• Journal of Pharmaceutical Investigation
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• v.37 no.5
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• pp.315-321
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• 2007

The purpose of the present study was to evaluate the bioequivalence of two lercanidipine hydrochloride tablets, Zanidip tablet (LG Life Sciences Ltd., Korea, reference drug) and Samchundang Lercanidipine tablet 10 mg (Sam Chun Dang Pharm. Co. Ltd., Korea, test drug), according to the guidelines of Korea Food and Drug Administration (KFDA). After adding an internal standard (amlodipine maleate) to human serum, serum samples were extracted using hexan-isoamyl alcohol (100:1, v/v). Compounds were analyzed by liquid chromatography/tandem mass spectrometry. This method showed linear response over the concentration range of 0.05-20 ng/mL with correlation coefficient of 0.9999. The lower limit of quantitation using 0.5 mL of serum was 0.05 ng/mL which was sensitive enough for pharmacokinetic studies. Thirty healthy male Korean volunteers received each medicine at the lercanidipine hydrochloride dose of 20 mg in a $2\;{\times}\;2$ crossover study. There was a one-week washout period between the doses. Serum concentrations of lercanidipine were monitored by an LC/MS/MS fer over a period of 24 hr after the administration. $AUC_t$ (the area under the serum concentration-time curve from time 0 to 24 hr) was calculated by the linear trapezoidal rule method. $C_{max}$ (the maximum serum drug concentration) and $T_{max}$ (the time to reach $C_{max}$) were compiled from the serum concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_t$ and $C_{max}$. No significant sequence effect was found for all of the bioavailability parameters, indicating that the crossover design was properly performed. The 90% confidence intervals of the $AUC_t$ ratio and the $C_{max}$ ratio for Samchundang Lercanidipine/Zanidip were log 0.9505-log 1.2258 and log 0.9987-log 1.2013, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Samchundang Lercanidipine tablet 10 mg and Zanidip tablet are bioequivalent.

• Journal of Pharmaceutical Investigation
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• v.40 no.2
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• pp.109-115
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• 2010

The purpose of the present study was to evaluate the bioequivalence of two choline alphoscerate soft capsules, Gliatilin soft capsule (Daewoong Pharmaceuticals Co., Ltd.) and Cholicerin soft capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Serum concentrations of choline after oral administration of choline alphoscerate were determined using a validated LC/MS/MS method. This method showed linear response over the concentration range of 0.5-20 ${\mu}g$/mL with correlation coefficient of 0.9999. The lower limit of quantitation using 100 ${\mu}L$ of serum was 0.5 ${\mu}g$/mL which was sensitive enough for pharmacokinetic studies. Thirty six healthy male Korean volunteers received each medicine at the choline alphoscerate dose of 1200 mg in a $2{\times}2$ crossover study. There was a one-week washout period between the doses. Blood samples were taken at predetermined time intervals up to 8 hr. $AUC_t$ (the area under the serum concentration-time curve from time 0 to 8 hr) was calculated by the linear trapezoidal rule method. $C_{max}$ (the maximum serum drug concentration) and $T_{max}$ (the time to reach $C_{max}$) were compiled from the serum concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_t$ and $C_{max}$. No significant sequence effect was found for all of the bioavailability parameters, indicating that the crossover design was properly performed. The 90% confidence intervals of the $AUC_t$ ratio and the $C_{max}$ ratio for Cholicerin/Gliatilin were log0.9998-log1.1172 and log0.9938-1.0944, respectively. These values were within the acceptable bioequivalence intervals of log0.80-log1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Cholicerin soft capsule and Gliatilin soft capsule are bioequivalent.

• Journal of Pharmaceutical Investigation
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• v.40 no.2
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• pp.101-107
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• 2010

A rapid and sensitive reversed-phase high performance liquid chromatography (HPLC) method was developed for the determination of N-(-4-Chlorophenyl)-6-hydroxy-7-methoxy-2-chromanecarboxamide (KAL-1120), a novel anti-inflammation agent, in the rat plasma. The method was applied to analyze the compound in the biological fluids such as bile, urine and tissue homogenates. After liquid-liquid extraction, the compound was analyzed on an HPLC system with ultraviolet detection at 275 nm. HPLC was carried out using reversed-phase isocratic elution with a $C_{18}$ column, a mobile phase of a mixture of acetonitril (40 v/v%) at a flow rate of 1.0 mL/min. The chromatograms showed good resolution and sensitivity and no interference of plasma. The calibration curve for the drug in plasma was linear over the concentration range of 0.05-50 ${\mu}g$/mL. The intra- and inter-day assay accuracies of this method ranged from 0.06% to 9.33% of normal values and the precision did not exceed 6.28% of relative standard deviation. The plasma concentration of KAL-1120 decreased to below the quantifiable limit at 1.5 hr after the i.v. bolus administration of 2-10 mg/kg to rats ($t_{1/2,({\alpha})}$ and $t_{1/2,({\beta})$ of 2.15 and 26.7 min at a dose of 2 mg/kg, 3.91 and 33.0 min at a dose of 10 mg/kg, respectively). The steady-state volume of distribution ($V_{dss}$) and the total body clearance ($CL_t$) were not significantly altered in rats given doses from 2 to 10 mg/kg. Of the various tissues tested, KAL-1120 was mainly distributed in the lung and heart after i.v. bolus administration. KAL-1120 was detected in the bile by 30 min after its i.v. bolus administration. However, the concentration in the urine after i.v. bolus administration became too low to measure, suggesting that KAL-1120 is mostly excreted in the bile. In conclusion, this analytical method was suitable for the preclinical pharmacokinetic studies of KAL-1120 in rats.

• Journal of Food Hygiene and Safety
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• v.5 no.1
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• pp.7-12
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• 1990

The disposition of Brazilin including plasma concentration-time profiles, excretions via urine and bile, and plasma protein binding was investigated after intravenous or oral administration of radio labeled Brazilin ($^3H-Brazilin$) to male Wistar rats. The main pharmac:okinetic parameters were as follows; $t\;_{ 1/2}$, 13.71 hr; AUC, $53.38\;\mu\textrm{g}{\cdot}hr/ml$; AUMC, $1013.4I\;\mu\textrm{g}{\cdot}hr^2/ml$, MRT, 18.95 hr; Vss, 17778 mllkg and CL, 936.77 ml/hr.kg. The 2nd peak was found in the plasma concentration-time profiles indicating potential enterohepatic circulation. The enterohepatic circulation was supported by the bile excretion. After oral administration, about 64.4 % of administered radioactivity was excreted into the bile within 10 hours and its excretion rate reached maximum at 3 hours after administration. The Vss was extremely high, 17.8 l/kg indicating distribution of brazilin in most organs (tissues) with high concentration of brazilin in some organs. Brazilin was distributed into most of organs (spleen, adrenal, pancreas, kidney, thymus, lung, heart, liver, prostate, epididymus, testis, fat, muscle and done) except brain. High concentration of Brazilin was detected especially in liver, kidney, epididymus and testis. Approximately, 62.9% and 44.1% of the dose was excreted for intravenous and oral administration, respectively. About 80% of the dose eventually excreted into urine was excreted within 24 hr after dosing. Plasma protein binding of brazilin resulted in $40\;{\pm}\;4%$ by ultrafiltration method.

• Journal of Ginseng Research
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• v.44 no.2
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• pp.247-257
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• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• Journal of Ginseng Research
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• v.26 no.3
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• pp.111-131
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• 2002

Korean ginseng (Panax ginseng C.A. Meyer) received a great deal of attention from the Orient and West as a tonic agent, health food and/or alternative herbal therapeutic agent. However, controversy with respect to scientific evidence on pharmacological effects especially, evaluation of clinical efficacy and the methodological approach still remains to be solved. Author reviewed those articles published since 1980 when pharmacodynamic studies on ginseng have intensively started. Special concern was paid on metabolic disorders including diabetes mellitus, circulatory disorders, malignant tumor, sexual dysfunction, and physical and mental performance to give clear information to those who are interested in pharmacological study of ginseng and to promote its clinical use. With respect to chronic diseases such as diabetes mellitus, atherosclerosis, high blood pressure, malignant disorders, and sexual disorders, it seems that ginseng plays preventive and restorative role rather than therapeutics. Particularly, ginseng plays a significant role in ameliorating subjective symptoms and preventing quality of life from deteriorating by long term exposure of chemical therapeutic agents. Also it seems that the potency of ginseng is mild, therefore it could be more effective when used concomitantly with conventional therapy. Clinical studies on the tonic effect of ginseng on work performance demonstrated that physical and mental dysfunction induced by various stresses are improved by increasing adaptability of physical condition. However, the results obtained from clinical studies cannot be mentioned in the indication, which are variable upon the scientist who performed those studies. In this respect, standardized ginseng product and providing planning of the systematic clinical research in double-blind randomized controlled trials are needed to assess the real efficacy for proposing ginseng indication. Pharmacological mode of action of ginseng has not yet been fully elucidated. Pharmacodynamic and pharmacokinetic researches reveal that the role of ginseng not seem to be confined to a given single organ. It has been known that ginseng plays a beneficial role in such general organs as central nervous, endocrine, metabolic, immune systems, which means ginseng improves general physical and mental conditons. Such multivalent effect of ginseng can be attributed to the main active component of ginseng,ginsenosides or non-saponin compounds which are also recently suggested to be another active ingredients. As is generally the similar case with other herbal medicines, effects of ginseng cannot be attributed as a given single compound or group of components. Diversified ingredients play synergistic or antagonistic role each other and act in harmonized manner. A few cases of adverse effect in clinical uses are reported, however, it is not observed when standardized ginseng products are used and recommended dose was administered. Unfavorable interaction with other drugs has also been suggested, which the information on the products and administered dosage are not available. However, efficacy, safety, interaction or contraindication with other medicines has to be more intensively investigated in order to promote clinical application of ginseng. For example, daily recommended doses per day are not agreement as 1-2g in the West and 3-6 g in the Orient. Duration of administration also seems variable according to the purpose. Two to three months are generally recommended to feel the benefit but time- and dose-dependent effects of ginseng still need to be solved from now on. Furthermore, the effect of ginsenosides transformed by the intestinal microflora, and differential effect associated with ginsenosides content and its composition also should be clinically evaluated in the future. In conclusion, the more wide-spread use of ginseng as a herbal medicine or nutraceutical supplement warrants the more rigorous investigations to assess its effacy and safety. In addition, a careful quality control of ginseng preparations should be done to ensure an acceptable standardization of commercial products.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.205-212
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• 2001

Background : The information on nasal transport and the metabolism of peptides have been obtained from pharmacokinetic investigations in experimental animals. However, there are no transport and metabolic studies of human nasal epithelial cells. In this study, the permeability characteristics and the metabolic properties of in vitro human nasal cell monolayers were investigated. Material and Methods : Normal human inferior nasal conchal tissue samples were obtained from patients undergoing endoscopic nasal cavitary surgery. The specimens were cultured in a transwell using an air-liquid Interface (ALI) culture, and the transepithelial electrical resistance (TEER) value of the blank filter and confluent cell monolayers were measured. To determine the % leakage of mannitol, $4{\mu}mol%$ $^{14}C$-labelled mannitol was added and the % leakage was measured every 10 minute for 1 hour. Result : Human nasal epithelial cells in the primary culture grew to a confluent monolayer within 7 days and expressed microvilli. The tight junction between the cells was confirmed by transmission electron microscopy. The TEER value of the blank filter, fifth day and seventh day reached $108.5\;ohm.cm^2$, $141\;ohm.cm^2$ and $177.5\;ohm.cm^2$, respectively. Transcellular % leakage of the $^{14}$-mannitol at 10, 20, 30, 40, 50 and 60 minutes was $35.67{\pm}5.43$, $34.42{\pm}5.60$, $32.75{\pm}5.71$, $31.76{\pm}4.22$, $30.96{\pm}3.49$ and $29.60{\pm}3.68\;%$, respectively. Conclusion : The human nasal epithelial monolayer using ALI culture techniques is suitable for a transcellular permeability study. The data suggests that human nasal epithelial cells In an ALI culture technique shows some promise for a nasal transport and metabolism study.

• Tuberculosis and Respiratory Diseases
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• v.52 no.2
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• pp.128-136
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• 2002

Background: There are few studies that have reported on the pharmacokinetic(PK) disposition of fluoroquinolones in patients with multi-drug resistant tuberculosis(MDR-Tb), even though fluoroquinolones are frequently co-prescribed to those patients. In this study, the PK disposition of ofloxacin, a fluoroquinolone, was evaluated in patients with MD R -Tb. Methods: Twenty patients with MDR-Tb were given 2nd line Tb drugs including ofloxacin (300mg twice a day), prothionamide, cycloserine, para-aminosalicylic acid, kanamycin, and streptomycin. The patients were grouped according to their body mass index(BMI) as an index of emaciation (group A : 18.5$\leq$BMI <23, group B : BMI < 18.5). Blood samples were serially drawn and urine samples were collected upto 24 hours after the last dose of those drugs at steady state (over 1 month). The ofloxacin concentrations were determined using HPLC (High Performance Liquid Chromatography). Results: The AUC of ofloxacin in group B was greater than that in group A ($31.4{\pm}8.9{\mu}g/ml{\cdot}h$ vs. $24.1{\pm}6.2{\mu}g/ml{\cdot}h$)(Check the symbols), (p<0.05). The total clearance(Cl/F) of ofloxacin was $0.16{\pm}0.03$ L/h/kg in group A, and $0.14{\pm}0.03$ L/h/kg in group B. The half-lives of ofloxacin in two groups were similar (group A : $5.3{\pm}0.8$ hours, group B : $5.7{\pm}0.9$ hours). In addition, the other PK parameters in two groups were also similar. Conclusions: The pharmacokinetics of ofloxacin in patients with MDR-Tb appears to be comparable with those of normal subjects, and the extent of emaciation appears to have an influence on the pharmacokinetics of ofloxaicn in chronic debilitated MDR-Tb patients.