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나성범,김완주,지웅길,La, Sung-Bum,Kim, Wan-Joo,Jee, Ung-Kil 대한약학회 1994 약학회지 Vol.38 No.2
${\beta}-Lactamase$ stability, chemotherapeutic activity, and pharmacokinetics of 7-[(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl]thiocarbonylthiomethyl-3-cephem-4-carboxylic acid(CEN1), 7-[(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyrimidyl)piperazinyl]thiocarbonylthiomethyl-3-cephem-4-carboxylic acid(CEN2), pivaloyloxymethyl-7-[(Z)-2-(2-aminothizaole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl]thiocarbonyl-thiomethyl-3-cephem-4-carboxylate(CEN1P), and pivaloyloxymethyl-7-{(Z)--2-(2-aminothizaole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl]thiocarbonyl-thiomethyl-3-cephem-4-carboxylate(CEN2P) were examined. CEN1, CEN2, CEN1P, and CEN2P were very stable to the ${\beta}-lactamase$ obtained from three strains(Enterobacter cloacae P99, Escherichia coli TEM, and Citrobacter freundii). Chemotherapeutic activities$(ED_{50})$ of CEN2 and CEN2P against experimental systemic infections due to Streptococcus pyogenes 77A and Escherichia coli 078 were superior to those of CEN1 and CEN1P, respectively. The $ED_{50}$ values of CEN1, CEN2 were 5.82 mg/kg, 0.89 mg/kg(s.c., S. pyogenes 77A) while those of CEN1P, CEN2P were 14.56mg/kg, 6.40mg/kg(p.o., S. pyogenes 77A), respectively. The pharmacokinetics of CEN1, CEN2, CEN1P, and CEN2P were investigated in mice and rats. In mice, peak blood levels of $1.25\;{\mu}g/ml$ were recorded within 20 min after oral administration of a single dose equivalent to 40 mg/kg CEN1P. Cmax of CEN1P was much higher than that of CEN1 in mice and rats. Oral absorption of CEN2P was much higher than that of CEN2.
새로운 경구용 세팔로스포린류의 물리화학적 성질 및 분해특성
나성범,김완주,지웅길,La, Sung-Bum,Kim, Wan-Joo,Jee, Ung-Kil 대한약학회 1994 약학회지 Vol.38 No.2
Physicochemical properties and hydrolysis kinetics of new some oral cephalosporins were examined in buttered solution and human plasma or rat liver homogenate. The test cephalosporins were 7-[(Z)-2-(2-aminothiazole-4-yl)-2- methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl] thiocarbonylthhiomethyl-3-cephem-4-carboxylic acid (CEN1), 7-[(Z)-2-(2-aminoth iazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyrimidyl)piperazinyl]th iocarbonylthiomethyl-3-cephem-4-carboxylic acid (CEN2), pivaloyloxymethyl-7-[ (Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazi nyl]thiocarbonylthiomethy1-3-cephem-4-carboxylate (CEN1P), and pivaloyloxymethyl-7-[(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[ 4-(2-pyrimidyl)piperazinyl]thiocarbonyl-thiomethyl-3-cephem-4-carboxylate (CEN2P). The partition coefficient(Ko/w) of CEN1P, CEN2P were higher than those of CEN1, CEN2. The calculated pKa values of CEN1, CEN2, CEN1P, and CEN2P were 7.09, 7.75, 4.92, and 5.39, respectively. The hydrolysis of CEN1P and CEN2P were not depend on the composition of pH of the test medium except weak alkaline buffered solution (pH 8.00). CEN1 and CEN2 were very stable in pH 6.80 and 8.00 buffer solutions. CEN1P and CEN2P were rapidly deesterified to CEN1 and CEN2 in human plasma and in rat liver homogenate. Half-lives$(t_{1/2})$ of CEN1 and CEN2 were 3.49 and 4.93 hr in human plasma, 1.47 and 1.26 hr in rat liver homogenate, respectively.
나성범(Sung Bum La),정명희(Myung Hee Jung),김완주(Wan Joo Kim),지웅길(Ung Kil Jee) 대한약학회 1993 약학회지 Vol.37 No.2
To a suspension of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-{3,7-diazabicyclo[3.3.0]oct-1(5)-en-3-yl}-4-oxo-3-quinoline carboxylic acid(C1) in sodium hydroxide solution and water is added dropwise with stirring carbon disulfide. [6R-[6alpha, 7beta(Z)]]-7-[[[(2-Amino-4-thiazoly)methoxyimino]-acetyl]amino]-3-[[[[7-(3-carboxy-1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxo-7-guinolonyl)-3,7-diazabicyclo[3.3.0]oct-1(5)-en-3-yl]thioxomethyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (DACD) was synthesized from 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[7-(mercapto)thioxomethyl-{3,7-diazabicyclo[3.3.0]oct-1(5)-en-3-yl}]-4-oxo-3-quinoline carboxylic acid disodium salt(C2) and cefotaxime. The in vitro activity of novel dual-action cephalosporin, DACD, was compared with the in vitro activities of CENO(cefotaxime 3''-norfloxacin dithiocarbamate), cefotaxime, and norfloxacin against a variety of bacterial species. In vitro activity of DACD was superior to that of norfloxacin against Streptococcus pyogenes. Against Gram-positive and Gram-negative bacteria, its activity was almost equal to that of CENO.
나성범(Sung Bum La),정명희(Myung Hee Jung),김완주(Wan Joo Kim),지웅길(Ung Kil Jee) 대한약학회 1993 약학회지 Vol.37 No.3
In order to develop oral cephalosporin having a new substituent at 3 position, the synthesis of cephalosporins modified at C-3 and the effect of the substituents on the oral absorption is studied. 7-[(Z)-2-(2-Aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl] thiocarbonylthiomethyl-3-cephem-4-carboxylic acid (CEN1) and 7-L(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyrimidyl)piperazinyl]thiocarbonylthiomethyl-3-cephem-4-carboxylic acid (CEN2) were synthesized from 4-(2-piridyl)piperazinyl dithiocarbamate potassium salt or 4-(2-pirimidyl)piperazinyl dithiocarbamate potassium salt and cefotaxime. Also pivaloyloxymethyl esters of CEN1 and CEN2, pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyridyl)piperazinyl]thiocarbonylthiomethyl-3-cephem-4-carboxylate (CEN1P) and pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-[4-(2-pyrimidyl)piperazinyl]thiocarbonylthiomethyl-3-cephem-4-carboxylate (CEN2P) were synthesized. The in vitro activities of two new oral cephalosporins, CEN1 and CEN2, were compared with the in vitro activities of cefaclor and cefotaxime against a variety of bacterial species. CEN2 has a broad antibacterial spectrum covering Gram-positive and Gram-negative bacteria, similar to that exhibited by CEN1 and cefotaxime. CEN1 and CEN2 were more active in vitro than cefaclor against Streptococcus pyogenes, Klebsiella aerogenes and Enterobacter cloacae.
조한진(Han Jin Jo),나성범(Sung Bum La),남상철(Sang Cheol Nam),박목순(Mork Soon Park),지웅길(Ung Kil Jee) 대한약학회 1990 약학회지 Vol.34 No.2
To enhance the activity of ibuprofen, amides of ibuprofen, 1-piperazinyl-2-(4-isobutylphenyl)propionamide(Ibu-P.A.) and 1-(4-methylpiperazinyl)-2-(4-isobutylphenyl)propionamide (Ibu-M.P.), were synthesized and the pharmaceutical properties and the pharmacological activities of the amides were studied. The lipid:water partition coefficients and pKa values were examined in vitro, and the antiinflammatory effect, analgesic effects, acute toxicity, and intestinal absorption were studied for the amides and compared with ibuprofen in vivo. The results are summarized as belows; 1) The lipid:water partition coefficients of Ibu-M.P. were higher than those of ibuprofen. 2) The calculated pKa values of ibuprofen and Ibu-M.P. were 5.49 and 8.66, respectively. 3) The antiinflammatory effects of ibuprofen, lbu-P.A., and lbu-M.P. were same intensity, but the duration of the effects of Ibu-P.A. and Ibu-M.P. were longer than that of ibuprofen. 4) The analgesic effect of Ibu-M.P. was more potent than those of ibuprofen and Ibu-P.A. in the acetic acid-induced writhing test. 5) The LD50 was 495mg/kg for ibuprofen, 187mg/kg for Ibu-M.P., and over 1250mg/kg for Ibu-P.A.. 6) The absorption rate constants(k) and half-life(t1/2) were 0.74(hr-1) and 0.94(hr) for ibuprofen, and 0.72 (hr-1) and 0.96 (hr) respectively for Ibu-M.P..
양재헌(Jae Heon Yang),나성범(Sung Bum La),김영일(Young Il Kim),김남순(Nam Soon Kim) 대한약학회 2000 약학회지 Vol.44 No.5
Microspheres of felodipine, which is one of the calcium channel blocker, using a mixture of Eudragit(R) RL, L, E, and cellulose on the base of Eudragit(R) RS were investigated. Cremophor(R) was added to each preparation of polymers in order to increase the release of felodipine from microspheres. Felodipine-loaded microspheres were prepared by a solvent evaporation method, which is based on dispersion of methylene chloride containing felodipine and polymers in 0.5 w/v% polyvinyl alcohol solution. The average diameter based on the size distribution of the felodipine-loaded microspheres was observed to be ca. 40-55mcm. A good and smooth surface were showed in all types of the microspheres. The amount of felodipine loaded was over 90 w/w% in all types of microspheres. The dissolution profiles of felodipine from microspheres were similar with each type of polymer, and about a 60 w/w% of the total amount of felodipine loaded to microsphere was released within 7 hours. Dissolution rate of felodipine from the microsphere was increased by addition of Cremophor(R). After oral administration of the felodipine-loaded microspheres in PVA solution and felodipine alone in PEG solution to rats, respectively, the pharmacokinetic study revealed that (R)the Tmax values of the microspheres were observed in the range of 0.67-1.0hr while that of the felodipine solution was obtained 0.33hr. In addition, the AUC of the microspheres at 0 to 7hr was remarkably increased in comparison to that of felodipine solution. These results revealed that the microspheres based on Eudragit(R) RS could be a good candidate for the controlled release drug delivery system for felodipine.