• The Korean Journal of Physiology
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• v.8 no.2
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• pp.1-17
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• 1974

This experiment was designed to explore the specific functional interrelations between the vestibular semicircular canals and the extraocular muscles which may disclose the neural organization, connecting the vestibular canals and each ocular motor nuclei in the brain system, for vestibuloocular reflex mechanism. In urethane anesthetized rabbits, a fine wire insulated except the cut cross section of its tip was inserted into the canals closely to the ampullary receptor organs through the minute holes provided on the osseous canal wall for monopolar stimulation of each canal nerve. All extraocular muscles of both eyes were ligated and cut at their insertio, and the isometric tension and EMG responses of the extraocular muscles to the vestibular canal nerve stimulation were recorded by means of a physiographic recorder. Upon stimulation of the semicircular canal nerve, direction if the eye movement was also observed. The experimental results were as follows. 1) Single canal nerve stimulation with high frequency square waves (240 cps, 0. 1 msec) caused excitation of three extraocular muscles and inhibition of remaining three muscles in the bilateral eyes; stimulation of any canal nerve of a unilateral labyrinth caused excitation (contraction) of the superior rectus, superior oblique and medial rectus muscles and inhibition (relaxation) of the inferior rectus, inferior oblique and lateral rectos muscles in the ipsilateral eye, and it caused the opposite events in the contralateral eye. 2) By the overlapped stimulation of triple canal nerves of a unilateral labyrinth, unidirectional (excitatory or inhibitory) summation of the individual canal effects on a given extraocular muscles was demonstrated, and this indicates that three different canals of a unilateral vestibular system exert similar effect on a given extraocular muscles. 3) Based on the above experimental evidences, a simple rule by which one can define the vestibular excitatory and inhibitory input sources to all the extraocular muscles is proposed; the superior rectus, superior oblique and medial rectus muscles receive excitatory impulses from the ipsilateral vestibular canals, and the inferior rectus, inferior oblique and lateral rectus muscles from the contralateral canals; the opposite relationship applies for vestibular inhibitory impulses to the extraocular muscles. 4) According to the specific direction of the eye movements induced by the individual canal nerve stimulation, an extraocutar muscle exerting major role (a muscle of primary contraction) and two muscles of synergistic contraction could be differentiated in both eyes. 5) When these experimental results were compared to the well known observations of Cohen et al. (1964) made in the cats, extraocular muscles of primary contraction were the same but those of synergistic contraction were partially different. Moreover, the oblique muscle responses to each canal nerve excitation appeared to be all identical. However, the responnes of horizontal (medial and lateral) and vertical (superior and inferior) rectus muscles showed considerable differences. By critical analysis of these data, the author was able to locate theoretical contradictions in the observations of Cohen et al. but not in the author's results. 6) An attempt was also made to compare the functional observation of this experiment to the morphological findings of Carpenter and his associates obtained by degeneration experiments in the monkeys, and it was able to find some significant coincidence between there two works of different approach. In summary, the author has demonstrated that the well known observations of Cohen et al. on the vestibulo-ocular interrelation contain important experimental errors which can he proved by theoretical evaluation and substantiated by a series of experiments. Based on such experimental evidences, a new rule is proposed to define the interrelation between the vestibular canals and the extraocular muscles.

• 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 agricultural medicine and community health
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• v.8 no.1
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• pp.44-65
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• 1983

As a part of the epidemiological studies of clonorchiasis, this study was conducted to evaluate the current endemicity and the natural transition of the Clonorchis infection in Gimhae Gun and delta area a high endemic area in Korea in recent years, prior to the introduction of praziquantel which will eventually influence the status of the prevalence. The data obtained in this study in 1983 were evaluated for natural transition of the infection in comparison with those obtained 16 years ago in 1967 by the author(Kim, 1974). The areas of investigation, villages and schools surveyed, methods and techniques used in this study were the same as in 1967, except for the contents of the questionnaire for raw freshwater fish consumption by the local inhabitants. 1) The prevalence rate of clonorchiasis in the general population of the villages was 48.1% on the average out of a total of 484 persons examined. The average of those of the riverside-delta area was 65.2% and 43.0% in the inland area. Among the schoolchildren, the prevalence rate was 8.2% on the average out of a total of 1,423 examined. By area, the prevalence rate was 10.8% in the riverside delta area and 2.8% in the inland area. By sex, difference in the prevalence was seen only in the inhabitants of the inland area showing 52.4% in the male and 33.5% in the female. 2) In the natural transition of the infection, the prevalence rate among the inhabitants has decreased from 68.8% in 1967 to 48.1% in 1983, and in the schoolchildren from 56.4% in 1967 to 8.2% in 1983. The reduction rate was higher in the riverside-delta area than in the inland area. 3) In the prevalence rate by age, 11.9% was first seen in the 5-9 age group and the rate gradually increased up to 75.0% in the 50-59 age group. By sex, the rate was higher in the male than in the female in the 20-29 age group and over. 4) In the natural transition of the prevalence rate by age, the reduction rate of the infection during the past 16 years was greater in the younger age groups up to the 40-49 age group and reached the same level in the age group 50-59. Reduction was seen again in the age group over 60s. By sex, the reduction rate was greater in the female than in the male in the 20-29 age group and over. By area, the reduction rate was greater in the riverside delta area than in the inland area, particularly in the young age groups. 5) In the intensity of the infection among the cases, the mean egg out-put per mg feces per infected cases(EPmg) in the inhabitants was 6.3. EPmg of those of the river-side-delta area was 15.4 and that of the in-land was 2.8. On the other hand, in the schoolchildren, EPmg was 3.2, and no difference was seen between the two areas, the river-side-delta area and the inland area. 6) In the transition of the intensity of the infection by area, EPmg among the inhabitants inexplically increased from 7.8 in 1967 to 15.4 in 1983. This was probably caused by uneven specimen collection in the process of sampling the population. EPmg of the inhabitants in the inland area and those of the schoolchildren of both riverside delta and inland areas showed a similar decrease in the past 16 years. 7) The intensity of the infection by age showed a relatively low level in the 20-29 age group and below, and EPmg 5.1-9.5 was seen in the 30-39 age group and over. Sex, Epmg was 5.8 in the male and 4.7 the female. By in 8) In the transition of the intensity of the infection, EPmg decreased from 6.2 in 1967 to 5.4 in 1983. By age, in contrast to the figures of 1967 in which EPmg gradually increased with some fluctuation from 1.1 in the 0-4 age group to peak 10.5 in the 50-59 age group, in 1983 lower intensity of the infection was seen in the age group from 10-14 to 20-29 with the EPmg range of 0.6-2.7. 9) In the distribution of the clonorchiasis cases by the range of EPmg value, 43.2% of the cases were in 0.1 0.9 and 34.6% in 1.0-4.9. As a whole by cumulative percent, 44.6% of them were under 0.9 as light infection and 86.1% of them under 9.9 up to moderate infection. By sex, no difference was seen in Epmg. 10) In the transition of the distribution by the range of Epmg, the cases were distributed up to the range 80.0-99.9 in 1967 and to 60.0-79.9 in 1983. By cumulative percent, in the range of 0.1-0.9 and less, light infection, 34.3% of them were distributed in 1967 and 44.6% in 1983 with about 10% increase. In the range of 5.0-9.9 and less, up to moderate infection, 83.2% in 1967 and 86.1% in 1983 of the cases were seen, respectively. 11) The practice of raw freshwater fish consumption among the inhabitants seems to have decreased in recent years. Those who admitted to raw freshwater fish consumption in the last two years among the infected inhabitants were 59.3%, although 86.8% of them professed to have experience with raw freshwater fish consumption. 31.7% of those who have had experience of the raw freshwater fish consumption denied any further consumption in recent years. From an interview of 543 school-children, 24.1% of them admitted to an experience of raw freshwater fish consumption. However, those who have practised in the past two years comprized 17.9%. Those who denied raw freshwater fish consumption in recent years among those who had such experience were 26.0% out of 131 interviewed. The rate of raw freshwater fish consumption in both inhabitants and schoolchildren were higher in the male than in the female. On the contrary, the rate of those who did not practise in recent years among those who had experience of raw freshwater fish consumption was higher in the female than in the male. 12) The major reason for the reduction of raw freshwater fish consumption among the local inhabitants was the risk of the fluke infection. However, it has become apparent that such change of taste has resulted from water pollution impact which has affected throughout the areas of the freshwater systems in this locality since last several years. 13) In animal survey, Clonorchis infection was seen in 14.8% of 88 dogs examined and 3.7% of 27 house rats examined. It was noted that populations of dogs and cats have increased in the villages surveyed. Although the prevalence rate was lower in the present survey than those of 1967, the significance of the animals as the reservoir host has not changed. 14) Prevalence rate of Clonorchis infection by cercariae in the first intermediate host, Parafossarulus manchouricus, was 0.6% out of 517 snails examined. The infection rate was lower in comparison with 2.3% out of 2,124 examined in 1967. Moreover, sharp decreases in number and distribution of the intermediate host snails in many watershed areas of the huge freshwater systems in this locality seemed to reduce transmission of Clonorchis in connection with the intermediate host stage of its life cycle. 15) Clonorchis infection in the second intermediate fish hosts was relatively low. The mean number of Clonorchis metacercaria per fish in Pseudorasbora parva was 517 in 1983, whereas it was 1943 in 1968 through 1969. Environmental water pollution has also caused the decreased fish population density in these areas, and this has also apparently affected to the practice of raw freshwater fish consumption among the local inhabitants. 16) In conclusion, endemicity of Clonorchis infection in Gimhae Gum and delta area of the Nagdong River has sharply decreased during the past 16 years. The major cause of the regressive transition of the infection was the water pollution of the land water systems of this locality. The pollution has upset the ecosystems comprizing of the intermediate hosts of Clonorchis in many areas, and also affected to a significant extent to the discontinuance of the local inhabitants for raw freshwater fish consumption.

• Parasites, Hosts and Diseases
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• v.24 no.2
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• pp.177-186
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• 1986

This study was designed to evaluate the partially purified antigens which were fractionated from crude extract of Paragonimus westermani and to monitor the enzyme-linked immunosorbent assay (ELISA) in experimental cat paragonimiasis during the course of infection as well as before and after chemotherapy. Crude extract of 6-month-old adult P. westermani was fractionated to 5 antigens by successive applications of ammonium sulfate precipitation, ion exchange chromatography and gel filtration. And the cats, 10 in each group, were infected with 60, 30, 15, and 5 metacercariae, then the half of each group was treated with praziquantel 2 times in one day of 100mg per kilogram of weight on 150 days after the infection. Sera were collected every 10 days. ELISA was performed with the concentration of $2{\mu}g/ml$ antigen, 100 times diluted sera and 1,000 times diluted alkaline phosphatase conjugated anti-cat IgG. The results were as follows: 1. Absorbance by ELISA with proteins precipitated by differential concentration of ammonium sulfate was the highest at $51{\sim}65%$ precipitate (PA2), followed by $0{\sim}50%$ precipitate (PAl), $66{\sim}80%$ precipitate (PA3), and $81{\sim}90%$ precipitate (PA4). Unprecipitated protein over 90% ammonium sulfate (PA5) showed the lowest antigenicity. 2. Fractionation of PA1, PA2, and PA3 through the DEAE-cellulose column did not differentiate the antigenic proteins. 3. By passing through the Sephadex G-200 column, PA1 and PA2 were fractionated to high molecular weight proteins and those of low molecular weight which showed high absorbance by ELISA (PA1-I, II and PA2-I, II). But PA3 was shown to have a fraction of high molecular weight proteins (PA3-I) which showed high antigenicity. 4. SDS-polyacrylamide gel electrophoresis of PA1-I, P A1-II, PA2-I, PA2-II, PA3-I, and crude extract was performed. Fraction PA1-I was composed of proteins which had the molecular weight of 270 kilodaltons(KD) to 196 KD; of them 220KD protein was major band. Fraction PA2-I was composed of $255{\sim}225\;KD$, and PA3-I, $255{\sim}240\;KD$, respectively. Fraction PA1-II and fraction PA2-II consisted of 30 KD proteins. 5. Absorbance by ELISA began to increase within $10{\sim}20$ days after the infection and reached the highest on $140{\sim}180$ days, then made plateau thereafter. 6. Absorbance by ELISA decreased after praziquantel treatment. In 60 metacercariae infection group, the absorbance had been decreasing, but remained within the positive range during observation period, while those of 30, 15, and 5 metacercariae infection groups turned to negative range. 7. Fraction PA1-II showed the highest antigenicity in ELISA, then fraction PA2-I, fraction PA1-I, fraction PA2-II, fraction PA3-I and crude extract followed. In early phase of infection, the absorbance of fraction PA1-II showed more rapid increase than those of the other fractions and it came to positive range at $20{\sim}30$ days after infection.