Effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

Inhibitory effects of compounds isolated from the dried branches and leaves of murta (Myrceugenia euosma) on lipid accumulation in 3T3-L1 cells.

As obesity is a global health concern the demand for anti-obesity drugs is high. In this study, we investigated the anti-obesity effect of the dried branches and leaves of murta (Myrceugenia euosma Legrand, Myrtaceae). A methanol extract of the dried branches and leaves of murta inhibited adipogenesis in 3T3-L1 cells. Three known flavanones-cryptostrobin (1), pinocembrin (4), and 5,7-dihydroxy-6,8-dimethylflavanone (6), and three chalcones-2',6'-dihydroxy-3'-methyl-4'-methoxychalcone (2), pinostrobin chalcone (3), and 2',6'-dihydroxy-4'-methoxy-3',5'-dimethylchalcone (5) were isolated from the active fraction. Structures of these compounds were identified using various spectral data. Each of these compounds also inhibited adipogenesis in 3T3-L1 cells. In particular, compound 3 was a more potent inhibitor of triglyceride accumulation than the positive control berberine. Gene expression studies revealed that treatment of 3T3-L1 cells with 3 lowers the expression levels of CCAAT/enhancer-binding protein α and peroxisome proliferator activator γ2 during adipogenesis without affecting cell viability. Treatment of 3T3-L1 cells with 3 reduced the expression levels of mRNAs encoding sterol regulatory element-binding protein 1c and several lipogenic enzymes, including fatty acid synthase and stearoyl CoA desaturase-1. These results indicate that the methanol extract and compounds isolated from the dried branches and leaves of murta exert their anti-obesity effects through the inhibition of adipogenesis.