Effects of acute renal failure on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). After intravenous administration in rats with U-ARF, the time-averaged total body clearance (Cl) was significantly faster (2.45 versus 0.932 ml/min/kg) than controls due to significantly faster nonrenal clearance (2.25 versus 0.855 ml/min/kg) in rats with U-ARF. The faster nonrenal clearance could be due to significantly greater gastrointestinal (including biliary) excretion; the amount of unchanged DA-7867 recovered from the entire gastrointestinal tract at 24 h was significantly greater (30.3% versus 9.38% of intravenous dose) in rats with U-ARF. In rats with U-ARF, the Vss was significantly larger (1420 ml/kg compared with 580 ml/kg), but this was not due to a difference in plasma protein binding; the values were comparable between the two groups of rats. After oral administration to rats with U-ARF, the total area under the plasma concentration-time from time zero to time infinity (AUC) of DA-7867 was significantly smaller than the controls (2560 microg min/ml versus 7440 microg min/ml), and this was not due mainly to a decrease in absorption from the gastrointestinal tract in rats with U-ARF.     

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.     

(-)-Syringaresinol inhibits proliferation of human promyelocytic HL-60 leukemia cells via G1 arrest and apoptosis

We examined the effect of (-)-syringaresinol, a furofuran-type lignan isolated from Daphne genkwa, on cell cycle regulation in HL-60 human promyelocytic leukemia cells in vitro. (-)-Syringaresinol decreased the viability of HL-60 cells by inducing G(1) arrest followed by apoptosis in a dose- and time-dependent manner. The G(0)/G(1) phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the (-)-syringaresinol-induced G(1) arrest was mediated through the increased expression of Cdki proteins (p21(cip1/waf1) and p27(kip1)) with a simultaneous decrease in cdk2, cdk4, cdk6, cyclin D(1), cyclin D(2), and cyclin E expression. The induction of apoptosis after treatment with (-)-syringaresinol for 24 h was demonstrated by morphological changes, DNA fragmentation, altered ratio of Bax/Bcl-2, cleavage of poly(ADP-ribose) polymerase and flow cytometry analysis. (-)-Syringaresinol also induced cytochrome c release and activation of caspase-3 and caspase-9. To our knowledge, this is the first time that (-)-syringaresinol has been reported to potently inhibit the proliferation of human promyelocytic HL-60 cells through G(1) arrest and induction of apoptosis. These findings suggest that (-)-syringaresinol may be a potential chemotherapeutic agent for the treatment of cancer.     

Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats

Although, numerous studies have attempted to reduce the oxygen radical injury induced by the antioxidants in paraquat intoxication, these antioxidant therapies have showed few survival benefits. Ethyl pyruvate (EP) may function as an effective scavenger of oxygen radicals, an anti-inflammatory agent and an energy source in many ischemia reperfusion models. The aim of this study was to evaluate the antioxidant and anti-inflammatory effects of EP on the lung and the liver tissues in paraquat-intoxicated rats. Rats were randomly given either a low (2 mg/kg i.p.) or high (40 mg/kg i.p.) EP dose, 30 min before or 1 h after paraquat (50 mg/kg i.p.) administration, and subsequently killed at 6 and 24 h. Glutathione (GSH) and malondialdehyde (MDA) levels of the lungs and the livers, and plasma nitric oxide (NO) concentrations were measured. Pretreatment of EP significantly decreased the MDA level in the lung and the liver tissues. EP also significantly decreased plasma NO concentrations at 6 h. EP pretreatment, however, failed to show significant change in GSH concentration. In post-treatment of EP, MDA levels in the lung tissue and plasma NO levels were significantly decreased. In conclusion, EP decreased the lipid peroxidation and seemed to exert an anti-inflammatory action in the paraquat intoxication rat model.     

Modulation of the genomic estrogen receptor pathway by water extracts of Cirsium japonicum

We investigated the estrogenic activity of Cirsium japonicum water extracts, which have long been used to treat vascular-related diseases. The activity of the extracts was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids in HEK 293 cells. The extract activated both and estrogen receptors. Activation was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor isoforms. Treatment with the extracts increased expression of the progesterone receptor and pS2 genes and expression of estrogen receptor was decreased in MCF-7 cells. These results suggested that the Cirsium japonicum water extracts showed estrogenic effects and may be a potential clinical application for treatment of estrogen related vascular diseases. These two authors contributed equally to this work.     

NMR-based metabolomics approach for the differentiation of ginseng (<Emphasis Type="Italic">Panax ginseng</Emphasis>) roots from different origins

Agro-herbal materials vary in prices and qualities depending on the origin and age and the differentiation is both scientific and public health issue. Here, we describe a metabolomics approach used to discriminate ginseng roots from different sources. Six different types of ginseng roots from China and Korea were analyzed by NMR-based metabolomics. Chinese Dangsam showed prominent differences and was easily differentiated. The difference was mainly due to the large signals in the sugar region. We further analyzed the metabolomics results in subgroups. Jeonra (Korean), Choongcheong (Korean), and Chinese ginseng in subgroup 1 could be easily differentiated by the first two principal components. The loading plot for PC1 showed that the Jeonra and Chinese ginseng roots were mainly separated by sugar signals and methyl signals but that they were reverse-correlated. A diffusion-ordered spectroscopy (DOSY) analysis showed that the methyl signals are from high molecular weight compounds and that the sugar signals are either from oligosaccharides or ginsenosides. In subgroup 2, composed of Korean Choongcheong ginseng at different ages, we were able to see age-dependent transitions in the score plot. We believe our approach can be applied to detecting the adulteration of ginseng root powders and other herbal products from different origins. Jinho Kang and Seoyoung Lee contributed equally to this work.     

Taq1A polymorphism in the dopamine D2 receptor gene predicts brain metabolic response to aripiprazole in healthy male volunteers

OBJECTIVE: The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene has been reported to be associated with the pharmacodynamics of antipsychotic drugs. We investigated the metabolic response of glucose in the brain to aripiprazole in relation to the DRD2 Taq1A polymorphism. METHODS: Twenty healthy male volunteers were recruited and were divided into two groups of 10 participants, according to their DRD2 genotypes (A1A1, n=10; A2A2, n=10). The volunteers received single oral doses of aripiprazole (10 mg) and a placebo, following a single-blind, placebo-controlled, randomized, two-way crossover study design. Brain glucose metabolism was assessed using positron emission tomography, scanned with 18F-fluorodeoxyglucose 12 h after the administration of the drug or placebo. RESULTS: In voxel-based analysis using SPM2, volunteers with the A2A2 genotype showed decreased metabolism in the right middle frontal gyrus, the left middle and inferior frontal gyrus, the right and left inferior temporal gyrus, and the right cingulate gyrus, and increased metabolism in the pons. In contrast, volunteers with the A1A1 genotype exhibited increased metabolism in the right caudate head, and no brain region showed decreased metabolism. In a region-of-interest analysis, significant interactions between drug and genotype were observed in the right medial orbitofrontal gyrus and the left caudate nucleus. CONCLUSIONS: This suggests that DRD2 Taq1A polymorphism status may be associated with the clinical response to aripiprazole.     

Effect of cholesterol on the release of amphotericin B from PEG-phospholipid micelles

Micelles formed from PEG-DSPE solubilize high levels of the poorly water-soluble antifungal amphotericin B (AmB). AmB release from PEG-DSPE micelles is slow in buffer but remarkably rapid in the presence of bovine serum albumin (BSA). Sequential changes in the absorbance spectrum of AmB in PEG-DSPE micelles point to a rapid dissociation of incorporated drug in the presence of BSA. In this context, we have studied micelles formed from PEG-DSPE which coincorporate cholesterol (PEG-DSPE|cholesterol). (1)H NMR measurements point to a lower mobility of lipid in PEG-DSPE|cholesterol micelles compared to PEG-DSPE micelles. The absorbance spectrum of AmB incorporated in PEG-DSPE|cholesterol micelles is distinct from that in PEG-DSPE micelles, which may point to differences in the drug-micelle interaction. AmB release from PEG-DSPE|cholesterol micelles is slow in buffer and in the presence of BSA. The absorption spectrum of AmB in PEG-DSPE|cholesterol micelles remained unchanged in BSA, further supporting stable incorporation and the slow release from the carrier.     

A beverage of Asiatic plantain extracts alleviated postprandial oxidative stress in overweight hyperlipidemic subjects challenged with a high-fat meal: a preliminary study

There is emerging interest in the potential of the phenolic compounds of Asiatic plantain (Plantago asiatica L.) to attenuate in vitro and in vivo oxidative stress. We hypothesized that a single administration of Asiatic plantain beverage may exert protective effects against postprandial oxidative stress. This preliminary study was designed to compare the ability of different doses of Asiatic plantain beverage to mitigate the postprandial effects of a high-fat meal on the oxidation of lipids and DNA in overweight hyperlipidemic subjects. In a randomized, double-blind, placebo-controlled parallel design (n = 10/group), 40 subjects were administered a single high-fat meal with either a placebo or 1 of 3 Asiatic plantain extract beverages (low, intermediate, or high dose). Blood samples were obtained at fasting and 60, 120, 240, and 360 minutes (total of 5 samples) after intervention. The data showed a tendency for plasma free fatty acid levels to decrease in response to high-dose Asiatic plantain at all time points. Plasma oxidized low-density lipoprotein levels were significantly reduced with high-dose Asiatic plantain at 120 minutes (P = .0251 vs placebo). A comet assay revealed that DNA damage in lymphocytes was significantly decreased by Asiatic plantain at 360 minutes (P = .0225 vs placebo). There were no treatment differences in triglyceride or malondialdehyde levels. The maximum suppression was achieved with a high dose (20 g Asiatic plantain extract/80 mL). These results suggest that by protecting low-density lipoprotein and DNA, an Asiatic plantain beverage may be useful to enhance antioxidant.     

Effect of dissolved oxygen in alcoholic beverages and drinking water on alcohol elimination in humans

Oxygen plays an important role in the metabolism of alcohol. An increased dissolved oxygen level in alcoholic beverages reportedly accelerates the elimination of alcohol. Therefore, we evaluated the effect of dissolved oxygen in alcohol and the supportive effect of oxygenated water on alcohol pharmacokinetics after the excessive consumption of alcohol, i.e., 540 ml of 19.5% alcohol (v/v). Fifteen healthy males were included in this randomized, 3 × 3 crossover study. Three combinations were tested: X, normal alcoholic beverage and normal water; Y, oxygenated alcoholic beverage and normal water; Z, oxygenated alcoholic beverage and oxygenated water. Blood alcohol concentrations (BACs) were determined by conversion of breath alcohol concentrations. Four pharmacokinetic parameters (C_max, T_max, K_el, and AUCall) were obtained using non-compartmental analysis and the times to reach 0.05% and 0.03% BAC (T_0.05% and T_0.03%) were compared using one-way analysis of variance (ANOVA) and Duncan's post hoc test. With combination Z, the BAC decreased to 0.05% significantly faster (p < 0.05) than with combination X. Analyzing the pharmacokinetic parameters, the mean K_el was significantly higher for combination Z than for combinations X and Y (p < 0.05), whereas the mean values of C_max, T_max and AUCall did not differ significantly among the combinations. Dissolved oxygen in drinks accelerates the decrease in BAC after consuming a large amount of alcohol. However, the oxygen dissolved in the alcoholic beverage alone did not have a sufficient effect in this case. We postulate that highly oxygenated water augments the effect of oxygen in the alcoholic beverage in alcohol elimination. Therefore, it is necessary to investigate the supportive effect of ingesting additional oxygenated water after heavy drinking of normal alcoholic beverages.