Investigation of the Inhibitory Effect of Simvastatin on the Metabolism of Lidocaine Both in vitro and in vivo.

BACKGROUND: Lidocaine has cardiovascular and neurologic toxicity, which is dose-dependent. Due to CYP3A4-involved metabolism, lidocaine may be prone to drug-drug interactions. MATERIALS AND METHODS: Given statins have the possibility of combination with lidocaine in the clinic, we established in vitro models to assess the effect of statins on the metabolism of lidocaine. Further pharmacokinetic alterations of lidocaine and its main metabolite, monoethylglycinexylidide in rats influenced by simvastatin, were investigated. RESULTS: In vitro study revealed that simvastatin, among the statins, had the most significant inhibitory effect on lidocaine metabolism with IC50 of 39.31 µM, 50 µM and 15.77 µM for RLM, HLM and CYP3A4.1, respectively. Consistent with in vitro results, lidocaine concomitantly used with simvastatin in rats was associated with 1.2-fold AUC(0-t), 1.2-fold AUC(0-∞), and 20%-decreased clearance for lidocaine, and 1.4-fold Cmax for MEGX compared with lidocaine alone. CONCLUSION: Collectively, these results implied that simvastatin could evidently inhibit the metabolism of lidocaine both in vivo and in vitro. Accordingly, more attention and necessary therapeutic drug monitoring should be paid to patients with the concomitant coadministration of lidocaine and simvastatin so as to avoid unexpected toxicity.

Genistein Improves the Major Depression through Suppressing the Expression of miR-221/222 by Targeting Connexin 43.

OBJECTIVE: Recent studies have indicated the possibility that genistein may improve depression via regulating the expression of miR221/222. This study is to explore whether genistein could improve depression by altering miR-221/222 levels and investigate the possible mechanisms involved in the improvement effect of genistein. METHODS: The animal model of depression was established through unpredictable chronic mild stress. Nest building test and splash test were adapted to evaluate the effects of genistein on depressive symptoms in mice. qRT-PCR and western blot analysis were used to detect the expression of miR-221/222 and connexin 43 (Cx43) in the prefrontal cortex of the mice. In vitro, U87-MG astrocytes were treated with genistein and the expression of miR-221/222 and Cx43 was measured. The dual-luciferase reporter assay was used to verify whether Cx43 was a direct target of miR-221/222. RESULTS: The behavioral tests showed that genistein could significantly reduce depression symptoms of mice, and this remission was not affected by gender. Genistein in vivo and in vitro could reduce increased levels of miR-221 and miR-222 in the prefrontal cortex of depressed mice, while upregulate Cx43 expression. Dual-luciferase reporter assay suggested Cx43 was directly regulated by miR-221/222 in astrocytes. CONCLUSION: Genistein can play its antidepressant effect through down-regulating miR-221/222 by targeting Cx43.