• Toxicological Research
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• v.23 no.2
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• pp.159-164
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• 2007

Toxicity screening of a newly developed oral heparin derivative were carried out in 6 male cynomolgus monkeys (Macaca fascicularis), composed of a treatment group and vehicle control group. A newly orally active heparin derivative, developed by Seoul National University, was once given to treatment group at dose of 500 mg/kg. A treatment group did not show any change in body weights, hematological parameters including platelet-related varivables (platelet, PDW, PCT, MPV) and serum biochemical parameters (e.g., AST, ALT, BUN, etc.) for 2 weeks compared with those of vehicle control group. We also confirmed the maximum plasma concentration (Cmax, 1.73 IU/ml) and the time (Tmax, 1 hr) to reach Cmax. The present study will be valuable in the proper interpretation for nonclinical study using cynomolgus monkeys in the development of new drug of heparin derivative.

• Asian-Australasian Journal of Animal Sciences
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• v.23 no.8
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• pp.1089-1095
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• 2010

Four biological candidate genes, natural resistance associated macrophage protein 1 (SLC11A1 or NRAMP), prosaposin (PSAP), interferon Gamma (IFNG), and toll-like receptor 4 (TLR4), were examined to identify single nucleotide polymorphisms (SNP) and associations of the SNP with antibody response kinetics in hens. An $F_2$ population was produced by mating $G_0$ highly inbred (<99%) males of two MHC-congenic Fayoumi lines with highly inbred Leghorn hens. The $F_2$ hens (n = 158) were injected twice with SRBC and whole, fixed Brucella abortus (BA). Blood samples were obtained before each immunization, at 7 d after primary immunization, and at several time points after secondary immunization. Minimum titers (Ymin) and the time needed to reach them (Tmin), and maximum (Ymax) titers and the time needed to reach them (Tmax), were estimated from the seven post-secondary immunization titers using a nonlinear regression model. The $F_2$ hens were genotyped for the four candidate genes by using PCR-RFLP for one SNP per gene, which identified the parental allele. General linear models were used to test associations of SNP genotypes with antibody response parameters and BW measured at 4 ages. The IFNG SNP was highly significantly (p<0.0125) associated with primary response to SRBC, Tmin to BA, Ymin to BA, and 12-week BW. The current study demonstrated that the novel IFNG promoter SNP was associated with antibody kinetics for BA and SRBC in laying hens, and also with BW, suggesting that this cytokine may play a pivotal role in the relationship between immune function and growth.

• YAKHAK HOEJI
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• v.37 no.5
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• pp.544-548
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• 1993

The pharmacokinetics of DWP302, a new combined ranitidine preparation in rats and dogs was studied using HPLC. DWP302 was composed of ranitidine, sucralfate and tripotassium dicitrato bismuthate. Especially, this study was focused on the possibilities that the concomitant administration of either sucralfate or TDB may affect the absorption of orally administered ranitidine. Ranitidine and DWP302 were orally administered to rats at a dose of ranitidine 10mg/kg. Several rats showed the biphasic peak of plasma concentration. AUC$_{S_{0-8}}$ of ranitidine and DWP302 group were found to be 1040$\pm$109 and 945$\pm$124 ng.hr/ml, respectively, and there was no significant difference between both AUCs. In a cross-over study for dogs, $C_{max}$, t$_{1/2}$ beta and total AUC of ranitidine group were found to be 625.8$\pm$86.7 ng/ml, 2.80$\pm$0.28 hr and 1688$\pm$127 ng.hr/ml, and those of DWP302 group were 562.6$\pm$120.9 ng/ml, 3.05$\pm$0.30 hr and 1673$\pm$123 ng.hr/ml, respectively. There was no significant difference between those parameters, but Tmax of DWP302 group (1.69$\pm$0.31 hr) was significantly different from ranitidine group (1.13$\pm$0.26 hr). The results suggest that either sucralfate or TDB may affect the lag-time or rate of absorption of ranitidine but not the extent of absorption.

• The Korean Journal of Nuclear Medicine
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• v.3 no.1
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• pp.19-32
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• 1969

Radioisotope renography was carried out in 564 cases consisting of 150 normal controls, 140 hypertensives, 102 hypertensive nephropathys, 62 chronic renal diseases, non-functioning kidneys. It was aimed to study which parameter of the renogram is most applicable to any definite disease of the kidney. The analytical methods adopted were; Tobe, Spencer, Krueger, Matchida and Takeuchi. In the non-functioning kidney groups, the hemograms and serum nitrogen series were also studied to evaluate the relationships between the renograms and renal anemia. The parameters were; time of maximum amplitude (Tmax), half-time of maximum amplitude ($T\frac{1}{2}$), Kac value calculated from these two parameters in Tobe's method, slopes of Band C phase, B/A and B/C values in Spencer's method, total concentration (T.C.), minute concentration (M.C.) and minute excretion (M.E.) in Krueger's method, Matchida's K value and Takeuchi's renal function Index (R.F.I.). Following were the results: 1. In general, marked differences in the patterns of the renogram were observed between the normal controls and nephropathys. In Tobe's method, each parameter showed statistically significant delay or decrease in patients with hypertensive nephropathys and chronic renal diseases. In Spencer's method, slopes of B and C phase and B/C, also showed the statistically significant decrease in patients with hypertension, hypertensive nephropathys and chronic renal diseases. In Krueger's method, M.C. and ME showed the statistically significant differences between the control and patients with hypertension, hypertensive nephropathys and chronic renal diseases, In Matchida's method, K value showed the statistically significant differences between the control and patients with hypertensive nephropathys and chronic renal diseases. 2. It appeared, therefore, that Tobe's $T\frac{1}{2}$, Kac value, Spencer's slopes of Band C phase, B/A, B/C values, Krueger's T.C., M.C., and M.E. values, Matchida's K value are useful for the differentiation of various renal diseases, however, qualitative analysis of the renogram with one or two parameters is not accurate. 3. In bilateral non-functioning kidney groups, a positive correlation between anemia and nitrogen retention was observed, although the quantitative assessment of the degree of non-functioning was impossible.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.1
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• pp.77-88
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• 2013

Objectives : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. Methods : After 10mg/kg of donepezil treatment, Gongjindan 100mg/kg was administered within 5 min. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of Gongjindan treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. PK parameters of donepezil were analysis as compared with donepezil single administered rats. Results : Gongjindan markedly inhibited the absorption of donepezil regardless of sample time, from 30min to 8hrs after end of co-administration comparing with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2hrs after co-administration as compared with donepezil single treated rats, in the present study. Accordingly, the Cmax(-27.76%), $AUC_{0-t}$(-27.22%) and $AUC_{0-inf}$(-26.54%) of donepezil in co-administered rats were significantly decreased as compared with donepezil single treated rats, respectively. Conclusions : Based on the results of the present study, co-administration of Gongjindan decreases the oral bioavailability of donepezil by inhibiting the absorption. It is considered that the more detail pharmacokinetic studies should betested to conclude the effects of Gongjindan on the pharmacokinetics of donepezil, when they were co-administered, like the effects after co-administration with reasonable intervals considering the Tmax of donepezil and after repeated co-administrations.

• Biomolecules & Therapeutics
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• v.9 no.4
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• pp.285-290
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• 2001

Bioequivalence of two acetyl-1-carnitine tablets, test product (Carnitile tablet: Hanmi Pharm. Co., Ltd.) and reference product (Nicetil $e^{R}$ tablet: Dong-A Pharm. Co., Ltd.), was evaluated according to the guide- lines of Korea Food and Drug Administration (KFDA). Twenty-six healthy volunteers were divided randomly into two groups and administered the drug orally at the dose of 500 mg as acetyl-1-carnitine in a 2$\times$2 crossover study. Blood samples were taken at predetermined time intervals for 12 hours and the plasma concentration of acetyl-1-carnitine was determined using HPLC by derivatization with p-bromophenacyl bromide. The pearmacokinetic parameters (AU $C_{0-}$12h/ $C_{max}$ and $T_{max}$) were calculated and ANOVA was utilized for the statistical analysis of parameters. The apparent differences of these parameters between two drugs were less than 20% (i.e., 1.26,-5.08 and 8.59% for AU $C_{0-}$12h/ $C_{max}$ and $T_{max}$, respectively). The powers (1-$\beta$) for AU $C_{0-}$12h/ $C_{max}$ and $T_{max}$, and Tmax were over 0.9. Minimal detectable difference ($\Delta$) at $\alpha$=0.05, 1-$\beta$=0.8 were less than 20% (i.e.,7.31, 14.88 and 11.77% for AU $C_{0-}$12h/ $C_{max}$ and $T_{max}$, respectively). The confidence intervals ($\delta$) for these parameters were also within $\pm$ 20% (i.e.,-3.03$\leq$$\delta$$\leq$5.54, -13.80$\leq$$\delta$$\leq$3.64 and 1.69$\leq$$\delta$$\leq$15.48 for AU $C_{0-}$12h/ $C_{max}$ and $T_{max}$, respectively). These results satisfied the criteria of KFDA guideline for bioequivalence, indicating Carnitile bioequivalent to Nicetil $e^{R}$ .TEX>$^{R}$ .> R/ . R/ .

• Journal of Pharmaceutical Investigation
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• v.24 no.2
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• pp.73-83
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• 1994

Applications of liposomes as a drug carrier for the oral delivery of poorly-absorbable macromolecular drugs have been limited, because of their instability in gastrointestinal environments including pH, bile salts, and digestive enzymes. Two polysaccharides, dextran(DX) and pullulan(PL), were introduced to the preformed liposomes in order to enhance the stability. Palmitoyl derivatives of polysaccharides, palmitoyldextran(PalDX) and palmitoylpullulan(PalPL), were synthesizd and introduced to the liposomes during preparation for the same purpose of stability. The effects of these polysaccharides coating were evaluated basically by physical properties of particle size distribution and optical microscopy, then compared with uncoated liposomes by the observations of both in vitro stability and in vovo absorption characteristics. The geometric mean diameters of polysaccharide-coated liposomes were greater than that of uncoated liposome, showing the outermost polysaccharide-coated layer under the optical microscopy. In vitro stabilities of uncoated or polysaccharides-coated liposomes were measured by turbidity changes in various pH buffer solutions containing sodium choleate as bile salts. While uncoated liposome was very sensitive to bile salts, polysaccharides-coated liposomes were stable in relatively higher concentrations of sodium choleate, giving the results of better stability of PalDX- and PalPL-coated liposomes than that of DX- and PL-coated liposomes. After liposomal encapsulation of acyclovir(ACV), an antiviral agent as a model drug, it has been administered orally to rats as dose of ACV 40 mg/kg. Plasma concentrations of ACV were assayed by HPLC and analyzed by model-independent pharmacokinetics. Pharmacokinetic parameters of Cmax, tmax, and [AUC] have been compared.

• Archives of Pharmacal Research
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• v.26 no.2
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• pp.162-167
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• 2003

Liquid suppository systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and mucoadhesive to the rectal tissues without leakage after the dose. However, a liquid suppository containing diclofenac sodium could not be developed using bioadhesive polymers. since the drug was precipitated in this preparation. To develop a liquid suppository system using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers and sodium chloride were investigated. Furthermore, the pharmacokinetic study of diclofenac sodium delivered by the liquid suppository was performed. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. The liquid suppositories with less than 1.0％ of sodium chloride, in which the drug was not precipitated, were inserted into the rectum without difficulty and leakage. Furthermore, liquid suppository gave significantly higher initial plasma concentrations and faster Tmax of diclofenac sodium than did solid suppository, indicating that drug from liquid suppository could be absorbed faster than that from solid one in rats. Our results suggested that a thermosensitive liquid suppository system with sodium chloride and poloxamers was a more physically stable, convenient and effective rectal dosage form for diclofenac sodium.

• Archives of Pharmacal Research
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• v.18 no.6
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• pp.385-390
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• 1995

The analytical methods for the analysis of cyclosporine (CsA), a fluorescence polarization immunoassay (FPIA) and HPLC method, were compared in a pharmacokinetic study of two CsA soft capsule formultaions ($Sandimmun^{\circledR}$; Sandoz, $Implanta^{\circledR}$; Hanmi). Sixteen healthy volunteers completed the study and each subjected single doses ($4{\tiems}100$ mg) of the test and the reference formulations in a two-way crossover design with a one-week drug-free interval between doses. Following each administration, whole blood concentrations of CsA were monitored over a period of 24 hour by both FPIA and HPLC methods. Blood concentrations nad pharmacokinetic parameters determined by either analytical method showed large intersubject variation, with the FPIA data showing relatively higher magnitude of intersubjecte variation than the HPLC data. The blood concentrations determined by FPIA were 1.1-1.3 times higher than those determined by HPLC. There were strong and significant correlations between the two methods (r>0.83 : p<0.0001). Intersubuject variation for the $AUC_{inf}{\;}and{\;}AUC_{24hr}$ of the test formulation was slightly reduced without statistical significance (paried -t test : p>0.05 $t_{max}$ was earlier nad $C_{max}$ was slightly lower for the test formulation, $AUC_{24h}, {\;}C_{max}, {\;}T_{max}$ and MRT determined separately from the data obtained by the two methods for the two formulations were examined by analyses of variance (ANOVA) for the bioequivalency evaluation. Results of ANOVA and confidence limits of terst/reference ratios of $AUC_{24th}$, $C_{max}$, $t_{max}$ and MRT, and statistical tests indicated the bioequivalence of the two formulations (i.e., test/reference ratio was within $100{\times}20%$) except for $C_{max}$ and $t_{max}$. The mean of tmax also showed 11.1% and 9.3% differences but the detection limit were 29.2% and 29.6% as determined by FPIA and HPLC resepctively. This experiments suggest that the data yielded for the two formulations demonstrated that they were bioequivalent.

• YAKHAK HOEJI
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• v.42 no.5
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• pp.513-518
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• 1998

Fluoxetine is a nontricyclic antidepressant which blocks serotonin reuptake selectively. Its N-demethyl metabolite, norfluoxetine is also selective inhibitor of serotonin uptake . This study was carried out to compare the bioavailability of Myung-in fluoxetine (20mg/cap.) with that of Prozac$^{\circde{R}}$. The bioavailability was conducted on 24 healthy volunteers who received a single dose (80mg) of each drug in the fasting state, in a randomized balanced 2-way crossover design. After closing, serial blood samples were collected for a period of 48 hours, Plasma was analyzed for fluoxetine and norfluoxetine by a sensitive and validated HPLC assay. The major pharmacokinetic parameters ($AUC_{0-48\;hr}$, Cmax, Tmax , $AUC_{inf.}$, MRT. $T_{1/2}$, Vd and Cl) were, calculated from the plasma fluoxetine concentration-time data of each volunteer. The microcomputer program, 'WinNonlin' was used for compartmental analysis. A two-compartment model with first-order input, first-order output and no lag time was chosen as the most appropriate pharmacokinetic model. The data were best described by using a weighting factor of $1/y^2$. Though the plasma fluoxetine concentrations of Myung-in fluoxetine were higher than those of Prozac$^{\circde{R}}$ at all observed time from 7.9% to 16.9% (P<0.05 at 6.7 and 10 hr), the bioavailability of Myung-in fluoxetine appeared to be bioequivalent with that of Prozac$^{\circde{R}}$. There were no statistical significant differences between the two drugs in all pharmacokinetic parameters including $AUC_{0-48\;hr}$ of norfluoxetine.