Effect of chongmyungtang, a traditional Korean polyherbal formula, on the Pharmacokinetic profiles of donepezil in rats

Chongmyungtang [CMT] is a famous Korean herbal medicine for improving learning and memory, which has been reported to have anti-cholinergic and neuroprotective effects. Therefore, drug-drug interactions were examined between CMT and donepezil as a first screening of combination therapy for cognitive deficits. Rats received oral coadministration of donepezil with distilled water as a control or donepezil with CMT as a combination. The distilled water or CMT was co-administered at intervals within 5min after donepezil or 1.5h intervals. The plasma samples were analyzed for donepezil concentration and its pharmacokinetic parameters of T[max], C[max], AUC, t[1/2] and MRT[inf]. In the single co-administration at intervals within 5min, donepezil was detected lower in the combination than control at 0.5h and 2h post-treatment [P<0.05]. In addition, the combination showed significant increases in MRT[inf] compared to the control [P<0.05]. This suggests drug-drug interactions between donepezil and CMT in the co-administration within 5 min. However, no meaningful differences were found in the pharmacokinetic profiles of donepezil by single dosing with CMT at 1.5h intervals and even by the repeated dosing for a week at 1.5h intervals potential combination therapy of donepezil with CMT

The Influence of Antioxidant Resveratrol on Paraquat-induced Oxidative Stress in Cultured Lung Cells

PURPOSE: Paraquat (1,1'-dimethy-4,4'-bipyridinium dichloride, PQ) is an effective and widely used herbicide, which was introduced commercially in 1962. It is reduced by an electron donor, such as NADPH, and then transfers the electron to molecular oxygen. As a result, the reactive oxygen species (ROS) produced are related to its cellular toxicity. Resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine, possessing chemopreventive properties. However, the influence of resveratrol on PQ-induced oxidative cell damage has not fully been investigated. METHODS: This experiment was conducted in vitro using cultured lung cells from SD rats. The MTT and LDH methods were used for assessment of cytotoxicity. The 2',7'-dichlorofluorescein diacetate (DCF-DA) assay was used for measurement of intracellular ROS levels. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used for measurement of pro-oxidant capacity of resveratrol. The Thiobarbituric acid reactive substances (TBARS) assay, which reflects lipid peroxidation, was used for estimation of oxidative stress. RESULTS: According to results of the MTT and LDH assays, incubation of cultured lung cells with resveratrol did not protect lung cells from PQ-induced cytotoxicity, and no decrease in ROS production was observed, according to results of the DCF-DA assay. On the other hand, incubation of lung cells with non-lethal resveratrol resulted in aggravation of PQ-induced oxidative stress. CONCLUSION: Results of this study showed that incubation of cells with resveratol did not result in reduction of PQ toxicity, but lead to elevation of PQ-induced oxidative stress in cultured lung cells.

Continuous hypoxia attenuates paraquat-induced cytotoxicity in the human A549 lung carcinoma cell line

Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride; PQ), an effective and widely used herbicide, was commercially introduced in 1962. It is reduced by the electron donor NADPH, and then reduced PQ transfers the electrons to molecular oxygen, resulting in the production of reactive oxygen species (ROS), which are related to cellular toxicity. However, the influence of continuous hypoxia on PQ-induced ROS production has not fully been investigated. We evaluated in vitro the protective effect of continuous hypoxia on PQ-induced cytotoxicity in the human carcinogenic alveolar basal epithelial cell line (A549 cells) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and live and dead assay, and by measuring lactate dehydrogenase (LDH) release. To elucidate the mechanism underlying this effect, we monitored the immunofluorescence of intracellular ROS and measured malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Continuous hypoxia protected the A549 cells from PQ-induced cytotoxicity. Continuous hypoxia for a period of 24 h significantly reduced intracellular ROS, decreased MDA concentration in the supernatant, and normalized SOD and GPx activities. Continuous hypoxia attenuated PQ-induced cell toxicity in A549 cells. This protective effect might be attributable to the suppression of PQ-induced ROS generation.