• 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.

• 한국임상수의학회지
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• 제29권3호
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• pp.233-236
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• 2012

Cefquinome은 제4세대 cephalosporin으로 동물전용의약품으로 개발되었으며, ${\beta}$-lactamases에 대해서 매우 안정하고, 그람 음성 세균 및 양성 세균에 대한 광범위한 살균력을 가지고 있다. 본 연구는 현재 시판중인 cefquinome 주사제를 이유 자돈에 2 mg/kg 용량으로 근육 주사한 후 약물동태학적 특성을 파악하여 두 제제의 생물학적 동등성을 평가하였다. Cefquinome의 혈중 농도는 액체크로마토그래프/질량분석기를 이용하여 분석하였으며, 생물학적 동등성을 판정하기 위한 약물동태학적 인자로는 혈중 최고 농도 ($C_{max}$)와 혈장 농도 곡선하 면적 ($AUC_{0{\rightarrow}{\infty}}$)을 사용하였다. 시험약과 대조약의 혈중 최고 농도는 $4.34{\pm}0.58{\mu}g/mL$과 $4.22{\pm}0.47{\mu}g/mL$로 각각 나타났으며, 혈장 농도 곡선 하 면적은 $10.43{\pm}1.96{\mu}g{\cdot}h/mL$과 $10.25{\pm}2.98{\mu}g{\cdot}h/mL$로 관찰되었다. 로그변환한 약물동태학적 인자의 평균비율의 90% 신뢰 구간은 $C_{max}$의 경우 0.941-1.115이었고, $AUC_{0{\rightarrow}{\infty}}$의 경우 0.927-1.172로서 생물학적 동등성 기준인 0.8-1.25를 모두 만족시켰다. 이상의 결과로 시판중인 두 cefquinome 제제는 생물학적으로 동등하다고 판단된다.

• 대한화장품학회지
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• 제39권3호
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• pp.241-249
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• 2013

2012년 1월에서 10월 사이에 전국에서 유통 중인 산화형 염모제(1제) 125개 제품에서 납(Pb), 비소(As), 카드뮴(Cd), 크롬(Cr), 망간(Mn), 니켈(Ni), 구리(Cu)의 농도 측정과 국산, 수입산 및 헤나별, 성상별, 색상별로 비교해 봄으로써 이에 관련된 분야의 기초자료를 제공하고자 본 연구를 시행하였다. 분석된 전체 염모제의 평균 중금속 농도는 납 0.211 ${\mu}g/g$, 비소 0.051 ${\mu}g/g$, 카드뮴 0.008 ${\mu}g/g$, 크롬 0.954 ${\mu}g/g$, 망간 6.250 ${\mu}g/g$, 니켈 0.591 ${\mu}g/g$, 구리 0.544 ${\mu}g/g$으로 측정되었으며 납, 비소의 경우 우리나라 화장품 안전기준 등에 관한 규정에서 허용기준인 납 20 ${\mu}g/g$, 비소 10 ${\mu}g/g$보다 낮은 수치이다(식품의약품안전처 고시 제2013-24 호). 또한 헤나 염모제는 통계적으로 유의한 차이를 보였으며(p < 0.05), 납 1.264 ${\mu}g/g$, 비소 0.267 ${\mu}g/g$, 카드뮴 0.025 ${\mu}g/g$, 크롬 4.055 ${\mu}g/g$, 망간 72.044 ${\mu}g/g$, 니켈 3.076 ${\mu}g/g$, 구리 4.640 ${\mu}g/g$으로 국산 및 수입 염모제보다 높았다. 염모제의 성상별 중금속 농도는 통계적으로 유의한 차이를 보였으며(p < 0.05), 크림과 액체 타입에서 크롬이 각각 0.708 ${\mu}g/g$, 0.478 ${\mu}g/g$로 가장 높았고, 분말타입에서는 망간이 60.041 ${\mu}g/g$로 높았다. 염모제의 색상별 중금속 농도는 통계적으로 유의한 차이를 보이지 않았으며, 노란색의 경우 납, 크롬이 높은 평균 농도를 보였고, 적색과 분홍색의 염모제는 크롬, 갈색과 흑색은 망간이, 녹색은 니켈이 높은 평균 농도를 나타내었다.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제33권5호
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• pp.426-436
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• 2007

Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.

• 한국식품위생안전성학회지
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• 제34권6호
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• pp.562-570
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• 2019

경기도에서 유통되고 있는 건조수산물 95건에 대하여 유해중금속인 납, 카드뮴, 수은 및 미량영양소인 셀레늄 함량을 조사하였다. 금아말감법의 수은분석기, 유도결합플라즈마 질량분석기를 사용하여 측정하였으며, 각 항목별 평균함량은 납 0.062±0.071(0.002-0.428) mg/kg[평균값±표준편차(최소값-최대값) mg/kg], 카드뮴 0.083±0.100(0.004-0.540) mg/kg, 수은 0.012±0.012(N.D-0.054) mg/kg, 셀레늄 0.839±0.371(0.362-2.124) mg/kg으로 나타났으며, 유해중금속인 납, 카드뮴, 수은 모두 기준규격 이하로 나타났다. 멸치 크기에 따른 중금속 및 셀레늄 함량은 수은이 대멸치에서 통계적으로 유의하게 높게 나타났으며(P<0.05), 셀레늄은 잔멸치와 대멸치의 크기에 따른 유의적인 함량 차이를 나타냈다(P<0.05). 새우 종류에 따른 중금속 및 셀레늄 함량을 비교한 결과 보리새우가 납, 카드뮴, 수은에서 유의적으로 높게 나타났다(P<0.05). 대멸치, 밴댕이의 부위별 중금속 및 셀레늄 함량은 내장부위가 가장 높았고, 새우는 머리부위가 중금속 및 셀레늄 함량이 높게 나타났다. 건조수산물을 통해 섭취하는 수은, 카드뮴의 주간 및 월간섭취량은 JECFA에서 설정한 PTW(M)I의 0.712%와 2.978%로 조사된 건조수산물 내 중금속 함량은 안전한 농도수준으로 판단된다.

• 한국식품영양과학회지
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• 제33권1호
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• pp.52-58
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• 2004

배추김치의 생리활성물질인 3-(4-hydroxyl-3',5'-dimethoxyphenyl)propionic acid의 고지혈증 치료효과를 살펴보기 위하여 고콜레스테롤 혈증을 유발시킨 토끼에게 1차 실험에서는 정상식이를 공급하고 2차 실험에서는 고콜레스테롤 식이를 공급하면서 각각 16일간 정맥으로 투여하여 혈장지질 농도 변화를 살펴보았고, 그 효과는 고지혈증 치료제로 사용되고 있는 Simvastatin과 비교하였다. 정상식이 공급시 Kimchi군 및 Simvastatin군에 의한 총콜레스테롤 감소는 대조군에 비해 18.65%와 29.67%이었고 고콜레스테롤 식이 공급시에는 각각 33.79%및 21.81%이었다. LDL-C의 저하현상은 정상식이 공급시에는 미미하게 관찰되었고, 고콜레스테롤 식이 공급시에는 Kimchi군 및 Simvastatin군에서 약 130%정도의 감소 효과가 관찰되었다. 중성지방의 감소효과는 정상식이시에는 거의 관찰되지 않았고, 고콜레스테롤 식이시에는 Kimchi군에서 약 105%, 그리고 Simvastatin군에서 약 62%정도의 감소가 관찰되었다. HDL-C의 변화는 모든 군에서 관찰되지 않았다. 고콜레스테롤 식이를 섭취한 토끼간의 HMG-CoA reductase 활성을 살펴보았을 때 Kimchi군 및 Simvastatin군의 활성이 48.44% 그리고 139.06% 증가하였다. 본 연구결과 Kimchi군은 고지혈증을 치료하는 효과가 있음이 관찰되었고, 그 효과는 Simvastatin군과 유사하였다. Kimchi군 및 Simvastatin군에서 관찰된 HMG-CoA reductase 활성의 증가는 지질저하 현상에 대한 보상 작용으로 생체 항상성 유지를 위한 현상으로 사료된다 3-(4-hydroxyl-3',5'-dimethoxyphenyl)propionic acid의 고지혈증 치료기전은 Simvastatin과 유사할 것으로 예상된다.