• The Korean Journal of Pharmacology
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• v.16 no.2 s.27
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• pp.55-70
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• 1980

The pharmacological and microbiological studies of Cefoperazone (T-1551, Toyama Chemical Co., Japan) were conducted in vitro and in vivo. The studies included stability and physicochemical characteristics, antimicrobial activity, animal and human pharmacokinetics, animal pharmacodynamics and safety evaluation of Cefoperazone sodium for injection. 1) Stability and physicochemical characteristics. Sodium salt of cefoperazone for injection had a general appearance of white crystalline powder which contained 0.5% water, and of which melting point was $187.2^{\circ}C$. The pH's of 10% and 25% aqueous solutions were 5.03 ana 5.16 at $25^{\circ}C$. The preparations of cefoperazone did not contain any pyrogenic substances and did not liberate histamine in cats. The drug was highly compatible with common infusion solutions including 5% Dextrose solution and no significant potency decrease was observed in 5 hours after mixing. Powdered cefoperazone sodium contained in hermetically sealed and ligt-shielded container was highly stable at $4^circ}C{\sim}37^{\circ}C$ for 12 weeks. When stored at $4^{\circ}C$ the potency was retained almost completely for up to one year. 2) Antimicrobial activity against clinical isolates. Among the 230 clinical isolates included, Salmonella typhi was the most susceptible to cefoperazone, with 100% inhibition at MIC of ${\leq}0.5{\mu}g/ml$. Cefoperazone was also highly active against Streptococcus pyogenes(group A), Kletsiella pneumoniae, Staphylococcus aureus and Shigella flexneri, with 100% inhibition at $16{\mu}g/ml$ or less. More than 80% of Escherichia coli, Enterobacter aerogenes and Salmonella paratyphi was inhibited at ${\leq}16{\mu}/ml$, while Enterobacter cloaceae, Serratia marcescens and Pseudomonas aerogenosa were somewhat less sensitive to cefoperagone, with inhibitions of 60%, 55% and 35% respectively at the same MIC. 3) Animal pharmacokinetics Serum concentration, organ distritution and excretion of cefoperazone in rats were observed after single intramuscular injections at doses of 20 mg/kg and 50 mg/kg. The extent of protein binding to human plasma protein was also measured in vitro br equilibrium dialysis method. The mean Peak serum concentrations of $7.4{\mu}g/ml$ and $16.4{\mu}/ml$ were obtained at 30 min. after administration of cefoperazone at doses of 20 mg/kg and 50 mg/kg respectively. The tissue concentrations of cefoperazone measured at 30 and 60 min. were highest in kidney. And the concentrations of the drug in kidney, liver and small intestine were much higher than in blood. Urinary and fecal excretion over 24 hours after injetcion ranged form 12.5% to 15.0% in urine and from 19.6% to 25.0% in feces, indicating that the gastrointestinal system is more important than renal system for the excretion of cefoperazone. The extent of binding to human plasma protein measured by equilibrium dialysis was $76.3%{\sim}76.9%$, which was somewhat lower than the others utilizing centrifugal ultrafiltration method. 4) Animal pharmacodynamics Central nervous system : Effects of cefoperazone on the spontaneous movement and general behavioral patterns of rats, the pentobarbital sleeping time in mice and the body temperature in rabbits were observed. Single intraperitoneal injections at doses of $500{\sim}2,000mg/kg$ in rats did not affect the spontaneous movement ana the general behavioral patterns of the animal. Doses of $125{\sim}500mg/kg$ of cefoperazone injected intraperitonealy in mice neither increased nor decreased the pentobarbital-induced sleeping time. In rabbits the normal body temperature was maintained following the single intravenous injections of $125{\sim}2,000mg/kg$ dose. Respiratory and circulatory system: Respiration rate, blood pressure, heart rate and ECG of anesthetized rabbits were monitored for 3 hours following single intravenous injections of cefoperazone at doses of $125{\sim}2,000mg/kg$. The respiration rate decreased by $3{\sim}l7%$ at all the doses of cefoperazone administered. Blood pressure did not show any changes but slight decrease from 130/113 to 125/107 by the highest dose(2,000 mg/kg) injected in this experiment. The dosages of 1,000 and 2,000 mg/kg seemed to slightly decrease the heart rate, but it was not significantly different from the normal control. All the doses of cefoperazone injected were not associated with any abnormal changes in ECG findings throughout the monitering period. Autonomic nervous system and smooth muscle: Effects of cefoperazone on the automatic movement of rabbit isolated small intestine, large intestine, stomach and uterus were observed in vitro. The autonomic movement and tonus of intestinal smooth muscle increased at dose of $40{\mu}g/ml$ in small intestine and at 0.4 mg/ml in large intestine. However, in stomach and uterine smooth muscle the autonomic movement was slightly increased by the much higher doses of 5-10 mg/ml. Blood: In vitro osmotic fragility of rabbit RBC suspension was not affected by cefoperazone of $1{\sim}10mg/ml$. Doses of 7.5 and 10 mg/ml were associated with 11.8% and 15.3% prolongation of whole blood coagulation time. Liver and kidney function: When measured at 3 hours after single intravenous injections of cefoperaonze in rabbits, the values of serum GOT, GPT, Bilirubin, TTT, BUN and creatine were not significantly different from the normal control. 5) Safety evaluation Acute toxicity: The acute toxicity of cefoperazone was studied following intraperitoneal and intravenous injections to mice(A strain, 4 week old) and rats(Sprague-Dawler, 6 week old). The LD_(50)'s of intraperitonealy injected cefoperazone were 9.7g/kg in male mice, 9.6g/kg in female mice and over 15g/kg in both male and female rats. And when administered intravenously in rats, LD_(50)'s were 5.1g/kg in male and 5.0g/kg in female. Administrations of the high doses of the drug were associated with slight inhibition of spontaneous movement and convulsion. Atdominal transudate and intestinal hyperemia were observed in animals administered intraperitonealy. In rats receiving high doses of the drug intravenously rhinorrhea and pulmonary congestion and edema were also observed. Renal proximal tubular epithelial degeneration was found in animals dosing in high concentrations of cefoperazone. Subacute toxicity: Rats(Sprague-Dawley, 6 week old) dosing 0.5, 1.0 and 2.0 g/kg/day of cefoperazone intraperitonealy were observed for one month and sacrificed at 24 hours after the last dose. In animals with a high dose, slight inhibition of spontaneous movement was observed during the experimental period. Soft stool or diarrhea appeared at first or second week of the administration in rats receiving 2.0g/kg. Daily food consumption and weekly weight gain were similar to control during the administration. Urinalysis, blood chemistry and hematology after one month administration were not different from control either. Cecal enlargement, which is an expected effect of broad spectrum antibiotic altering the normal intestinal microbial flora, was observed. Intestinal or peritoneal congestion and peritonitis were found. These findings seemed to be attributed to the local irritation following prolonged intraperitoneal injections of hypertonic and acidic cefoperazone solution. Among the histopathologic findings renal proximal tubular epithelial degeneration was characteristic in rats receiving 1 and 2g/kg/day, which were 10 and 20 times higher than the maximal clinical dose (100 mg/kg) of the drug. 6) Human pharmacokinetics Serum concentrations and urinary excretion were determined following a single intravenous injection of 1g cefoperazone in eight healthy, male volunteers. Mean serum concentrations of 89.3, 61.3, 26.6, 12.3, 2.3, and $1.8{\mu}g/ml$ occured at 1,2,4,6,8 and 12 hours after injection respectively, and the biological half-life was 108 minutes. Urinary excretion over 24 hours after injection was up to 43.5% of administered dose.

• The Korean Journal of Physiology
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• v.23 no.2
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• pp.363-375
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• 1989

It has been well known that peripheral infusion of angiotensin II results in an increase of blood pressure, and an elevation of aldosterone secretion, and an inhibition of renin relase. However, the direct effect of angiotensin II on renal function has not been clearly established. In the present study, to investigate the effect of angiotensin II on renal function and renin release, angiotensin II (0.3, 3 and 10 ng/kg/min) was infused into a unilateral renal artery of the unanesthetized rabbit and changes in renal function and active and inactive renin secretion rate (ARSR, IRSR) were measured. In addition, to determine the relationship between the renal effect of angiotensin II and adenosine, the angiotensin II effect was evaluated in the presence of simultaneously infused 8-phenyltheophylline (8-PT, 30 nmole/min), adenosine A 1 receptor antagonist. Angiotensin II infusion at dose less than 10 ng/kg/min decreased urine flow, clearances of para-amino-hippuric acid and creatinine, and urinary excretion of electrolytes in dose-dependent manner. The changes in urine flow and sodium excretion were significantly correlated with the change in renal hemodynamics. Infusion of angiotensin II at 10 ng/kg/min also decreased ARSR, but it has no significant effect on IRSR. The change in ARSR was inversely correlated with the change in IRSR. The plasma concentration of catecholamine was not altered by an intarenal infusion of angiotensin II. In the presence of 8-PT in the infusate, the effect of angiotensin II on renal function was significantly attenuated, but that on renin secretion was not modified. These results suggest that the reduction in urine flow and Na excretion during intrarenal infusion of angiotensin II was not due to direct inhibitions of renal tubular transport systems, but to alterations of renal hemodynamics which may partly be mediated by the adenosine receptor.

• Nutrition Research and Practice
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• v.9 no.4
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• pp.385-392
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• 2015

BACKGROUND/OBJECTIVES: Recent studies have reported an association of the angiotensin II type 2 receptor (AT2R) 3123Cytosine/Adenine (3123C/A) polymorphism with essential hypertension and cardiovascular diseases. The purpose of the study was to investigate whether the AT2R 3123C/A polymorphism affects blood pressure for free-living hypertensive men during a 5-month intervention period. SUBJECTS/METHODS: The subjects were free-living hypertensive Japanese men aged 40 to 75 years who agreed to intervention in the period from 2004 to 2011. Detection of the AT2R 3123C/A polymorphism was determined by polymerase chain reaction. The dietary intervention was designed to decrease salt level and to increase potassium level through cooking instructions and self-monitoring of the diet. The exercise session consisted of activities such as stretching, resistance training, and walking. Blood pressure, urinary sodium and potassium excretion, dietary and lifestyle data, and non-fasting venous blood sample were collected at baseline and after the intervention period. RESULTS: Thirty nine subjects were eligible for participation and the follow-up rate was 97.4%. The C allele proportion was 57.9%. AT2R 3123C/A polymorphism was X-chromosome-linked, therefore we analyzed the C and A genotypes. At baseline, no significant differences were observed between the genotype groups. After the intervention, there were no significant differences in lifestyle habit between the groups. Nevertheless, the estimated salt excretion (g/day) was significantly decreased only in the C genotype (13.0-10.3, P = 0.031). No significant change was observed in systolic blood pressure (SBP) (mmHg) in the A genotype, but a significant decrease was observed in the C genotype (150.0-141.5, P = 0.024). CONCLUSTIONS: In the C genotype, it might be easy to improve SBP through lifestyle intervention in free-living hypertensive Japanese men, however generalization could not be achieved by the small sample size.

• The Korean Journal of Nuclear Medicine
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• v.31 no.4
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• pp.427-432
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• 1997

Re-188 is useful candidate for therapeutic radionuclide because it has a physical half life of 17 hours, contains beta emissions suitable for therapy(maximum energy 2.12MeV) and emits a gamma ray that is suitable for quantitative diagnostic scanning(155keV). To use Re-188 as a radionuclide compound of angioplasty balloon radiotherapy, we investigated the labelling method and biodistribution of Re-188-DTPA We postulated that labeled Re-188-DTPA is preferable because it would be excreted via urinary system more easily than other compounds. To label Re-188 with DTPA, 1ml of 222MBq(6mCi) of Re-188 was added to DTPA solution(DTPA 20mg, $SnCl_2{\cdot}2H_2O$ 10mg, pH 3.5) and boiled at $100^{\circ}C$ for 120min in water bath. pH was adjusted to 5 with 2.3% sodium acetate. Labeling efficiency was measured using TLC-SG(acetone, saline). We evaluated biodistribution of Re-188-DTPA in sacrificed mice at 10 and 60 minutes after injection. We acquired images of kidneys, and drew time-activity curves in normal dogs and rats and calculated Tmax and Tl/2 in rats. The labelling efficiency was 95.7% on average. Labelling of Re-188-DTPA was.stable(90% after 5hours) in vitro at room temperature. According to time-activity curves of dogs and rats, it took 15 to 20 minutes after injection for Re-188-DTPA to be washed out through kidneys. In conclusion, Re-188-DTPA was successfully labeled, Re-188-DTPA was stable in vitro and was excreted early via kidneys in animals. We could recommend Re-188-DTPA as radionuclide of potential use in angioplasty balloon radiotherapy.

• Asian-Australasian Journal of Animal Sciences
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• v.14 no.9
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• pp.1238-1244
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• 2001

Two calorimetric experiments were performed to investigate the effects of two diets with same concentrate: roughage ratio (70:30) but varying in composition on energy metabolism and methane production in faunated (F) and defaunated (DF) Muzaffarnagari sheep. For experiment I, ten animals were divided equally into two groups of which one was kept normally F as such while other was DF using 10% sodium lauryl sulphate. All the animals were offered diet I which comprised of oat hay and concentrate mixture I (CM I) containing maize grain (93%) as a major ingredient in 70:30 ratio. Similarly, the experiment II was conducted for which four F and four DF sheep (same as used for experiment I) were switched to diet II that consisted of maize hay and CM II (maize grain 59% + molasses 36%). Through diet II, DM intake in DF sheep was significantly (p<0.05) lower. Intake of GE through both the diets was similar in F and DF sheep. Digestibility of DM, OM, CP and GE and also metabolisability (ME/GE) was similar in F and DF sheep on both the diets. Total urinary energy loss did not differ in F and DF on both the diets, but methane energy loss as a percent of GE in DF was significantly (p<0.05) lower on diet I (3.75 vs 2.48), while it did not differ on diet II (3.20 vs 3.60). Heat production was significantly (p<0.01) reduced in DF on both the diets. Although, efficiency of utilisation of ME for maintenance calculated as per ARC (1984) did not differ in F and DF on both the diets, efficiency for maintenance and growth was higher (0.60 vs 0.672) on diet I in DF. It was inferred that methane production in DF sheep reduces on good quality hay-based diet supplemented with slowly fermentable carbohydrate (maize grain) but supplementation of molasses (rapidly fermentable CHO) nullify this effect when sheep were fed diets with concentrate: roughage ratio of 70:30.

• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.1
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• pp.84-92
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• 2004

The present study examined the effects of Taekunyukmijiwhang-tang (TV) on blood pressure and renal function in nitric oxide (NO)-dependent hypertensive rats. A phamacological inhibition of nitric oxide synthase (NOS) for 4-6 weeks produces renal vasoconstriction, renal dysfunction, and progressive severe hypertension. Treatment of rats with NG-Nitro-L-arginie methylester (L-NAME) (100 mg/L, 6 weeks), which is a nonspecific NOS inhibitor, cause a sustained increase in systolic blood pressure (SBP), along with the decrease in expression of ecNOS in the kidney and thoracic aorta. The expression of Na, K-ATPase α1 subunit in the kidney was also reduced in the L-NAME induced hypertensive rats group. The renal functional parameters including urine osmolality (Uosm), creatinine clearance (Ccr), which is an index of glomerular filtration (GFR) were decreased in rat with L-NAME induced hypertension. while solute-free water reabsoption (TcH₂O) was unchanged in all experimental group. However, the group combined treated with TV and L-NAME did not develop hypertension and expression of ecNOS in the aorta was restored. The expression of Na/sup +/, K/sup +/-ATpase α1 subunit in the kidney was markedly restored in L-NAME-induced hypertension rats by administration of TV along with the restoration of urinary volume (UV) and sodium excretion (UNaV), whlie Na/sup +/, K/sup +/-ATPase /β1 subunit was not altered. These results suggest that TV attenuates an increase in SSP in the L-NAME induced hypertension and restores partially renal function, which seems to be caused by up-regulation of expression of Na/sup +/, K/sup +/-ATPase α1 subunit in the kidney and ecNOS in thoracic aorta.

• Journal of Chest Surgery
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• v.3 no.2
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• pp.73-90
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• 1970

Clinical perfusion data on 16 cases of cardiopulmonary bypass using Sigmamotor pump and RyggKyvsgaard Oxygenator which performed at Seoul National University Hospital during the period of Aug. 1968 to Aug. 1970 was analized. AIl cases were hemodiluted and the perfusion was carried out under the normothermic condition. The age of the patients ranged between 6 and 43 years. The b:dy weight varied between 18.3 and 54.0 kg and the body surface area between 0.78 and 1. 59$M^2$. The priming solution was consiste:I with fresh ACD blood. Hartmann solution and Mannitol. The average amount of priming was approximately 2242 ml. The average hemodilution rate was 17%. The flow rate ranged from 1.7L to 3.5L/Min/$M^2$ and averaged 2.4L/Min/$M^2$ or 78mI/Min/kg. The duration of perfusion varied from 22 to 110 min with average of 56.9 minutes. Some hemodynamic responses were observed. The arterial pressure dropped immediately after the initiation of partial perfusion and was more marked after the total perfusion foIlowed by gradual increase to the safety level. The central venous pressure reflected the reduced blood volume especially in the cases of prolonged perfusion which lasted over 60 min. In most of the cases, red blood cell count decreased and white blood ceIl count increased after the perfusion. Hemoglobin level was decreased, averaging of 12.5mg%, Hct 3.3% and platelets count of 18% postoperatively. Plasma hemoglobin increased mildly, from pre-perfusion average value of 4. 06mg% to postperfusion value of 22.5mg%. Serum potassium was 4.4mEq/L pre-operatively and was decreased to 3.7mEq/L postoperatively. Five cases showed definite hypopotassemia immediately after the operation. Sodium and chloride decreased mildly. These electrolyte changes are thought to be related with hemodilution. diuretics and reduced blood volume during and after the perfusion. Arterial blood pH value revealed minimal to moderate elevation from preperfusion average value of 7.376 to 7.461 during perfusion and then 7.365 after perfusion. The pC02 and hicarbonate showed minimal to moderately lowered values. The total CO2 was decreased. Buffer base decreased during perfusion (Av. 42.6mEq/L) and further decreased after the perfusion (Av. 40.8mEq/L). These arterial blood acid base changes suggested that the metabolic acidosis was accompanied by respiratory alkalosis during and immediately after the perfusion. Authors belived that the acidosis could more effectively be corrected with the more additional dose of bicarbonate than we used by this study. The chest tune drainage during the first 24 hours following operation was 1158 ml in average. One case (Case No. 15) showd definite bleeding tendency and it was believed that the cause might be due to the defect of heparin and protamine titration. The average urinary out put during 24 hours post-perfusion was 1291ml. One case (Case No. ]) showed definite post perfusion oliguria. As conclusion hemodilution using fresh ACD blood. Hartmann and Mannitol solution added with Bivon and high flow rate unler normothermia. was thought to amelioratc the severity of mctabolic acidosis during and after perfusion with relatively satisfactory effect on the diuresis and bleeding tendency.

• Childhood Kidney Diseases
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• v.9 no.2
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• pp.128-136
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• 2005

Purpose : Urine collection using a sterile adhesive bag for urinalysis has been used commonly in infants and young children. However, this method has had some drawbacks. So, this study was performed to evaluate the usage of disposable diapers as a substitute for the routine urine collection method. Methods : 60 mL of self voided fresh urine was collected from 99 patients. Half of the urine was poured on the disposable diapers which did not contain absorbent gel beads. After 1 hr, we obtained the urine samples(extracted urine) by compressing the wet diapers using a 50 ml syringe. Routine, microscopic and biochemical analyses were performed on the other half of fresh urine and extracted urine. Then we compared each result by correlative analysis. Results : 198 samples from 99 patients were evaluated. The results of routine urinalysis except WBC and biochemical urinalysis showed a significant correlation between the two groups(P<0.05). The relative coefficients of urine SG, pH, glucose, protein, blood and leukocytes between the two groups were 0.964, 0.938, 0.977, 0.956, 0.931 and 0.738, respectively. Those of urinary sodium, potassium, chloride and creatinine were 0.997, 0.998, 0.995 and 0.998, respectively Microscopic examinations showed lower relative coefficients than the other results, 0.740 for RBC and 0.602 for WBC, but these were still significant(P<0.05). Conclusion : The results of the urine analysis with extracted urine from diapers correlates well with that of fresh urine. This new method is very helpful and can be used as an alternative of urine collection, especially for infants and young children. (J Korean Soc Pediatr Nephrol 2005;9:128-136)

• Korean Journal of Community Nutrition
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• v.7 no.1
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• pp.121-129
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• 2002

Osteoporosis, the typical metabolic bone disease of the elderly, is characterized by a reduction in bone mineral density (BMD) and increased fracture risk. Genetic and environmental factors are known to play a key role in bone metabolism, and diet is also considered to be one of the important factors. The purpose of the present study was to investigate the relationship among the factors affecting BMD, including stature, body weight, age, time period since onset of menopause, and biochemical markers of bone turnover in postmenopausal women. Seventy-eight postmenopausal women who visited health promotion center for health examinations volunteered to participate in this study and they were divided into two groups according to the time period since onset of menopause : women with a time period since onset of menopause of less than 5 years (Group 1) and women with a time period since onset of menopause of 5 years or more (Group 2). The demographic characteristics and dietary intake were surveyed using a questionnaire. BMDs of the lumbar spine and femoral neck of subjects were measured by dual energy X-ray absorptiometry. Serum levels of 25-hydroxy-vitamin D and parathyroid hormone (PTH), known to be indicators of bone related hormone status, were anlyzed. Serum samples were measured for calcium, phosphorus, alkaline phosphatase, and osteocalcin as bone formation indicators, and urine was analysed for deoxypyridinoline, creatinine, calcium, and sodium as bone resorption indicators. The results are as follow : The mean BMDs of the lumbar spin and femoral neck were $1.02 \pm 0.02 g/cm^2 and 0.81 \pm 0.02 g/cm^2 respectively, and the BMD level of Group 2 was significantly lower than tat of Group 1 (p<0.01, p<0.05, respectively). The mean daily intake of energy was 1838 $\pm$ 55 kcal. When nutrient intake was compared with the recommended dietary allowances (RDA) of the subjects, only calcium, vitamin A and riboflavin intake showed means lower than the RDA. The nutrient intake did not show any significant differences between Group 1 and 2 Serum and urine levels of biochemical markers of bone turnover did not show any significant differences between Group 1 and 2, and all were within the normal range. However, the PTH and deoxypyridinoline levels showed a tendency to be higher, and the osteocalcin level to be lower in Group 2 than in Group 1. Although age and years after menopause (YAM) showed negative correlations with lumbar spine bone mineral density (LBMD) (r= -0.38, p<0.001, and r= -0.26, p< 0.05, respectively), no correlation was found with femoral neck bone mineral density (NBMD). While height, body weight and body mass index (BMI) showed a positive correlation with LBMD (r= 0.32, p<0.001, r= 0.38, p<0.001, r= 0.22, p= 0.05, respectively), only body weight and BMI showed a positive correlation with NBMD (r= 0.30, p<0.01, and r= 0.27, p<0.05, respectivley). There was no significant corealtion between BMDs and the nutrient intake of subjects, except in the case of carbohydrates (r= 0.22, p<0.05). Also, serum and urine levels of bone turnover markers showed no significant correlation with nutrient intake. On the other hand, serum osteocalcin had a positive correlation with vitamin C intake (r= 0.22, p= 0.05), and urine deoxypyridinolin showed a negative correlation with niacin intake (r= -0.22, p= 0.05). Urinary na was negatively correlated with protein intake(r= -0.23, p= 0.05). The results suggested that it is difficult to prevent the decrease in bone mass among postmenopausal women eating the usual Korean diet. However, the BMDs of the lumbar spine and femoral neck were positively related to body weight ad BMI in postmenopausal women. Therefore, this study confirmed that one of the most effective ways to minimize bone loss in postmenopausal women would be to maintain an adequate body weight with balanced nutrient intake and activity in the pre-and postmenopausal periods.