• 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.

• Journal of Sericultural and Entomological Science
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• v.25 no.1
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• pp.34-43
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• 1983

These studies have been carried out to find better locations for sericultural service regardless of the international silk market fluctuation in Korea. In order to acieve the purpose, various investigations and analyses have been carried out for more than four hundred sericultural communities to find out the main factors which caused to decrease in cocoon production in spite of a gloomy past silk market. Now, we believe that we have set up some fundamental guide lines in developing sound serviceable sericultural communities in Korea in case the government accepts the written advices, and the results obtained are as follows: 1. The Korean sericulture has been very prosperous from the 60's to the 70's. In 1976 the cocoon production was at its peak, reaching 41,704M/T from which its decline took place with annual averages of 18.5% for total cocoon production and 16.4% for mulberry field. These figures represent a quantitative decrease to one-third of the total amount in 1976. Since then, the Korean sericulture had continuously suffered from a shortage of raw silk resulting in a slow development of sericulture. At present, a steady development through all possible measures is great importance. 2. The downfall of the korean sericulture resulted from two factors of such as the external, which led to the decline in the price of raw silk at the international market and restrain of import and, the internal, resulting in the little increase of cocoon price and a comparatively lower benefits from the sericulture than from other cash crops. 3. The already established sericultural zone collapsed and then reorganized with the outstanding regional specialization so the decline in total cocoon production in the country. Based on the agricultural regions, 1980 cocoon production was very stable in the mountaineaus area of the east-south which used with intercropping. In this area there was small decline of 33% compare with that of the 1979, and with 70% decline in the dry field farming area of Kangwon Do. In an administrative districtwise, six counties beginning with Sanchnung county of Kyungsang Nam Do, showed less than 20% decline of cocoon production, sixteen counties beginning with Samchuck county of Kangwon Do marked above 80% decrease of cocoon production. In the smaller unit area-wise, there was a big difference among them. twenty-five myons rather increased and a hundrd fourty-three myons decreased above 80% of it. 4. The cocoon production was positively correlated with the decreasing percentage of cocoon production per household. It was also affected by the ratio of the mulberry field area to the total cultivated area per household and cocoon productivity per 10a. 5. Four hundred sixty-four villages in the seventeen counties were surveyed on the basis of farm management and techniques concerned ('80/'79), and then the results were evaluated by using of computer. These results are summarized as foolows: (1) Cocoon production per household There was no difference among the agricultural regions in cocoon production. The cocoon production per household in the comparatively stable villages increased from 100.8kg in 1979 to 122kg in 1981. Cocoon yield in the stable villages decreased by 20% of '81/'79. The cocoon production per house hold in while that of the unstable villages decreased by more than 40% from 102.9kg in 1979 to 82kg in 1981. (2) Cocoon yield per 10a mulberry field The cocoon yield per 10a was higher in the plain area than in the mountaineous area. The stable villages had an average of 73.4kg cocoon yield/10a while the unstabe ones had only an average of 55kg. (3) Adoption the mulberry branch rearing method The branch rearing method was more popular in the plain area than in the mountainous area. In the stable vilages adopted 24.2% in spring and 16.7% in autumn of 1979. In 1981 it shwed increases of 34.3% and 10.1% in the two seasons respectivly. However, the unstable villages showed 13.3% and 126% in both seasons, respectively. (4) The patterns of the combined management system in the sericultural farming The popular management system in the sericultural from was combined with rice and other cash crops, showing 55% of the total households surveyed. Fourteen percent of the households combined the management system with rice and other cash crops and 14% of the households combined with rice only. The villages wich earned less than 20% of the total income from the sericulture reached 81% of the total houscholds indicating that they were still far beyond a complete combination system. (5) Damage by agricultural chemicals The damage caused by agricultural chemicals was mainly due to the protection of rice against insectpests and diseases in the plain areas and took place mostly in the autumn season. The chemicals applied was 65% of Iiquid and 35% of powder forms and 35% of damage was from granulat form of the chemicals. The use of the granular chemicals was low because of high cost.