• Archives of Pharmacal Research
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• v.28 no.7
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• pp.791-798
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• 2005

The hepatoprotective activity of flavonol glycosides rich fraction (F-2), prepared from 70% alcohol extract of the aerial parts of V calcarata Desf., was evaluated in a rat model with a liver injury induced by daily oral administration of $CCl_4$ (100 mg/kg, b.w) for four weeks. Treatment of the animals with F-2 using a dose of (25 mg/kg, b.w) during the induction of hepatic damage by $CCl_4$ significantly reduced the indices of liver injuries. The hepatoprotective effects of F-2 significantly reduced the elevated levels of the following serum enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). The antioxidant activity of F-2 markedly ameliorated the antioxidant parameters including glutathione (GSH) content, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), plasma catalase (CAT) and packed erythrocytes glucose-6-phosphate dehydrogenase (G6PDH) to be comparable with normal control levels. In addition, it normalized liver malondialdehyde (MDA) levels and creatinine concentration. Chromatographic purification of F-2 resulted in the isolation of two flavonol glycosides that rarely occur in the plant kingdom, identified as quercetin-3,5-di-O-$\beta$-D-diglucoside (5) and kaempferol-3,5-di-O-$\beta$-D-diglucoside (4) in addition to the three known compounds identified as quercetin-3-O-$\alpha$-L-rhamnosyl- (${\rightarrow}6$)-$\beta$-D-glucoside [rutin, 3], quercetin-3-O-$\beta$-D-glucoside [isoquercitrin, 2] and kaempferol-3-O-$\beta$-D-glucoside [astragalin, 1]. These compounds were identified based on interpretation of their physical, chemical, and spectral data. Moreover, the spectrophotometric estimation of the flavonoids content revealed that the aerial parts of the plant contain an appreciable amount of flavonoids (0.89%) calculated as rutin. The data obtained from this study revealed that the flavonol glycosides of F-2 protect the rat liver from hepatic damage induced by $CCl_4$ through inhibition of lipid peroxidation caused by $CCl_4$ reactive free radicals.

• Archives of Pharmacal Research
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• v.19 no.2
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• pp.116-121
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• 1996

Antisense oligonucleotides seem to provide a promising new tool for the therapy. Choi et al. (1995) reported antisense phosphorothioate oligonucleotides (PS-ODN, 25 mer) complementary to TGF-.betha. mRNA designed for scar formation inhibitor to eliminate scars, which was caused by undesired collagen deposition due to overexpression of TGF-.betha., in wounded skin. PS-ODN were evaluated in vitro for skin penetration using normal and tape-stripped damaged rat skin. The in vitro skin transports were carried out with partially modified PS-ODN (6S) and fully modified PS-ODN (25S). The cumulative amount of PS-ODN (6S) penetrated through normal rat skin was $0.234{\pm}0.041{\mu}g/cm^2$ and that of tape-stripped damaged rat skin was $1.077{\pm}0.301{\mu}g/cm^2$ over 8 hrs. PS-ODN (25S) can not be found in receptor medium through normal skin due to high molecular weight (Mol.Wt.=8,000) and polyanionic charge. However, the cumulative amount of PS-ODN (25S) penetrated across damaged rat skin in PBS was $0.340{\pm}0.296{\mu}g/cm^2$ over 8 hrs. The absense of dermis raised the cumulative amount of PS-ODN (6S) penetrated through rat skin. And the fluxes of PS-ODN (6S) and PSODN (25S) at 8hrs across damaged rat skin were $134.63{\pm}37.67{\mu}g/cm^2$ h, and $42.50{\pm}36.95ng/cm^2$ h, respectively. While PS-ODN (25S) was stable in 10% heat inactivated fetal bovine serum (FBS) during 24 hrs, PS-ODN (6S) was less stable than PS-ODN (25S), but was markedly stable than unmodified phosphodiester. It is suggested that the cumulative amount of PS-ODN (6S) penetrated through damaged rat skin is larger than that of PS-ODN (25S) since the former is easier to degrade by nuclease than the latter and then is apt to penetrate into skin. Thus, PS-ODN represents a logical candidate for further evaluation due to the potential for delivery into the wounded skin.

• Korean Journal of Clinical Pharmacy
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• v.12 no.2
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• pp.91-95
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• 2002

The pharmacokinetics of intravenous paclitaxel (1 mg/kg) were investigated in rabbits with renal failure induced by folic acid. The area under the plasma concentration-time curve from time zero to time infinity (AUC) of paclitaxel was significantly (p<0.05) greater in rabbits with severe renal failure induced by folic acid $(1030\pm382)$ compared to that in rabbits with in moderate renal failure induced by folic acid $(780\pm209\;ng/ml{\cdot}hr)$. The apparent volume of distribution (Vd) $(0.008\pm0.002\;L/kg)$ and the elimination rate constant $(\beta)\;(0.09\pm0.025\;hr^{-1})$ of paclitaxel in rabbits with severe renal failure were significantly (p<0.05) smaller and slower respectively than those of control rabbits $(0.016\pm0.004\;L/kg,\;0.12\pm0.03\;hr^{-1})$, but not significantly different compared with that in rabbits with moderate renal failure $(0.010\pm0.003\;L/kg,\;0.10\pm0.026\;hr^{-1})$. total body clearance (CL) of paclitaxel in rabbits with severe renal failure $(0.97\pm0.183\;L/hr/kg)$ was significantly (p<0.05) slower than that in control rabbits $(1.68\pm0.440\;L/hr/kg)$, but not significantly different compared with that in rabbits with in moderate renal failure $(1.28\pm0.311\;L/hr/kg)$. The terminal half-life ($t_{1/2}$) of paclitaxel in rabbits with severe renal failure $(7.46\pm2.16\;hr)$ was significantly (p<0.05) longer than that in control rabbits $(5.75\pm1.44\;hr)$, but not significantly different compared to that in rabbits with moderate renal failure rabbits $(6.67\pm1.76\;hr)$. The above data could be at least partly decrease in due to paclitaxel excretion in rabbits with renal failure, since $7-15\%$ of interavenous paclitaxel was excreted via kidney as unchanged forms plus its metablites.

• Korean Journal of Clinical Pharmacy
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• v.12 no.1
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• pp.22-28
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• 2002

Aceclofenac, 2-[(2',6'-dichlorphenyl)amino]phenylacetoxiacetic acid, is a new nonsteroidal anti-inflammatory drug that belongs to the family of phenylacetic acids. It shows good tolerance and potent analgesic/antiinflammatory properties, and acts on cartilaginous chondriocytes, stimulating their repair mechanism. The purpose of the present study was to evaluate the bioequivalence of two aceclofenac products, $Airtal^{TM}$ tablet (Daewoong Pharmaceutical Co.) and $Acer^{TM}$ capsule (Kyungdong Pharmaceutical Co.), according to the guideliner of Korea Food and Drug Administration (KFDA). The aceclofenac release from the two aceclofenac products in vitro was tested using KP VII Apparatus II method at pH 7.8 dissolution media. Sixteen normal male volunteers, $23.13\pm2.03$ years in age and $66.33\pm7.08$ kg in body weight, were divided into two groups and a randomized $2\times2$ cross-over study was employed. After one tablet or capsule containing 100 mg of aceclofenac was orally administered, blood was taken at predetermined time intervals and the concentrations of aceclofenac in serum were determined using HPLC with UV detector. The dissolution profiles of the two aceclofenac products were very similar at pH 7.8 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. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two products were $6.50\%,\;-1.06\%\;and\;11.96\%$ respectively, when calculated against the $Airtal^{TM}$ tablet. The powers $(1-\beta)\;for\;AUC_t,\;C_{max}\;were\;89.82\%\;and\;82.84\%$, respectively. Minimum detectable differences $(\Delta)\;at\;\alpha=0.05\;and\;1-\beta=0.8$ were less than $20\%\;(e.g.,\;17.51\%\;and\;19.30\%\;for\;AUC_t,\;C_{max}$, ). The $90\%$ confidence intervals were within $\pm20\%\;(e.g.,\;-3.73\%\sim16.73\%\;and\;-12.34\%\sim10.22\%\;for\;AUC_t,\;C_{max},\;respectively)$. Two parameters met the criteria of KFDA for bioequivalence, indicating that $Acer^{TM}$ capsule is bioequivalent to $Airtal^{TM}$ tablet.

• Korean Journal of Clinical Pharmacy
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• v.12 no.1
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• pp.29-38
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• 2002

Hypertension is an important public health problem because it increases the risk of stroke, angina, myocardial infarction, heart failure, and end-stage renal disease. If it is not actively treated, morbidity and mortality increase with hypertension-induced complications and quality of life decreases. This study was to evaluate the use of antihypertensive drugs and blood pressure changes and to compare algorithms chosen (or the 1st and 2nd line therapy of hypertension based on the JNC VI recommendations. The medical charts of 222 patients with essential hypertension at St. Vincent's Hospital in Suwon from January 1997 to January 2000 were reviewed retrospectively. Data collection and analysis included baseline BP underlying diseases and complications, administered antihypertensives, BP changes, changes of antihypertensive regimen, and adverse effects with treatments. As results, the higher BP the patients had, the more frequent they had target organ damages and clinical cardiovascular diseases. Mean duration to reduce blood pressure less than 140/90 mmHg was 8 weeks in $85.3\%$ of the patients. The rate of control in BP was $82.4\%$ at 6 months. The major antihypertensive drugs prescribed were calcium channel blockers $(61.8\%)$ , ACE inhibitors $(19.1\%),\;\beta-blockers\;(13.7\%)$ and diuretics $(5.3\%)$ as the 1st-line monotherapy. The methods of treatment used as the 1st-line therapy were monotherapy$(59\%)$ and combination therapy $(41\%)$. Blood pressure change was significantly greater for combination therapy than monotherapy$(-26.2\pm21.4\;vs.\;-18.56\pm16.7$ mmHg for systolic blood pressure; P<0.003, $-16.9\pm13.2\;vs.\;-9.2\pm12.8$ mmHg for diastolic blood pressure; p<0.001). When blood pressure was not completely controlled with the first antihypertensive selected, the 2nd line therapy had 4 options: addition of 2nd agent from different class; $66.2\%$, substitution with another drug, $21.9\%$ increase dose $11.9\%$ continue first regimen $27.9\%$ Calcium channel blockers were the most frequently prescribed agents. This was not comparable to the JNC VI guideline which recommended diuretics and $\beta-blockers$ for the 1st-line therapy. Most of patients achieved the goal BP and maintained it until 6 months, but the remaining patients should be controlled more tightly to improve their BP with combination of life style modification, patient education, and pharmacotherapy.

• Korean Journal of Clinical Pharmacy
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• v.12 no.2
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• pp.71-75
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• 2002

This study was carried out to compare the bioavailability of $Ceclex^{(R)}$ (test drug, cefaclor 250 mg/capsule) with that of $Ceclor^{(R)}$ (reference drug) and to estimate the pharmacokinetic parameters of cefaclor in healthy Korean adult. The bioavailability was examined on 20 healthy volunteers who received a single dose (250 mg) of each drug in the fasting state in a randomized balanced 2-way crossover design. After dosing, blood samples were collected for a period of 6hours. Plasma concentrations of cefaclor were determined using HPLC with UV detection. The pharmacokinetic parameters $(AUC_{0-6hr},\;C_{max},\;T_{max},\;AUC_{int},\;K_e,\;t_{1/2},\;Vd)$ F, and CL/F) were calculated with non-compartmental pharmacokinetic analysis. The ANOVA test was utilized for the statistical analysis of the $T_{max},\;log-transformed\;AUC_{0-6hr}\;log-transformed\;C_{max},\;t_{l/2},\;V_d/F$, and CL/F. The ratios of geometric means of AUC0-6hr and $C_{max}$ between test drug and reference drug were $103.2\%\;(6.74\;{\mu}g{\cdot}hr/ml\;vs\;6.53{\pm}g{\cdot}hr/ml)\;and\;100.4\%\;(4.85\;{\mu}g\ml\;vs\;4.82\;{\mu}g/ml)$, respectively. The $T_{max}$ of test drug and reference drug were $0.9\pm0.38\;hr\;and\;0.83\pm0.34$ hrs, respectively. The $90\%$ confidence intervals of mean difference of logarithmic transformed $AUC_{0-6h},\;and\;C_{max}$ were log $0.98{\sim}log$ 1.08 and log $0.88{\sim}log1.15$, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The estimated half-life of this study was longer $(1.21\pm0.27\;hrs\;vs\;0.5-1\;hr)$, the Vd/F was larger $(68.89\pm25.72L$ vs 24.9L), and the CL/F was higher $(38.62\pm7.09\;L/hr$ vs 24.9 L/hr) than the previously reported values.

• Korean Journal of Clinical Pharmacy
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• v.12 no.1
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• pp.39-50
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• 2002

Hypercholesterolemia is one of main causes of coronary heart disease(CHD). Clinical trials demonstrated that lowering serum cholesterol levels would reduce incidence of new cardiovascular events and mortality by primary or secondary preventions. The objective of this retrospective study was to compare efficacy and side effects of lovartatin and simvastatin in treatement of hypercholesterolemia. In Boramae Hospital, patients were included when they have taken lovastatin 20 mg or simvastatin 10 mg for 52 weeks with laboratory monitoring for cholesterol at baseline, 3, 6 and 12 month period. As results, total 128 outpatients were included with their total cholesterol level <240 mg/dl and triglyceride level <400 mg/dl at baseline. Total cholesterol and LDL cholesterol of lovastatin group (n=60) and simvastatin group (n=68) were significantly reduced from baseline (p=0.001). Lovastatin maximally reduced total cholesterol by $23.9\%,\;triglyceride\;by\;12.3\%$, LDL cholesterol by $36.1\;\%$ and increased HDL cholerterol by $7.8\%$ and simvastatin reduced by $24.1\%,\;20.5\%,\;34.3\%\;respectively$ and HDL increased by $11.2\%$. There were no significant differences between lovastatin and simvastatin in mean percent change of lipid levels at 12, 24 and 52 weeks from baseline. Cumulative percentage of patients reaching the target LDL cholesterol concentration by 24 weeks was $61.7\%$ in lovastatin and $64.7\%$ in simvastatin. Average time to reach the target LDL goal was 100.1 days in lovastatin and 99.8 days in simvastatin. Both lovastatin and simvastatin also significantly reduced total cholesterol and LDL cholesterol in all subgroups (diabetes mellitus, hypertension, and coronary heart disease). In this study, treatment efficacy in patients with coronary heart disease was lower than other patients. Considering clinical importance of secondary prevention, more intensive treatment is necessary to decrease LDL cholesterol level of 100 mg/dl or lower in patients with coronary heart disease or other clinical atherosclerotic disease. There were no serious side effects during the study period. Digestive side effects were most frequently reported (lovastatin $8.3\%\;vs\;simvastatin\;8.8\%$). In conclusion, both lovastatin and simvastatin were similar in lipid lowering effects and there was no difference in incidence of side effects.

• Korean Journal of Clinical Pharmacy
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• v.8 no.1
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• pp.13-18
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• 1998

The purpose of this study was to determine pharmacokinetic parameters of vancomycin using the compartment model dependent and compartment model independent analysis in 6 Korean normal volunteers and 8 ovarian cancer patients. Vancomycin was administered 1.0 g bolus by IV infusion over 60 minutes. The elimination rate constant ($\beta$), volume of distribution (Vd), total body clearance (CLt), and area under the plasma level-time curve (AUC) of vancomycin in normal volunteers using the compartment model dependent analysis were $0.150\pm0.030\;hr^{-1},\;32.9\pm2.81\;L/kg,\;5.36\pm0.63\;L/hr,\;and\;186.5\pm20.5\;{\mu}g/ml{\cdot}hr$, respectively. The $\beta$, Vd, CLt, and AUC of vancomycin in ovarian cancer patients using the compartment model dependent analysis were $0.109\;0.008\;hr^{-1},\;41.5\pm3.01\;L/kg,\;4.58\pm0.57\;L/hr\;and\;218.3\pm22.9\;{\mu}g/ml{\cdot}hr$, respectively. There were significant differences (p<0.05,\;p<0.01) in $\beta$, Vd, CLt, and AUC between normal volunteers and ovarian cancer patients. The elimination rate constant (Kel), CLt, and AUC of vancomycin in normal volunteers using the compartment model independent analysis were $0.152\pm0.022\;hr^{-1},\;5.77\pm0.75\;L/hr,\;and\;173.2\pm22.5;{\mu}g/ml{\cdot}hr$, respectively. The Kel, CLt, and AUC of vancomycin in ovarian cancer patients using the compartment model independent analysis were $0.126\pm0.012\;hr^{-1},\;4.96\pm0.55\;L/hr,\;and\;201.7\pm25.6;{\mu}g/ml{\cdot}hr$, respectively. There were significant differences (p<0.05, p<0.01) in Kel, CLt, and AUC between normal volunteers and ovarian cancer patients. And also, there was significant difference (p<0.05) in Kel of vancomycin in ovarian cancer patients between the compartment model dependent and independen analysis. It is necessary for effective dosage regimen of vancomycin in ovarian cancer patient to use these population parameters.

• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.1-17
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• 2009

Adverse drug reactions (ADR) caused by inappropriate prescription are responsible for major socioeconomic loss. Drug-drug interactions (DDI) has been recognized as a major part of ADRs and, therefore, healthcare professionals should prevent possible DDIs to minimize preventable ADRs. This study aimed to examine DDI information in drug information references and Korea Food & Drug Administration (KFDA) drug labeling information. Drug ingredients from the formulary of Health Insurance Review and Assessment Service in Korea (HIRA) were included for the study. DDI information source used for the study were Micromedex Drugdex and Drug Information Facts (DIF) with the DDI severity level of "moderate" or more. The DDI information in KFDA drug labeling were collected and compared. Drug ingredients were classified with KFDA Drug Classification and ATC Classification of WHO for the analysis. Among the total 1,355 drug ingredients satisfying inclusion criteria, 738 ingredients involved at least one DDI, which was described in Micromedex and/or DIF. Drug Ingredients of 176 involved DDI only described in KFDA drug labeling, but not Micromedex nor DIF. Drug ingredients of 35 which DDIs were described in Micromedex or DIF did not have DDI based on KFDA drug labeling. Micromedex and DIF retrieved 7,582 and 3,071 DDIs, respectively 57.6% and 58.5% of DDIs were also described in KFDA drug labeling. Central nervous system (CNS) drugs, cardiovascular system (CVS) drugs and the antiinfectives appeared to have higher frequency of DDIs among all drug classes. The highest number of DDIs with high severity level ("contraindicated" or "major") were the DDIs of CNS drugs. The antiinfectives are the second drug group having serious DDIs. The DDI pairs of the CNS drug and the antiinfective had the highest contraindication risk (13.6%). DDI information from Micromedex and DIF were not consistent with the result that only 465 ingredients' DDIs are common in both literature (total DDI numbers were 715 vs 488, respectively). And 1,652 DDI information are common in both references among 7,582 vs 3,071 DDIs, respectively. Only 55.2% of DDI information in the database contained in the KFDA drug labeling. Prescribers and pharmacists should pay attention to the drugs for CV system, CNS and infections because of higher risk of possible DDIs compared to other drug classes. KFDA drug labeling is not likely to be recommended as a good information source for DDI due to significant inconsistency of information. Drug information providers should be aware that DDI information from different sources are not consistent and therefore multiple references should be used.

• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.18-22
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• 2009

Oxaliplatin is a tolerable and effective drug of choice in the treatment of advanced or metastatic gastric cancer. However, it has many dose-limiting neurotoxicities. This study was performed to assess the incidence and types of oxaliplatin-related neurotoxicities. Sixty-four patients receiving oxaliplatin-involved regimen as salvage therapy on metastatic gastric cancer or as the first-line therapy on advanced gastric cancer were evaluated during the period between September 1, 2006 and February 29, 2008. The patients were treated with oxaliplatin 100 $mg/m^2$ and leucovorin 100 $mg/m^2$ simultaneously as 2-hour-lasting infusion on Day-1 followed by 5-FU 1200 $mg/m^2$ as a 22-hour-lasting continuous infusion both on Day-1 and Day-2 by every other week. We developed questionnaires to evaluate patient-recognized neurotoxic symptoms rather than the observer-described events. Surveys were completed at bedside or via telephone interview. Acute and chronic neurotoxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 3) as well as the Oxaliplatin-specific Neurotoxicity Scale. The Grade-3 neuropathy was reported in 19% of the patients (n=12) and grade-1/2 neuropathy occurred in 70% (n=45). The most common symptom was cold-related dysesthesia (83%) regarded as nociperception by the patients. Some patients (19%) experienced functional impairment affecting activities of daily living such as writing, buttoning, and walking. Even though 74% of the patients (42/57) were prescribed with gabapentin to reduce these peripheral symptoms, it did not appear to derive any benefit from this medication. It is suggested that notify the patients about their oxaliplatin-associated, debilitating symptoms, and educate them any self-care strategy at the initiating phase of the chemotherapy. Moreover, it needs to design the intervention studies regarding the prevention and management of the peripheral neuropathy.