• 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.

• KOREAN JOURNAL OF CROP SCIENCE
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• v.47
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• pp.15-32
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• 2002

The endeavors enhancing the grain quality of high-yielding japonica rice were steadily continued during 1980s-1990s along with the self-sufficiency of rice production and the increasing demands of high-quality rices. During this time, considerably great progress and success was obtained in development of high-quality japonica cultivars and quality evaluation techniques including the elucidation of interrelationship between the physicochemical properties of rice grain and the physical or palatability components of cooked rice. In 1990s, some high-quality japonica rice cultivars and special rices adaptable for food processing such as large kernel, chalky endosperm, aromatic and colored rices were developed and its objective preference and utility was also examined by a palatability meter, rapid-visco analyzer and texture analyzer, Recently, new special rices such as extremely low-amylose dull or opaque non-glutinous endosperm mutants were developed. Also, a high-lysine rice variety was developed for higher nutritional utility. The water uptake rate and the maximum water absorption ratio showed significantly negative correlations with the K/Mg ratio and alkali digestion value(ADV) of milled rice. The rice materials showing the higher amount of hot water absorption exhibited the larger volume expansion of cooked rice. The harder rices with lower moisture content revealed the higher rate of water uptake at twenty minutes after soaking and the higher ratio of maximum water uptake under the room temperature condition. These water uptake characteristics were not associated with the protein and amylose contents of milled rice and the palatability of cooked rice. The water/rice ratio (in w/w basis) for optimum cooking was averaged to 1.52 in dry milled rices (12% wet basis) with varietal range from 1.45 to 1.61 and the expansion ratio of milled rice after proper boiling was average to 2.63(in v/v basis). The major physicochemical components of rice grain associated with the palatability of cooked rice were examined using japonica rice materials showing narrow varietal variation in grain size and shape, alkali digestibility, gel consistency, amylose and protein contents, but considerable difference in appearance and texture of cooked rice. The glossiness or gross palatability score of cooked rice were closely associated with the peak, hot paste and consistency viscosities of viscosities with year difference. The high-quality rice variety "IIpumbyeo" showed less portion of amylose on the outer layer of milled rice grain and less and slower change in iodine blue value of extracted paste during twenty minutes of boiling. This highly palatable rice also exhibited very fine net structure in outer layer and fine-spongy and well-swollen shape of gelatinized starch granules in inner layer and core of cooked rice kernel compared with the poor palatable rice through image of scanning electronic microscope. Gross sensory score of cooked rice could be estimated by multiple linear regression formula, deduced from relationship between rice quality components mentioned above and eating quality of cooked rice, with high probability of determination. The $\alpha$-amylose-iodine method was adopted for checking the varietal difference in retrogradation of cooked rice. The rice cultivars revealing the relatively slow retrogradation in aged cooked rice were IIpumbyeo, Chucheongyeo, Sasanishiki, Jinbubyeo and Koshihikari. A Tonsil-type rice, Taebaegbyeo, and a japonica cultivar, Seomjinbyeo, showed the relatively fast deterioration of cooked rice. Generally, the better rice cultivars in eating quality of cooked rice showed less retrogradation and much sponginess in cooled cooked rice. Also, the rice varieties exhibiting less retrogradation in cooled cooked rice revealed higher hot viscosity and lower cool viscosity of rice flour in amylogram. The sponginess of cooled cooked rice was closely associated with magnesium content and volume expansion of cooked rice. The hardness-changed ratio of cooked rice by cooling was negatively correlated with solids amount extracted during boiling and volume expansion of cooked rice. The major physicochemical properties of rice grain closely related to the palatability of cooked rice may be directly or indirectly associated with the retrogradation characteristics of cooked rice. The softer gel consistency and lower amylose content in milled rice revealed the higher ratio of popped rice and larger bulk density of popping. The stronger hardness of rice grain showed relatively higher ratio of popping and the more chalky or less translucent rice exhibited the lower ratio of intact popped brown rice. The potassium and magnesium contents of milled rice were negatively associated with gross score of noodle making mixed with wheat flour in half and the better rice for noodle making revealed relatively less amount of solid extraction during boiling. The more volume expansion of batters for making brown rice bread resulted the better loaf formation and more springiness in rice breed. The higher protein rices produced relatively the more moist white rice bread. The springiness of rice bread was also significantly correlated with high amylose content and hard gel consistency. The completely chalky and large grain rices showed better suitability far fermentation and brewing. The glutinous rice were classified into nine different varietal groups based on various physicochemical and structural characteristics of endosperm. There was some close associations among these grain properties and large varietal difference in suitability to various traditional food processing. Our breeding efforts on improvement of rice quality for high palatability and processing utility or value-adding products in the future should focus on not only continuous enhancement of marketing and eating qualities but also the diversification in morphological, physicochemical and nutritional characteristics of rice grain suitable for processing various value-added rice foods.ice foods.