• 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 Korean Society of Forest Science
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• v.25 no.1
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• pp.13-47
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• 1975

Among the many species of bamboo, it is well known that the dwarf-type is widely distributed in the tropical regions, and the slender type in temperated zone. In the temperated zone the trees have extensively differentiated into one hundred species in 50 genera. In many oriental countries, the bamboo wood is being used as a material for construction and for the manufacture of technical instruments. The bamboo shoot is also regarded as a good and delicious edible resource. Moreover, recent medical investigation verifies that the sap of certain species of the bamboo is an antibiotic effect against cancer. Fortunately, it is very easy to propagate the bamboo trees by using cutting from southeastern Asian countries. This important resource can further be used as a significant source of pulp, which is becoming increasingly important. The classification system of this significant resource has not been completely established to date, even though its importance has been emphasized. Initiated by Canlevon Linne in the 18th century, a classification method concerning the morphological characteristics of flowers was the first step in developing a classification. But it was not an easy task to accomplish, because this type of classification system is based on the sexual organs in bamboo trees. Because the bamboo has a long life cycle of 60-120 years and classification according to this method was very difficult as the materials for the classification are not abundant and some species have changed, even though many references related to the morphological classification of bamboo trees are available nowadays. So, the certification of bamboo trees according to the morphological classification system is not reasonable for us. Consequently, the classification system of bamboo trees on the basis of endomorphological characteristics was initiated by Chinese-born Liese. And classification method based on the morphological characteristics of the vascular bundle was developed by Grosser. These classification methods are fundamentally related to Holltum's classification method, which stressed the morphology of the ovary. The author investigated to re-establish a new classification method based on the vascular sheath. Twenty-six species in 11 genera which originated from Formosa where used in the study. The results obtained from the investigation were somewhat coordinated with those of Crosser. Many difficulties were found in distinguishing the species of Bambusa and Dendrocalamus. These two species were critically differentiated under the new classification system, which is based on the existence of a separated vascular bundle sheath in the bamboo. According to these results, it is recommended that Babusa divided into two groups by placing it into either subspecies or the lower categories. This recommendation is supported by the observation that the evolutional pattern of the bamboo thunk which is from outward to inward. It is also supported by the viewpoint that the fundamental hypothesis in evolution is from simple to complex. There remained many problems to be solved through more critical examination by comparing the results to those of the classification based on the sexual organs method. The author observed the figure of the cross-sectional area of vascular trunk of bamboo tree and compared the results with those of Grosser and Liese, i.e. A, $B_1$, $B_2$, C, and D groups in classification. Group A and $B_2$ were in accordance with the results of those scholars, while group D showed many differences, Grosser and Liese divided bamboo into "g" type and "h" type according to the vascular bundle type; and they included Dendrocalamus and Bambusa in Group D without considering the type of vascular bundle sheath. However, the results obtained by the author showed that Dendrocalamus and Bambusa are differentiated from each other. By considering another group, "i" identified according to the existence of separated vascular bundle sheath. Bambusa showed to have a separated vascular bundle sheath while Dendrocalamus does not have a separated vascular bundle sheath. Moreover, Bambusa showed peculiar characteristics in the figure of vascular development, i.e., one with an inward vascular bundle sheath and the other with a bivascular bundle sheath (inward and outward). In conclusion, the bamboo species used in this experiment were classified in group D, without any separated vascular bundle sheath, and in group E, with a vascular bundle sheath. Group E was divided into two groups, i.e., and group $E_1$, with bivascular sheath, and group $E_2$, with only an inward vascular sheath. Therefore, the Bambusa in group D as described by Grosser and Liese was included in group E. Dendrocalamus seemed to be the middle group between group $E_l$ and group $E_2$ under this classification system which is summarized as follows: Phyllostachys-type: Group A - Phyllostachys, Chymonobambus, Arundinaria, Pseudosasa, Pleioblastus, Yashania Pome-type: Group $B_2$ - Schizostachyum, Melocanna Hemp-type: Group D - Dendrocalamu Bambu-type: Group $E_1$ - Bambusa ghi.