KEY FINDINGS: Although BBR was barely measurable in vivo, it significantly increased systemic exposure of MET in G3/G4. Consistent with pharmacokinetic findings, sequential in vitro incubations of MET and BBR in both rat intestinal content and human fecalase demonstrated significant increase on MET persisted after 24-h incubation in G3R/H & G4R/H. Moreover, post-dose (G3B) and pre-dose (G4B) of BBR decreased the MET degradation significantly in most selected bacteria. SIGNIFICANCE: Our finding for the first time demonstrated the significant effect of sequential co-administration of BBR and MET on their pharmacokinetic interactions, which could be related to their microbiota mediated metabolisms in gastrointestinal tract (GI).