• 대한약리학회지
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• 제16권2호
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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.

• 대한핵의학회지
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• 제1권1호
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• pp.55-66
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• 1967

In view of its prevalence in the Far East area, a more detailed knowledge on the hookworm infection is one of the very important medical problems. The present study was aimed to; determine the infectivity of the artificially hatched ancylostoma duodenale larvae in man after its oral administration, evaluate the clinical symptomatology of such infection, determine the date of first appearance of the ova in the stool, calculate the blood loss per worm per day, assess the relation-ships between the ova count, infectivity(worm load), blood loss and severity of anemia. An erythrokinetic study was also done to analyse the characteristics of hookworm anemia by means of $^{59}Fe\;and\;^{51}Cr$. Materials and Methods Ten healthy male volunteers(doctors, medical students and laboratory technicians) with the ages ranging from 21 to 40 years were selected as the experimental materials. They had no history of hookworm infection for preceding several years, and care was taken not to be exposed to reinfection. A baseline study including a through physical examinations and laboratory investigations such as complete blood counts, stool examination and estimation of the serum iron levels was done, and a vermifuge, bephenium hydroxynaphoate, was given 10 days prior to the main experiment. The ancylostoma duodenale filariform larvae were obtained in the following manner; The pure ancylostoma duodenale ova were obtained from the hookworm anemia patients and a modified filter paper method was adopted to harvest larger number of infective larvae, which were washed several times with saline. The actively moving mature larvae were put into the gelatine capsules, 150 in each, and were given to the volunteers in the fasting state with 300ml. of water. The volunteers were previously treated with intramuscular injection of 15mg. of chlorpromazine in order to prevent the eventual nausea and vomiting after the larvae intake. The clinical symptoms and signs mainly of the respiratory and gastrointestinal tracts, appearance of the ova and occult blood in the stool etc. were checked every day for the first 20 days and then twice weekly until the end of the experiment, which usually lasted for about 3 months. Roentgenological survey of the lungs was also done. The hematological changes such as the red blood cell, white blood cell and eosinophil cell counts, hemoglobin content and serum iron levels were studied. The appearance of the ova in the stool was examined by the formalin ether method and the ova were counted in triplicate on two successive days using the Stoll's dilution method. The ferrokinetic data were calculated by the modified Huff's method and the apparent half survival time of the red blood cells by the modified Gray's method. The isotopes were simultaneously tagged and injected intravenously, and then the stool and blood samples were collected as was described by Roche et al., namely, three separate 4-day stool samples with the blood sample drawing before each 4-day stool collection. The radio-activities of the stools ashfied and the blood were separately measured by the pulse-height analyser. The daily blood loss was calculated with the following formula; daily blood loss in $ml.=\frac{cpm/g\;stool{\times}weight\;in\;g\;of\;4-day\;stool}{cpm/ml\;blood{\times}4}$ The average of these three 4-day periods was given as the daily blood loss in each patient. The blood loss per day per worm was calculated by simply dividing the daily blood loss by the number of the hookworm recovered after the vermifuge given twice a week at the termination of the experiment. The iron loss in mg. through the gastrointestinal tract was estimated with the daily iron loss in $mg=\frac{g\;Hgb/100ml{\times}ml\;daily\;blood\;loss{\times}3.40}{100}$ 3.40=mg of iron per g Hgb following formula; Results 1. The respiratory symptoms such as cough and sputum were noted in almost all cases within a week after the infection, which lasted about 2 weeks. The roentgenological findings of the chest were essentially normal. A moderate degree of febril reaction appeared within 2 weeks with a duration of 3 or 4 days. 2. The gastrointestinal symptoms such as nausea, epigastric fullness, abdominal pain and loose bowel appeared in all cases immediately after the larvae intake. 3. The reduction of the red blood cell count was not remarkable, however, the hemoglobin content and especially the serum iron level showed the steady decreases until the end of the experiment. 4. The white blood cells and eosinophil cells, on the contrary, showed increases in parallel and reached peaks in 20 to 30 days after the infection. A small secondary rise was noted in 2 months. 5. The ova first appeared in the stool in 40. 1 days after the infection, ranging from 29 to 51 days, during which the occult blood reaction of the stool became also positive in almost cases. 6. The number of ova recovered per day was 164, 320 on the average, ranging from 89,500 to 253,800. The number of the worm evacuated by vermifuge was in rough correlation with the number of ova recovered. 7. The infectivity of ancylostoma duodenale was 14% on the average, ranging from 7.3 to 20.0%, which is relatively lower than those reported by other workers. 8. The mean fecal blood loss was 5.78ml. per day, with a range of from 2.6 to 11.7ml., and the mean blood loss per worm per day was 0.30ml., with a range of from 0.13 to 0.73ml., which is in rough coincidence with those reported by other authors. There appeared to exist, however, no correlation between the blood loss and the number of ova recovered. 9. The mean fecal iron loss was 2.02mg. per day, with a range of from 1.20 to 3.89mg., which is less than those appeared in the literature. 10. The mean plasma iron disappearance rate was 0.80hr., with a range of from 0.62 to 0.95hr., namely, a slight accerelation. 11. The hookworm anemia appeared to be iron deficiency in origin caused by continuous intestinal blood loss.

• 한국수산과학회지
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• 제25권2호
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• pp.79-92
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• 1992

건국대학교 축산대학 부설 양어장에서 사육중인 50마리의 무지개 송어 수컷에서 채취된 정액을 각각 1989년 12월부터 1990년 12월까지 $-20^{\circ}C$와 $-40^{\circ}C$에서 1년 1989년 12월부터 2월까지 2개월동안 $-196^{\circ}C$인 액체질소탱크내에서 그리고 1990년 12월부터 2월까지 $-20^{\circ}C,\;-40^{\circ}C,\;-70^{\circ}C$에서 2개월 동안 동결보존후, $-13^{\circ}C$ 냉수에 해동시켜 20분간 원심분리기에서 정자를 분리시킨 다음 Tyrode 용액으로 50배 정도 희석시킨 후의 정자의 생존율 및 운동성과 신선한 난자와 인공수정시킨 후의 수정률 및 부화율을 조사한 결과는 다음과 같다. 동결보존전과 해동후의 정자의 생존율을 비교해 볼 때 전반적으로 생존전과 큰 차이 없이 생존율이 높게 나타났다. 3가지의 항동해제로 동결보존시킨 후 해동된 정자가 포함된 희석액으로 인공수정시킨 후의 수정률은 모두 $99\%$ 이상으로서 이러한 수치는 $99\%$ 이상을 나타내는 대조구와 차이가 없었고, $-20^{\circ}C,\;-40^{\circ}C,\;-70^{\circ}C$\;-196^{\circ}C와 같이 서로 다른 온도에서도 수정률은 대조구와 큰 차이 없이 나타났다. 1M의 DMSO의 항동해제로 $-196^{\circ}C$에서 2개월 동안 동결보존시킨 후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 수정률 및 부화율은 BSA가 포함된 희석액이 각자 $96\%$ 및 $8\%$ 이고, 포함되지 않은 희석액은 각각 $98\%,\;10\%\;$로서 BSA가 포함되지 않은 경우에서 부화율이 약간 높게 나타났다. 1M DMSO의 항동해제로 2개월동안 동종보존시킨 후 해동된 정자가 포함된 희석액으펄 인공수정 시킨지 24일 이후의 부화율은 각각 $-196^{\circ}C$에서 $10\%,\;-40^{\circ}C$에서 $34\%,\;-70^{\circ}C$에서 $35\%$로 나타났다. 1M의 methanol의 항동해제 동결보존시친 후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 부화율은 각각 $-20^{\circ}C$에서 $22\%,\;-70^{\circ}C$에서 $28\%$로 나타났다. 1M glycerol의 항동해제로 동결보존시킨 후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 부화율은 각각 $-20^{\circ}C$에서 $22\%,\;-70^{\circ}C$에서 $33\%$로 나타났다. 1.5M DMSO의 항동제로 2개월동안 동결보존 시킨 후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 부화율은 각각 $-20^{\circ}C$에서 $27\%,\;-40^{\circ}C$에서 $36\%,\;-70^{\circ}C$에서 $35\%$로 나타났다. 1.5M glycerol의 항동해제로 2개월동안 동결보존시킨 후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 부화율은 각각 $-20^{\circ}C$에서 $34\%,\;-40^{\circ}C$에서 $31\%,\;-70^{\circ}C$에서 $31\%$로 나타났다. 1.5M methane의 항동해제로 2개월동안 동결보존시킨후 해동된 정자가 포함된 희석액으로 인공수정시킨지 24일 이후의 부화율은 각각 $-20^{\circ}C$에서 $28\%-40^{\circ}C$에서 $29\%-70^{\circ}C$에서 $28\%$로 나타났다. 신선한 정자의 중편부는 2본의 중앙섬유소, 9본의 외측조대섬유, 미토콘드리아초로 구성되어 있다. 동결보존시 정자는 편모의 구부러짐, 정자경부의 핵막의 이탈, 핵내용물이 유출되는 손상을 입었다.

• Journal of Nutrition and Health
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• 제41권8호
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• pp.701-710
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• 2008

본 연구에서는 총항산화능 및 DPPH radicals 소거활성도를 통하여 항산화능을 확인한 산양삼 에탄올 추출물이 사염화탄소 투여로 급성 손상이 유도된 생쥐의 간에 대하여 보호 효능이 있는지를 확인하고자 하였다. 생리적 지표물질로 혈장 지질, GPT 활성, 혈장과 간의 TBARS 및 항산화효소 활성, 혈액 백혈구의 DNA fragmentation 등을 측정하여 다음과 같은 결과를 얻었다. 산양삼의 DPPH radicals 소거능은 76.85 ${\pm}$ 1.06%, IC50은 33.3 ${\mu}g$/mL였으며 총 항산화능은 2.13 ${\pm}$ 0.06 mmoL/mg으로 양성대조군으로 사용한 아스코르브산 (96.45 ${\pm}$ 0.07%, IC50 = 16.5 ${\mu}g$/mL, 3.63 ${\pm}$ 0.06 mmoL/mg)과 BHT (95.40 ${\pm}$ 0.71%, 3.12 ${\pm}$ 0.02 mmoL/mg) 보다는 낮았지만 천연물질로써는 높은 수준을 보였다. 장기 무게 및 식이 섭취량은 산양삼 추출물 투여 및 사염화탄소 처치 여부에 따라서 어떤 차이도 보이지 않았다. 혈장의 GPT와 혈중 트리글리세리드의 경우 정상대조군에 비해 사염화탄소단독투여군에서 유의하게 낮았으며, 산양삼 추출물 투여군에서는 큰 차이를 보이지 않았다. 혈청 총콜레스테롤 농도는 사염화탄소단독 투여군 (84.5 ${\pm}$ 23.0 mg/dL)이 정상 대조군 (140.6 ${\pm}$ 30.3 mg/dL)에 비하여 유의하게 감소하였으며, 산양삼 추출물 투여군 (130.68 ${\pm}$ 31.33 mg/dL)은 정상대조군과 같은 수준이었다 (p < 0.001). 사염화탄소 단독투여군의 간조직에서 TBARS는 정상대조군 (N)에 비해 28.64% 유의하게 증가하였으며 산양삼 추출물 투여군은 정상대조군과 비슷한 수치를 보였으나 (p < 0.001) 적혈구내의 TBARS는 세 군간의 유의한 차이가 없었다. 간조직의 SOD의 활성은 산양삼 추출물 투여군에서 유의하게 증가하였으며, 적혈구에서는 이러한 차이를 보이지 않았다. 그리고 적혈구내 GPx 활성은 사염화탄소 투여에 의해 20.1% 유의한 감소를 보였으며, 산양삼 추출액을 투여받은 군은 정상대조군의 수준을 유지하였다. 사염화탄소 투여군에서 혈장 백혈구의 tail DNA, tail length, tail moment 모든 값은 정상대조군에 비하여 각각 84.4%, 98.8%, 123.7% 증가하였으며, 산양삼 투여군에서는 이 모든 수치가 대조군의 수준으로 감소하였다 (p < 0.001). 이상의 결과를 종합해 보면 5일간 산양삼 에탄올 추출물을 미리 투여한 후 사염화탄소로 급성 간 손상을 유도하였을 때 혈 중 콜레스테롤 대사를 개선하고, 간의 지질 과산화를 효과적으로 억제하였으며 간의 SOD와 적혈구 GPx의 효소 활성을 대조군 이상으로 유지시키고, 산화적 손상으로부터 DNA를 보호하는 등의 일부 생리 활성을 확인하였다. 그러나 이런 산양삼의 항산화 활성의 작용 기전에 대하여 확실히 규명되어 있지 않아 추후보다 세부적인 연구가 필요할 것으로 사료된다.

• The Korean Journal of Physiology
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• 제20권1호
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• pp.53-63
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• 1986

과산화수소$(H_2O_2)$가 급성 일산화탄소(CO)중독의 회복에 미치는 영향을 알아보기 위하여 가토를 1% Corktm에 30분간 노출시킨후 자연회복군, 100%산소 흡입군 및 $H_2O_2$관장군(10ml/kg의 0.5% $H_2O_2$용액을 2ml내외의 사람혈액과 함께 관장)으로 나누어, 회복기 15,30,60 및 90분에 동맥혈의 $pH,\;PCO_2,\;CO_2$ 및 HbCO 포화도를 측정하여 다음과 같은 결론을 얻었다. pH는 급성 CO중독시 3개군 모두에서 감소하였고, 회복기에는 서서히 증가하여 자연회복군과 100%산소 흡입군은 회복기 90분에 거의 회복되나, $H_2O_2$관장군에서는 pH의 회복이 다른군보다 늦었다. $PaCO_2$는 급성 Co중독시 3개군 모두에서 감소하였고, 회복기에는 서서히 증가하였으나, 자연회복군의 $PaCO_2$는 회복기 90분에 거의 회복하는데 반하여 100%산소흡입군과 $H_2O_2$관장군의 $PaCO_2$는 회복이 늦었고 회복기 90분에도 완전히 회복되지 못하였다. $PaO_2$는 급성 Co중독시 약간 감소하였다가 회복기에는 회복기 15분부터 급격히 증가하였고 회복기 90분까지 대조치보다 높은 $PaO_2$를 유지하였다. 회복기동안 $H_2O_2$관장군의 $PaO_2$는 $102{\sim}107mmhg$로 자연회복군보다 약 10 mmhg 높은 수준을 보였다. HbCO 포화도는 급성 CO중독시 $54{\sim}72%$까지 증가하였다. 회복기에는 $H_2O_2$관장군의 HbCO 포화도의 회복이 자연회복군이나 100%산소 흡입군보다 빨랐으며, 100%산소 흡입군은 회복기 30분에서 60분사이에 자연회복군보다 더 빠른 회복을 보였다. 이상의 결과에서 0.5% $H_2O_2$관장은 CO중독시 혈액의 산소분압을 어느정도 증가시킬 뿐 아니라 혈색소와 결합된 CO의 해리를 촉진시켜, 단독요법 또는 산소요법과 병행하여 사용할 때 급성CO중독에 효과적인 치료법이 될 수 있을 것으로 사료된다.