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The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats. HCT inhibited human OCT2 and human MATE1-mediated metformin transports in vitro. In in vivo rats, treatment with HCT and metformin for 28 days in rats (28MH rats) reduced the rat Oct2-mediated renal excretion of metformin and thereby the increased systemic exposure of metformin compared with only metformin-treated rats for 28 days (28M rats). In 28MH rats, rat Oct1-mediated metformin uptake into the liver was enhanced, leading to an improved glucose-lowering effect without hypoglycaemia compared with 28M rats. There was no impairment of renal function in HCT and metformin treatments. These results suggest that HCT-metformin combination therapy is applicable in terms of efficacy and safety.

BACKGROUND Bioactives extracted from cactus (Opuntia ficus-indica) stems were investigated for their chemopreventive activities using human cancer cells in vitro. The bioactives present in crude extracts were detected and quantified using high-performance liquid chromatography. RESULTS Among all the extracts, such as hexane, ethyl acetate (EtOAc), acetone, methanol (MeOH), and MeOH:water (80:20), the MeOH extract had the highest amount of polyphenolic compounds and the acetone extract exhibited the most potent effect at scavenging the 2,2,-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS•+) radical. In addition, most of the extracts, with the exception of hexane, exhibited significant cytotoxicity in human SW480 colon and MCF7 breast cancer cells. Overall, the SW480 cells were more sensitive than the MCF7 cells to the cytotoxic effect of the O. ficus-indica extracts (OFEs). Cell death by OFE treatment caused significant inhibition of cyclooxygenase-2 and increased the Bax/Bcl2 ratio in both SW480 and MCF7 cell lines. However, degradation of poly (ADP-ribose) polymerase was significantly increased by OFE only in the MCF7 cells, thereby inducing apoptosis. CONCLUSION These findings demonstrate the health-benefit roles, including anti-oxidative and anti-proliferative activities as well as pro-apoptotic effects, of bioactive compounds in OFEs, suggesting a chemopreventive role in human cancer cells. © 2014 Society of Chemical Industry

The fruit of Schisandra chinensis is a well-known herbal medicine and dietary supplement due to a variety of biological activities including antihepatotoxic and antihyperlipidemic activities. However, the simultaneous validation methodology and pharmacokinetic investigation of nine lignans of S. chinensis extract in biological samples have not been proved yet. Thus, the present study was undertaken to develop the proper sample preparation method and simultaneous analytical method of schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, schisandrin B, gomisin N, and schisandrin C in the hexane-soluble extract of S. chinensis to apply for the pharmacokinetic study in rats. All intra- and interprecisions of nine lignans were below 13.7% and accuracies were 85.1-115% and it is enough to evaluate the pharmacokinetic parameters after both intravenous and oral administration of hexane-soluble extract of S. chinensis to rats.

The present study was undertaken to investigate the pharmacokinetics of isoliquiritigenin (isoLQ) as determined by the automated dosing/blood sampling (ABS) and traditional manual blood sampling techniques in awake and freely moving mice using combined liquid chromatography tandem mass spectrometry. Pharmacokinetic comparison was conducted by allocating mice into two groups; an ABS group (intravenous study and oral studies, n = 5 each) and a manual group (intravenous and oral studies; n = 5 each). Significant differences in pharmacokinetic parameters (area under the curve and clearances) were observed between ABS and manual groups. This could be mainly due to the blood sampling site difference (via heart puncture in traditional manual group and via carotid artery in ABS groups). The low F of isoLQ could be mainly due to a considerable gastrointestinal and/or hepatic first-pass effect and not to incomplete absorption. The driving force for distribution and elimination of drugs is its concentration in the arterial blood. Therefore, the ABS method was found to be a useful drug development tool for accelerating the process of preclinical in vivo studies and for obtaining reliable and accurate pharmacokinetic parameters in mice. Copyright © 2013 John Wiley & Sons, Ltd.

Background and purpose Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats. Experimental approach Itraconazole (20 mg·kg(-1)) and metformin (100 mg·kg(-1)) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)) and intrinsic clearance (CL(int) ) for the disappearance of each drug, apparent inhibition constant (K(i) ) and [I]/K(i) ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro. Key results After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration-time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes. Conclusions and implications The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.

Background and purpose: Erectile dysfunction is highly prevalent in diabetic patients and PDE V inhibitors are effective and safe for the treatment of erectile dysfunction in men with diabetes. Therefore, in this study we investigated whether a pharmacokinetic interaction occurs between DA-8159 and metformin, as both drugs are metabolized via hepatic CYP3A1/2 in rats. Experimental approach: DA-8159 (30 mg kg–1) and metformin (100 mg kg–1), both separately and together, were administered to rats either intravenously or orally. The Vmax, Km, CLint, apparent inhibition constants (Ki), [I]/Ki and concentrations of each drug in the liver and intestine were then measured. Key results: After i.v. administration of both drugs simultaneously, the AUC of DA-8159 and metformin was significantly greater (21.2 and 33.9% increase for DA-8159 and metformin, respectively) than that of each drug alone. After p.o. administration of the drugs, the AUC of metformin was also significantly greater (20.7% increase) in the presence of DA-8159 than in its absence. However, the AUC of DA-8159 was similar in the absence and presence of metformin. Conclusions and implications: The significantly greater AUC of metformin and DA-8159 after i.v. administration of both drugs and of metformin after p.o. administration of both drugs is probably due to competitive inhibition for the metabolism of these drugs via hepatic CYP3A1/2. However, the similar AUCs of DA-8159 in the absence and presence of metformin, after p.o. administration, indicates that the dose of metformin used was insufficient to inhibit the hepatic and intestinal metabolism of DA-8159. British Journal of Pharmacology (2008) 153, 1568–1578; doi:10.1038/sj.bjp.0707680; published online 21 January 2008

It was reported that metformin was mainly metabolized via hepatic CYP2C11, 2D1 and 3A1/2 in rats, and in a rat model of dehydration, the expressions of hepatic CYP2C11 and 3A1/2 were not changed. Hence, it could be expected that the Clnr of metformin is comparable between two groups of rats if the contribution of CYP2D1 in the rat model of dehydration is not considerable. It was also reported that the timed-interval renal clearance of metformin was dependent on the urine flow rate in rats. In the rat model of dehydration, the 24h urine output was significantly smaller than in the controls. Hence, the urinary excretion of metformin was expected to be smaller than the controls. The above expectations were proven as follows. After intravenous administration of metformin (100mg/kg) to the rat model of dehydration, the Clnr were comparable between the two groups of rats. After both intravenous and oral administration of metformin (both 100mg/kg) to the rat model of dehydration, the 24h urinary excretion of the drug was significantly smaller than in the controls. After oral administration of metformin to the rat model of dehydration, the AUC was significantly greater (99.2% increase) than the controls. Copyright © 2007 John Wiley & Sons, Ltd.

It has been reported that the plasma (or serum) levels of albumin and globulins were lower and higher, respectively, than the serum levels in control rats. Hence, it could be expected that these changes could affect the renal clearance (Cl(r)) of methotrexate in Nagase analbuminemic rats (NARs) due to changes in plasma protein binding values. Therefore, methotrexate at a dose of 100 mg/kg was administered intravenously to control rats and NARs. The plasma protein binding of methotrexate in NARs was significantly greater (29.4% increase) than the controls, probably due to the considerable binding of the drug (34.2%) to 1.8% beta-plus 0.63% gamma-globulins. The Cl(r) of methotrexate in NARs was significantly slower (36.1% decrease) than the controls, due to the significantly smaller Ae(0-24h) (25.8% decrease). The smaller Ae(0-24h) could be due to the significantly smaller free (unbound to plasma proteins) fractions of methotrexate in plasma (13.8% decrease) in NARs, since methotrexate was mainly excreted in the urine via glomerular filtration. However, the Cl(nr) values were comparable between the control rats and NARs. This could be because methotrexate is not metabolized considerably via hepatic CYP isozymes based on control rats pretreated with SKF 525-A (a nonspecific inhibitor of hepatic CYP isozymes in rats).

It has been reported that plasma albumin concentrations were significantly lower in cancer patients than those in the healthy volunteers, and the expression and mRNA level of hepatic microsomal cytochrome P450 (CYP) 1A2 increased in mutant Nagase analbuminemic rats (NARs). After intravenous administration of 5-fluorouracil at a dose of 30 mg/kg to NARs, the time-averaged nonrenal clearance (Clnr) of the drug was significantly faster than the controls (51.3 versus 28.8 ml/min/kg), possibly due to an increase in the expression and mRNA level of CYP1A2 in NARs. In order to determine whether 5-fluorouracil is metabolized via CYP1A2 in male Sprague-Dawley rats, the rats were pretreated with 3-methylcholanthrene (a main inducer of CYP1A1/2 in rats). The Clnr of 5-fluorouracil was significantly faster (34.3 versus 27.3 ml/min/kg) in rats pretreated with 3-methylcholanthrene. The aforementioned data indicate that CYP1A is involved in the metabolism of 5-fluorouracil in rats.

Background and purpose: The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.

We previously reported that arctigenin, a lignan isolated from the bark of Torreya nucifera, showed significant neuroprotective activity against glutamate-induced toxicity in primary cultured rat cortical cells. In this study, the mode of action of arctigenin was investigated using primary cultures of rat cortical cells as an in vitro system. Arctigenin significantly attenuated glutamate-induced neurotoxicity when added prior to or after an excitotoxic glutamate challenge. The lignan protected cultured neuronal cells more selectively from neurotoxicity induced by kainic acid than by N-methyl-D-aspartate. The binding of [(3)H]-kainate to its receptors was significantly inhibited by arctigenin in a competitive manner. Furthermore, arctigenin directly scavenged free radicals generated by excess glutamate and successfully reduced the level of cellular peroxide in cultured neurons. These results suggest that arctigenin exerted significant neuroprotective effects on glutamate-injured primary cultures of rat cortical cells by directly binding to kainic acid receptors and partly scavenging of free radicals.

Cloning by nuclear transfer (NT) has been riddled with difficulties: most clones die before birth and survivors frequently display growth abnormalities. The cross-species similarity in abnormalities observed in cloned fetuses/animals leads us to suspect the fidelity of epigenetic reprogramming of the donor genome. Here, we found that single-copy sequences, unlike satellite sequences, are demethylated in pre-implantation NT embryos. The differential demethylation pattern between genomic sequences was confirmed by analyzing single blastocysts. It suggests selective demethylation of other developmentally important genes in NT embryos. We also observed a reverse relationship between methylation levels and inner cell mass versus trophectoderm (ICM/TE) ratios, which was found to be a result of another type of differential demethylation occurring in NT blastocysts where unequal methylation was maintained between ICM and TE regions. TE-localized methylation aberrancy suggests a widespread gene dysregulation in an extra-embryonic region, thereby resulting in placental dysfunction familiar to cloned fetuses/animals. These differential demethylations among genomic sequences and between differently allocated cells produce varied overall, but specified, methylation patterns, demonstrating that epigenetic reprogramming occurs in a limited fashion in NT embryos.

We examined whether porcine nuclear transfer (NT) embryos carrying somatic cells have a developmental potential and NT embryos carrying transformed fibroblasts express transgenes in the preimplantation stages. In Experiment 1, different activation methods were applied to NT embryos and the development rates were examined. Relative to A23187 only or A23187/6-DMAP, electrical pulse made a significant increase in both cleavage rate (58.1+/-13.9 or 60.7+/-6.3 vs. 74.9+/-7.5%) and development rate of NT embryos to the blastocyst stage (2.2+/-2.8 or 2.2+/-1.5 vs. 11.0+/-4.1%). In Experiment 2, in vitro developmental competence of NT embryos was investigated. The developmental rate to the blastocyst stage of NT embryos (9.9+/- 2.4% for cumulus cells and 9.8+/-1.6% for fibroblast cells) was significantly lower than that (22.9+/-3.5%) of IVF-derived embryos (P

The pharmacokinetics of SP-8203, a potential protective agent for the treatment of cerebral infarction, were evaluated after its intravenous (10, 20 and 30 mg/kg) and oral (10, 20, 30 and 100 mg/kg) administration in rats. After the intravenous administration of SP-8203, the AUCs of SP-8203 were dose-dependent; the dose-normalized AUCs were significantly greater with increasing doses. After the oral administration of SP-8203, plasma concentrations of SP-8203 were much lower than those after intravenous administration. This could be due to considerable hepatic and intestinal metabolism and the high percent of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h as unchanged drug.

Cystic lymphangioma of the breast is a rare benign lymphatic tumor. We report sonographic and mammographic findings in an unusual case in a 36-year-old woman. © 1999 John Wiley & Sons, Inc. J Clin Ultrasound 27:351–352, 1999.

In our search for cytotoxic compounds from marine animals we have isolated representatives from various classes of nitrogen-containing compounds, most of which show cytotoxic activity. Structure elucidation of these compounds is discussed. Included among the isolates are new acylated spermidines, polycyclic aromatic alkaloids related to amphimedine and 2-bromoleptoclinidinone, and a representative of a novel sulfur containing 3,5,8-isoquinolinetrione.

Due to advances in medicine and economic development, the percentage of Korean elderly is increasing markedly. If preparation is not made for the coming aged society, there is a possibility that the development of the Korean nation will be hindered. The increase in the number of the elderly is increasing the social/national burden of providing medical care for the elderly. Meanwhile, with the trend toward the nuclear family, the increase of female participation in social activities, and the increase of elderly who live alone, it is difficult for nursing homes alone to solve the problem of providing support for the elderly. Long-term medical treatment and care of the elderly has become the responsibility of both the government and society. Under these conditions, the Korean policy for elderly patients can be classified broadly into home care, community care, and institutional care. In order to prepare for the aged society, deficient facilities need to be supplemented and home care and community care need to be expanded so as to increase the communities’ ability to support the elderly . Homes, communities, government and the private sector should work together to provide integrated welfare and health care to the elderly.