• 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 Southeast Asian review
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• v.27 no.2
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• pp.37-76
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• 2017

$Nguy{\tilde{\hat{e}}}n$ Cư Trinh has two faces in the history of territorial expansion of Vietnam into the Mekong delta. One is his heroic contribution to the $Nguy{\tilde{\hat{e}}}n$ family gaining control over the large part of the Mekong delta. The other is his role to make the eyes of readers of Vietnamese history be fixed only to the present territory of Vietnam. To the readers, $Nguy{\tilde{\hat{e}}}n$ Cư Trinh's achievement of territorial expansion was the final stage of the nam $ti{\acute{\hat{e}}n$ of Vietnam. In fact, however, his achievement was partial. This study pays attention to the King $V{\tilde{o}}$ instead of $Nguy{\tilde{\hat{e}}}n$ Cư Trinh in the history of the territorial expansion in the Mekong delta. King's goal was more ambitious. And the ambition was propelled by his dream to build a new world, and its order, in which his new capital, $Ph{\acute{u}}$ $Xu{\hat{a}}n$ was to be the center with his status as an emperor. To improve my assertion, three elements were examined in this article. First is the nature of $V{\tilde{o}}$ Vương's new kingship. Second is the preparation and the background of the military operation in the Mekong Delta. The nature of the new territory is the third element of the discussion. In 1744, six years after this ascending to the throne, $V{\tilde{o}}$ Vương declared he was a king. Author points out this event as the departure of the southern kingdom from the traditional dynasties based on the Red River delta. Besides, the government system, northern custom and way of dressings were abandoned and new southern modes were adopted. $V{\tilde{o}}$ Vương had enough tributary kingdoms such as Cambodia, Champa, Thủy $X{\tilde{a}}$, Hoả $X{\tilde{a}}$, Vạn Tượng, and Nam Chưởng. Compared with the $L{\hat{e}}$ empire, the number of the tributary kingdoms was higher and the number was equivalent to that of the Đại Nam empire of the 19th century. In reality, author claims, the King $V{\tilde{o}}^{\prime}s$ real intention was to become an emperor. Though he failed in using the title of emperor, he distinguished himself by claiming himself as the Heaven King, $Thi{\hat{e}}n$ Vương. Cambodian king's attack on the thousands of Cham ethnics in Cambodian territory was an enough reason to the King $V{\tilde{o}}^{\prime}s$ military intervention. He considered these Cham men and women as his amicable subjects, and he saw them a branch of the Cham communities in his realm. He declared war against Cambodia in 1750. At the same time he sent a lengthy letter to the Siamese king claiming that the Cambodia was his exclusive tributary kingdom. Before he launched a fatal strike on the Mekong delta which had been the southern part of Cambodia, $V{\tilde{o}}$ Vương renovated his capital $Ph{\acute{u}}$ $Xu{\hat{a}}n$ to the level of the new center of power equivalent to that of empire for his sake. Inflation, famine, economic distortion were also the features of this time. But this study pays attention more to the active policy of the King $V{\tilde{o}}$ as an empire builder than to the economic situation that has been told as the main reason for King $V{\tilde{o}}^{\prime}s$ annexation of the large part of the Mekong delta. From the year of 1754, by the initiative of $Nguy{\tilde{\hat{e}}}n$ Cư Trinh, almost whole region of the Mekong delta within the current border line was incorporated into the territory of $V{\tilde{o}}$ Vương within three years, though the intention of the king was to extend his land to the right side of the Mekong Basin beyond the current border such as Kampong Cham, Prey Vieng, and Svai Rieng. The main reason was $V{\tilde{o}}$ Vương's need to expand his territory to be matched with that of his potential empire with the large number of the tributary kingdoms. King $V{\tilde{o}}^{\prime}s$ strategy was the variation of 'silkworm nibbling' and 'to strike barbarians by barbarians.' He ate the land of Lower Cambodia, the region of the Mekong delta step by step as silkworm nibbles mulberry leave(general meaning of $t{\acute{a}}m$ thực), but his final goal was to eat all(another meaning of $t{\acute{a}}m$ thực) the part of the Mekong delta including the three provinces of Cambodia mentioned above. He used Cham to strike Cambodian in the process of getting land from Long An area to $Ch{\hat{a}}u$ Đốc. This is a faithful application of the Dĩ Man $C{\hat{o}}ng$ Man (to strike barbarians by barbarians). In addition he used Chinese refugees led by the Mạc family or their quasi kingdom to gain land in the region of $H{\grave{a}}$ $Ti{\hat{e}}n$ and its environs from the hand of Cambodian king. This is another application of Dĩ Man $C{\hat{o}}ng$ Man. In sum, author claims a new way of looking at the origin of the imperial world order which emerged during the first half of the 19th century. It was not the result of the long history of Đại Việt empires based on the Red River delta, but the succession of the King $V{\tilde{o}}^{\prime}s$ new world based on $Ph{\acute{u}}$ $Xu{\hat{a}}n$. The same ways of Dĩ Man $C{\hat{o}}ng$ Man and $T{\acute{a}}m$ Thực Chi $K{\acute{\hat{e}}}$ were still used by $V{\tilde{o}}^{\prime}s$ descendents. His grandson Gia Long used man such as Thai, Khmer, Lao, Chinese, and European to win another man the '$T{\hat{a}}y$ Sơn bandits' that included many of Chinese pirates, Cham, and other mountain peoples. His great grand son Minh Mạng constructed a splendid empire. At the same time, however, Minh Mạng kept expanding the size of his empire by eating all the part of Cambodia and Cham territories.