• Environmental Mutagens and Carcinogens
• /
• v.24 no.1
• /
• pp.15-18
• /
• 2004

There are significant differences in the extent of drug interactions between subjects. The influence of the genetic make up of drug metabolizing enzyme activities (CYP3A5, CYP2C19 and UDP-glucuronosyl transferase) on the pharmacokinetic drug interaction potential were studied in vivo. Nineteen healthy volunteers were grouped with regard to the $CYP3A5^{*}3$ allele, into homozygous wild-type (CYP3A5^{*}1/1^{*}1$, n=6), heterozygous $(CYP3A5^{*}1/^{*}3$, n=6), and homozygous variant-type $(CYP3A5^{*}3/^{*}3$, n=7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days), and also following rifampin pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. For omeprazole and moclobemide pharmacokinetic interaction study 16 healthy volunteers were recruited. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study n, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. In the UGT study pharmacokinetics and dynamics of 2 mg intravenous lorazepam were evaluated before and after rifampin pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. The subjective and objective pharmacodynamic tests were done before and 1, 2, 4, 6, 8, and 12 hrs after lorazepam administration. The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the $CYP3A5^{*}3/^{*}3$ group showed a greater decrease in systemic clearance than the $CYP3A5^{*}1/^{*}1$ group $(8.5\pm3.8$ L/h/70 kg vs. $13.5\pm2.7$ L/h/70 kg, P=0.027). The 1'-hydroxymidazolam to midazolam AUC ratio was also significantly lower in the $CYP3A5^{*}3/^{*}3$,/TEX> group $(0.58\pm0.35,$ vs. $1.09\pm0.37$ for the homozygous wild-type group, P=0.026). The inhibition of moclo-bemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor meta-bolizers, no remarkable changes in the pharmacokinetic parameters were observed. The area under the time-effect curves of visual analog scale(VAS), choice reaction time, and continuous line tracking test results of lorazepam was reduced by 20%, 7%, 23% respectively in induced state, and in spite of large interindividual variablity, significant statistical difference was shown in VAS(repeated measures ANOVA, p=0.0027).

• Progress in Medical Physics
• /
• v.20 no.4
• /
• pp.235-243
• /
• 2009

The purpose of this experiment is to know the relation of the detection and characterization of liver's diseases as comparison of finding at MR imaging using a Ferucarbotran (SPIO) and Gd-EOB-DTPA (Primovist) agents in diffuse liver disease. A total of 50 patients (25 men and 25 women, mean age: 50 years) with liver diseases were investigated at 3.0T machine (GE, General Electric Medical System, Excite HD) "with 8 Ch body coil for comparison of diseases and contrast's uptake relation, which used the LAVA, MGRE." All images were performed on the same location with before and after Ferucarbotran and Gd-EOB-DTPA administrations (p<0.05). Contrast to noise ratio of Ferucarbotran and Gd-EOB-DTPA in the HCC were $3.08{\pm}0.12$ and $7.00{\pm}0.27$ with MGRE and LAVA pulse sequence, $3.62{\pm}0.13$ and $2.60{\pm}0.23$ in the hyper-plastic nodule, $1.70{\pm}0.09$ and $2.60{\pm}0.23$ in the meta, $2.12{\pm}0.28$ and $5.86{\pm}0.28$ in the FNH, $4.45{\pm}0.28$ and $1.73{\pm}0.02$ in the abscess and ANOVA test was used to evaluate the diagnostic performance of each disease (p<0.05). In conclusions, two techniques were well demonstrated with the relation of the detection and characterization of liver's diseases.

• Korean Journal of Microbiology
• /
• v.46 no.1
• /
• pp.21-26
• /
• 2010

As the causative agent of Anthrax, Bacillus anthracis causes an acute fatal disease in herbivores such as cattle, sheep, and horses as well as humans. The therapeutics and prevention of anthrax currently available are based on antibiotics and the live attenuated vaccine strains, which may be problematic due to the emergency of antibiotic resistant strains or residual virulence in those vaccine strains. Therefore, it has been required to develop novel therapeutics and vaccines which are safer and applicable to humans. Recently, the development of the multivalent vaccine targeting both spores and vegetative cells of B. anthracis along with anthrax toxin has been reported. In our attempts to screen potential candidates for those multivalent vaccines, the whole genomic expression library of B. anthracis was constructed in this study. To the end, the partial digests of the genomic DNA from B. anthracis (ATCC 14578) with Sau3AI were ligated with the inducible pET30abc expression vectors, resulting in approximately $1{\times}10^5$ clones in E. coli BL21(DE3). The redundancy test by DNA nucleotide sequencing was performed for the randomly selected 111 clones and found 56 (50.5%) B. anthracis genes, 17 (15.3%) vector sequences, and 38 (34.2%) unknown genes with no sequence homology by BLAST. An inducible expression of the recombinant proteins was confirmed by Western blot. Interestingly, some clones could react with the antiserum against B. anthracis. These results imply that the whole genomic library constructed in this study can be applied for analyzing the immunomes of B. anthracis.

• Microbiology and Biotechnology Letters
• /
• v.33 no.1
• /
• pp.16-23
• /
• 2005

In order to develop a new microbial fungicide using endophytic bacteria for the control of anthracnoses occurring on various crops, a total of 260 bacterial strains were isolated from fresh tissues of 5 plant species. After they were cultured in broth medium, their antifungal activities were tested for in vivo antifungal activity against cucumber anthracnose caused by Colletotrichum orbiculare. As the results, liquid cultures of 28 strains showed potent antifungal activities more than $90\%$ against cucumber anthracnose. At 3-fold dilutions of liquid cultures, 18 strains inhibited the development of cucumber anthracnose of more than $70\%$. They were further tested for in vivo antifungal activity against red pepper anthracnose caused by C. coccodes and in vitro antifungal activity against C. acutatum, a fungal agent causing red pepper anthracnose. Among 18 strains, a bacterial strain EB215 isolated from cucumber roots displayed the most potent antifungal activity against Colletotrichum species. It was identified as Burkholderia cepacia based on its physiological and biochemical characteristics, Biolog test and 16S rDNA gene sequence. It also controlled effectively the development of rice blast (Magnaporthe grisea), rice sheath blight (Corticium sasaki), tomato gray mold (Botrytis cinerea), and tomato late blight (Phytophthora infestans). Studies on the characterization of antifungal substances produced by B. cepacia EB215 are in progress.

• Journal of Pharmaceutical Investigation
• /
• v.34 no.1
• /
• pp.49-55
• /
• 2004

To develop a aceclofenac soft capsule, four preparations with various solubilizers were prepared and their dissolution test was carried out. Among four preparations tested, a preparation with ethanolamine was selected as a formula of aceclofenac soft capsule (Clanza $S^{TM}$), since it showed the fastεst dissolution rate. Bioequivalence of aceclofenac tablet, $Airtal^{TM}$ (Dae-Woong Pharmaceutical Co., Ltd.) and aceclofenac soft capsule, Clanza $S^{TM}$ (Korea United Pharmaceutical Co., Ltd.) was evaluated according to the guideline of KA Fourteen normal male volunteers (age 20 - 25 years old) were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After oral administration of one tablet or capsule containing 100 mg of aceclofenac, blood was taken at predetermined time intervals and the concentration of aceclofenac in plasma was determined with an HPLC method under UV detector The pharmacokinetic parameters ($C_{max}$ and $AUC_t$) were calculated and ANOVA was utilized for the statistical analysis of parameters using logarithmetically transformed $AUC_t$, $C_{max}$ and $T_{max}$. The results showed that the differences in $AUC_t$, $C_{max}$ and $T_{max}$ between Aral tablet and Clanza soft capsule were 2.89%, 0.18% and 43.0%, 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(15) (e.g. log(0.81) -log(1.23) ad log(0.89) -log(1.4)) fo $AUC_t$ and $C_{max}$, respectively. Thus, the criteria of the KFDA guidelines for the equivalence was satisfied, indicating that Clanza $S^{TM}$ soft capsule is bioequivalent to$Airtal^{TM}$ tablet.

• Microbiology and Biotechnology Letters
• /
• v.37 no.4
• /
• pp.389-398
• /
• 2009

Development of expression vectors is important for the basic and applied researches on kimchi LAB (lactic acid bacteria). An expression vector, pSJE6c was constructed by inserting P6C promoter sequence from Lactococcus lactis into pSJE, a shuttle vector for E. coli and Leuconostoc species. To test the efficiency of pSJE6c, aga ($\alpha$-galactosidase) and lacZ ($\beta$-galactosidase) genes were expressed in Lactobacillus brevis 2.14. Compared to the pSJE, expression levels of both genes were increased, indicating P6C promoter was better than indigenous promoters. Enzyme activities of L. brevis cells harboring pSJE6caga (pSJE6c with aga) or pSJE6Z (pSJE6c with lacZ) were 1.5-2 fold higher than those with pSJEaga (pSJE with aga) or pSJEZ (pSJE with lacZ). More RNA transcripts were detected in cells harboring pSJE6c based recombinant plasmid. The results indicated that heterologous gene expressions in kimchi LAB could be improved significantly by use of efficient expression vectors.

• Journal of Pharmaceutical Investigation
• /
• v.35 no.3
• /
• pp.179-185
• /
• 2005

Acebrophylline is a compound produced by salifying ambroxol with theophylline-7 -acetic acid. After acebrophylline administration, the salt splits into these two components which feature a peculiar pharmacokinetic behavior, an adequate ambroxol and a low theophylline-7-acetic acid serum levels. The purpose of the present study was to evaluate the bioequivalence of two acebrophylline capsules, Surfolase (Hyundai Pharm. lnd. Co., Ltd.) and Burophil (Kuhnil Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of ambroxol from the two acebrophylline formulations in vitro was tested using KP VIII Apparatus II method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty eight healthy male subjects, $23.25{\pm}1.43$ years in age and $64.82{\pm}6.77$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After two capsules containing 100 mg as acebrophylline were orally administered, blood was taken at predetermined time intervals and the concentrations of ambroxol in serum were determined using HPLC with electrochemical detector (ECD). The dissolution profiles of two formulations were similar at all dissolution media. In addition, the pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated and ANOVA test 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 Surfolase, were -1.64, -3.33 and -0.92% 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 $(e.g., \;log\;0.93{\sim}log\;1.05\;and\;log\;0.88{\sim}log\;1.05$ for $AUC_t$, and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Burophil capsule was bioequivalent to Surfolase capsule.

• Journal of Pharmaceutical Investigation
• /
• v.36 no.3
• /
• pp.209-215
• /
• 2006

Zaltoprofen, (2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid) is an NSAID with powerful anti-inflammatory effects as well as an analgesic action on inflammatory pain. The purpose of the present study was to evaluate the bioequivalence of two zaltoprofen tablets, $Soleton^{\circledR}$ (CJ Corp.) and SCD Zaltoprofen (Samchundang Pharmaceutical Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of zaltoprofen from the two zatoprofen formulations in vitro was tested using KP Vlll Apparatus ll method with various dissolution media. Twenty six healthy male subjects, $23.2{\pm}2.26$ years in age and$64.7{\pm}8.08$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single tablet containing 80 mg as zaltoprofen was orally administered, blood samples were taken at predetermined time intervals and the concentrations of zaltoprofen in serum were determined using 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 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, $Soleton^{\circledR}$ were 6.33, 5.91 and 17.7% for $AUC_t$, $C_{max}$ and untransformed $T_{max}$, 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 (e.g.,log $1.01{\sim}1og\;1.11$ and log $0.928{\sim}1og\;1.18$ for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating SCD Zaltoprofen tablet was bioequivalent to $Soleton^{\circledR}$ tablet.

• Environmental Mutagens and Carcinogens
• /
• v.23 no.4
• /
• pp.131-134
• /
• 2003

There are significant differences in the extent of drug interactions between subjects. The influence of the genetic make up of drug metabolizing enzyme activities (CYP3A5, CYP2C19 and UDP-glucuronosyl transferase) on the pharmacokinetic drug interaction potential were studied in vivo. Nineteen healthy volunteers were grouped with regard to the $CYP3A5^{*}3$ allele, into homozygous wild-type (CYP3A5^{*}1/1^{*}1$, n=6), heterozygous $(CYP3A5^{*}1/^{*}3$, n=6), and homozygous variant-type $(CYP3A5^{*}3/^{*}3$, n=7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days), and also following rifampin pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. For omeprazole and moclobemide pharmacokinetic interaction study 16 healthy volunteers were recruited. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study n, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. In the UGT study pharmacokinetics and dynamics of 2 mg intravenous lorazepam were evaluated before and after rifampin pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. The subjective and objective pharmacodynamic tests were done before and 1, 2, 4, 6, 8, and 12 hrs after lorazepam administration. The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the $CYP3A5^{*}3/^{*}3$ group showed a greater decrease in systemic clearance than the $CYP3A5^{*}1/^{*}1$ group $(8.5\pm3.8$ L/h/70 kg vs. $13.5\pm2.7$ L/h/70 kg, P=0.027). The 1'-hydroxymidazolam to midazolam AUC ratio was also significantly lower in the $CYP3A5^{*}3/^{*}3$,/TEX> group $(0.58\pm0.35,$ vs. $1.09\pm0.37$ for the homozygous wild-type group, P=0.026). The inhibition of moclo-bemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor meta-bolizers, no remarkable changes in the pharmacokinetic parameters were observed. The area under the time-effect curves of visual analog scale(VAS), choice reaction time, and continuous line tracking test results of lorazepam was reduced by 20%, 7%, 23% respectively in induced state, and in spite of large interindividual variablity, significant statistical difference was shown in VAS(repeated measures ANOVA, p=0.0027).

• Tuberculosis and Respiratory Diseases
• /
• v.59 no.3
• /
• pp.298-305
• /
• 2005

Background : Obstructive sleep apnea syndrome (OSAS) is believed to have multifactorial causes. The major risk factors for OSAS are obesity, narrowed upper airways, and abnormal cranial-facial structures. A genetic basis for OSAS has been also suggested by reports of families with many members affected. This study analyzed the HLA typing in patients with OSAS to determine the possible role of genetics in OSAS. Methods : Twenty-five Korean patients with OSAS (1 woman and 24 men; age range 30-66 years) were enrolled in this study. A diagnosis of OSAS was made using full-night polysomnography. The control group consisted of 200 healthy Korean people. Serologic typing of the HLA-A and B alleles was performed in all patients using a standard lymphocyte microcytotoxicity test. Analysis of the polymorphic second exons of the HLA-DRB1 gene was performed using a polymerase chain reaction-sequence specific oligonucleotide probe. Results : The allele frequency of HLA-A11 was significantly lower in patients with OSAS compared with the controls (p<0.05). The HLA-B allele frequencies in the patients and controls had a similar distribution. Analysis of the HLADRB1 gene polymorphisms showed an increased frequency of DRB1*09 in the OSA patients compared with the controls (p<0.05). When the analysis was performed after dividing the OSAS patients according to the severity of apnea, the allele frequency of HLA-DRB1*08 was significantly higher in the severe OSA patients (apnea index >45) than in the controls (p<0.05). Conclusion : This study revealed an association between OSAS and the HLA-A11 and DRB1*09 alleles as well as association between the disease severity and the HLA-DRB1*08 allele in Korean patients. These results suggest that genetics plays an important role in both the development and the disease severity of OSAS.