• Korean Journal of Clinical Pharmacy
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• v.20 no.3
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• pp.235-241
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• 2010

Bambuterol hydrochloride, dimethylcarbamic acid 5-[2-(1,1-dimethylethyl)amino-1-hydroxyethyl]-1,3-phenylene ester hydrochloride, is the prodrug of active ${\beta}_2$-adrenergic metabolite terbutaline. The purpose of the present study was to evaluate the bioequivalence of two bambuterol hydrochloride tablets, $Bambec^{(R)}$ tablet 10 mg (Yuhan Co., Ltd.) and Bambucol tablet 10 mg (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). In vitro release of bambuterol from two bambuterol hydrochloride formulations was tested using KP VIII Apparatus II method with various dissolution media. Twenty eight healthy male Korean volunteers, $23.86{\pm}1.65$ years in age and $68.98{\pm}9.58$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After two tablets containing 10 mg as bambuterol hydrochloride were orally administered, blood samples were taken at predetermined time intervals, and the concentrations of bambuterol in serum were determined using column switching HPLC with UV detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated, and ANOVA test with K-BE Test 2002 was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$, $C_{max}$ and untransformed $T_{max}$. The results showed that the differences between two formulations based on the reference drug, $Bambec^{(R)}$, were -8.10%, -3.82% and 12.65% for $AUC_t$, $C_{max}$ and $T_{max}$, respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (i.e., log 0.8093~log 1.0302 and log 0.8564~log 1.1280 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Bambucol tablet 10 mg was bioequivalent to $Bambec^{(R)}$ tablet 10 mg.

• Herbal Formula Science
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• v.21 no.1
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• pp.99-110
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• 2013

Objectives : This study was designed to investigate the effect of a herbal preparation HJ01 consisting of Salicornia herbacea, Citri Reticulatae Pericarpium, Crataegi Fructus and Glycyrrhizae Radix on adipocyte differentiation in OP9 cells and on poloxamer 407(P-407)-induced hyperlipidemia in mice. Methods : 1. MTT assay was used to evaluate the potential cytotoxicity of Salicornia herbacea, Citri Reticulatae Pericarpium, Crataegi Fructus, Glycyrrhizae Radix and HJ01, respectively. 2. Bone-marrow derived OP9 cells were treated with HJ01, and the alterations in fat storage in the cells were determined by the Oil red O assay. 3. The protein level of CAAAT/enhancer binding protein alpha($C/EBP{\alpha}$), as a adipocyte differentiation marker, was examined using western blot analysis in differentiated OP6 cells. 4. Adult male C57BL6 mice received intraperitoneal injections of P407 to induce hyperlipidemia, simultaneously, were treated with HJ01 for 4 weeks. Then the cholesterol (TC), triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-c) levels in sera and liver tissues were measured. Results : 1. The MTT assay exhibited that Salicornia herbacea, Citri Reticulatae Pericarpium, Crataegi Fructus, Glycyrrhizae Radix and HJ01 showed no significant cytotoxicity in tested dosages. 2. Ten days' treatment with HJ01 markedly inhibited the increases in fat storage in differentiated OP6 cells. 3. Four weeks' treatment with HJ01 down-regulated the protein level of CAAAT/enhancer binding protein alpha($C/EBP{\alpha}$) but up-regulated the levels of adiponectin in differentiated OP9 cells. 5. HJ01 inhibited the accumulation of TC and TG in liver tissues and increased serum levels of TC in hyperlipidemic mice. Conclusions : These results suggest that HJ01 can in vitro inhibit adipocyte differentiation and fat storage in OP6 cells, in vivo improve the hyperlipidemia induced by P-407 in mice, which may be mediated by promoting glucose uptake and improving a lipid metabolite profile.

• Korean journal of applied entomology
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• v.51 no.3
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• pp.245-253
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• 2012

Benzylinedeneacetone (BZA) is a bacterial metabolite which is synthesized by at least two entomopathogenic bacteria, namely Xenorhabdus nematophila and Photorhabdus temperata subsp. temperata. It has been shown to possess inhibitory effects on insect cellular and humoral immune responses as well as antimicrobial activities against various species of bacteria and fungi. However, its relatively high phytotoxicity, and nonsystematic effect have thus far prevented its development into an optimal pesticide. This study screened five different BZA derivatives in order to select an optimal compound, which would have relatively high solubility and low phytotoxicity while retaining sufficient degrees of the immunosuppressive and antimicrobial activities associated with BZA. Hydroxylation of the benzene ring of BZA was found to significantly suppress its immunosuppressive and antimicrobial activities. Transformation of the ketone of BZA by carboxylation also suppressed the inhibitory activities. However, a shortening of the aliphatic chain of BZA into acetate form (4-hydroxyphenylacetic acid: HPA) did not decrease the inhibitory activity. HPA also showed much less phytotoxicity against the hot pepper plant Capsicum annuum, when compared to BZA. This study identified an optimal BZA derivative, which exhibited relatively little phytotoxicity, but retained a high degree of inhibitory activity to suppress insect immune responses and antimicrobial activities against plant pathogens.

• Journal of Korean Society of Forest Science
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• v.101 no.4
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• pp.640-647
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• 2012

A metabolomic study was conducted to identify key metabolic components, which are correlated with the growth of 4-year-old Pinus koraiensis seedlings harvested at actively height growing season (May 18th). Among 105 individual metabolites identified by GC/MS analysis, alanine, threonine, oleic acid, and butanoic acids were negatively correlated with both height and weight of 4-year-old seedlings, while malic acid, xylose, glucose, d-turanose and inositol had positive correlation with various growth parameters. During the actively growing season, the concentrations of both amino acids and organic acids in the main stem of Superior seedling group were lower but the photosynthates such as mono-saccharide and sucrose were higher than in other seedling groups such as Intermediate and Inferior. Interestingly, d-turanose, an analogue of sucrose that is not metabolized in higher plants but used as carbon source by many organisms including numerous species of bacteria and fungi, showed the highest correlation (r=0.896, p<0.001) with height of 4-year-old seedlings, indicating that possible interaction with mycorrhizal organisms. Therefore we suggest that several metabolites selected in this study may be used as metabolic markers for complex traits in P. koraiensis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3335-3341
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• 2014

Background: Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11) UDPglucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but the relationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guide clinical use of CPT-11. Materials and Methods: 89 cancer patients with advanced disease received CPT-11-based chemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail and UGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variables and tumor response. Results: The prevalence of grade III-IV diarrhea was 10.1%, this being more common in patients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropenia was 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance (p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, $12.75{\mu}mol/L$) with compared to TA6/6 (mean, $9.92{\mu}mol/L$) with p<0.05. Conclusions: Our study support the conclusion that patients with a $UGT1A1^*28$ allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whether with mid-or low-dosage. However, the $UGT1A1^*28$ allele (s) did not increase severe neutropenia. Higher serum total bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usage of CPT-11.

• Analytical Science and Technology
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• v.23 no.5
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• pp.437-445
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• 2010

The aim of this study was to develop an analytical method for sulfonamide antibiotics (sulfadiazine, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfathiazole) and their metabolites ($N^4$-acetylsulfadiazine, $N^4$-acetylsulfamerazine, $N^4$-acetylsulfamethazine, $N^4$-acetylsulfamethoxazole, sulfamethoxazole-$N^1$-glucuronide) in environmental samples. The solid phase extraction (SPE) with LC/ESI-MS/MS have been used for the analysis of target compounds, and the recoveries of SPE clean-up were at the range of 12-94% for C18 cartridge, 60-95% for HLB cartridge, 25-123% for MCX cartridge, and 70-90% for tandem HLB/MCX. By established method, detection limit, recovery, and relative standard deviation were 0.001~0.187 ng/mL, 66~115%, and 5~17%, respectively. This method was effective and sensitive to use for the simultaneous determination of sulfonamide antibiotics and their metabolites in environmental samples. Four sulfonamide antibiotics were detected at the range of 0.008~2.153 ng/mL. For metabolites, only $N^4$-acetylsulfamethoxazole was detected, but the concentration was under the MDL level.

• Biomolecules & Therapeutics
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• v.26 no.5
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• pp.512-519
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• 2018

Phthalates widely used in the manufacture of plastics have deeply penetrated into our everyday lives. Recently, a concern over the toxicity of phthalates on thyroid, has been raised but in most of cases, the doses employed were unrealistically high. To investigate the effects of phthalates on thyroid, we investigated the effects of the repeated oral exposure to low to high doses (0.3, 3, 30 and 150 mg/kg) di-2-ethylhexylphthalate (DEHP) from weaning to maturity for 90 days in juvenile rats on the thyroid. The histological examination revealed that DEHP significantly induced hyperplasia in the thyroid from the doses of 30 mg/kg, which was confirmed with Ki67 staining. In line with this finding, increased mRNA expression of thyrotropin releasing hormone (Trh) was observed in the thyroid of female at 0.3 mg/kg and 150 mg/kg as determined by RNAseq analysis. Moreover, significantly increased expression of parathyroid hormone (Pth) in the female at 0.3 mg/kg, and thyroglobulin (Tg) and thyroid hormone responsive (Thrsp) in the male at 0.3 mg/kg were noted in the blood, of which changes were substantially attenuated at 150 m/kg, alluding the meaningful effects of low dose DEHP on the thyroid hormone regulation. Urinary excretion of mono-2-ethylhexyl-phthalate (MEHP), a major metabolite of DEHP was determined to be 4.10 and 12.26 ppb in male, 6.65 and 324 ppb in female at 0.3 and 30 mg/kg DEHP, respectively, which fell within reported human urine levels. Collectively, these results suggest a potential adverse effects of low dose phthalates on the thyroid.

• Analytical Science and Technology
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• v.23 no.2
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• pp.179-186
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• 2010

The oxidative metabolism of ibuprofen in healthy male urine collected at 3, 6, 9, 12 and 15 h after oral administration of ibuprofen was studied by GC/MS assay. To detect conjugated metabolites of ibuprofen, urine sample was acid-hydrolyzed with 6 M HCl at $100^{\circ}C$ for 30 min. To effectively extract ibuprofen and its metabolites, liquid-liquid extraction (LLE) was conducted at pH 3, 5, and 7, respectively. As a result, LLE at pH 3 was shown to be the best extraction condition. For the determination of trace amounts of ibuprofen and its metabolites in extract, trimethylsilylation (TMS) with BSTFA was applied and followed by GC/MS analysis. In this study, main 5 metabolites including parent drug were detected and these metabolites were assigned as three hydroxylated forms and one carboxylated form. Each metabolite was tentatively identified by both interpretation of mass spectrum and comparison with previously reported results. In addition, time profile of urinary excretion rate for parent drugs and metabolites was studied. Finally, the metabolic pathways of ibuprofen were suggested on the basis of the structural elucidation of its metabolites and excretion profiles.

• Korean Journal of Food Science and Technology
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• v.33 no.6
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• pp.656-663
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• 2001

The most representative nitrosamine derived from nicotine, nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), has been reported to cause lung cancer in A/J mice. It has been also demonstrated that NNK-induced lung tumorigenesis involves $O^6-methylguanine(O^6MeG)$ formation, leading to $GC\;{\rightarrow}\;AT$ transitional mispairing during DNA replication. Our in vitro experiment, modified from the method of DBA assay, examined the ability of phyto-extract mixture to inhibit the metabolism of nicotine to nitrosamines. The production of nitromorpholine from morpholine was inhibited about 75% at the concentration of 20 mg/mL of phyto-extract mixture, which was lower than vitamine C and green tea powder. NNK, which is a pro-carcinogen in laboratory animals, is hydroxylated primarily in liver and lung by CYP 1A2, 2A6 and 3A4. A critical phase. of NNK activation is its change to an unstable metabolite methyl-diazohydroxide via CYP-mediated ${\alpha}-hydroxylation$; and then it provides a methyl group to the DNA to form DNA adducts which can easily induce mutations. $Aroclor^R$ 1254 was used to induce CYPs in the liver of a Sprague-Dawley rat. The ability of various test samples to inhibit CYPs that participate in NNK activation was evaluated, following the removal of the liver from the rat. Microsomal CYPlA2 catalyzing the conversion of NNK into strong carcinogenic chemicals was inhibited more efficiently by phyto-extract mixture than green tea powder. These results indicate that phyto-extract mixture can be used to reduce $O^6MeG$ DNA adducts for chemoprevention.

• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.122-132
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• 1998

SB-31 which contains Pursatilla, Licoris and Ginseng extracts was recently proved as an anticancer agent. In a preclinical effort to be applied this drug to human, pharmacokinetics of SB-31 was carried out in rats and rabbits. Glycyrrhizin(GZ), a saponin of Licoris was used as a standard ingradient for the pharmacokinetics of SB-31. The rat's blood, bile and urine samples were serially collected in femoral vein, common bile duct and bladder, respectively, after bolus i.v. injection at a dose of 1 or 1/5 ampul/rat and rabbit's blood samples from the marginal ear vein at a dose of 1 or 3 amp./rabbit. GZ and glycyrrhetic acid(GA), a major metabolite of GZ in the physiological samples were analysed by HPLC with UV detection. The decline of GZ in plasma concentration was generally biexponential at each dose. GZ was almost completely recovered in bile within 18 hour. GA wasn't detected in the samples with UV detector. In the rat, Vss and Kel at a dose of 1 and 1/5 ampul of SB-31 were $98.06\pm6.07\;ml,\;0.33\pm0.05\;hr^{-1}\;and\;65.46\pm11.19\;ml,\;0.68\pm0.25\;hr^{-1}$, respectively. Those in rabbits at a dose of 3 and 1 ampul of SB-31 were $235.24\pm30.72\;ml,\;0.13\pm0.36\;hr^{-1}\;and\;341.32\pm28.58\;ml,\;0.27\pm0.04\;hr^{-1}$, respectively. 'WinNonlin' was utilized for the compartmental analysis. A two-compartment model was chosen as the most appropriate pbarmaco-kinetic model. The data were best described by using a weighting factor of $1/y^2$. To evaluate the effect of SB-31 on cardiovascular system, serially diluted SB-31 was directly injected into coronary artery in the isolated perfused rat heart and the effect of PSF, PSH, saponins of Pursatilla, and SB-31 on PT, APTT of healthy human plasma was examined. Except the positive inotropic effect of ten times diluted solution of SB-31, there was no significant effect on LVDP, (- dp/dt)/(+dp/dt), heart rate and coronary flow in comparision with that of vehicle. SB-31 had no effect on PT but slightly delayed APTT about $6.9{\sim}11.5\%$. There was no significant effect of PSF and PSH on PT & APTT. Conclusively, SB-31 did not show any notable toxic effects on cardiovascular system.