STUDIES OF SYNERGISTIC NEPHROTOXICOLOGICAL ALTERATIONS INDUCED BY CIPROFLOXACIN AND GENTAMICIN IN SPRAGUE-DAWLEY RATS : Sprague-Dawley 랫트에 있어서 Gentamicin과 Ciprofloxacin에 의한 상승적인 신장 독성학적 변화 연구

국문 초록 (Abstract)

Ciprofloxacin과 gentamicin은 임상에서 이용하는 광범위 항생제로 gentamicin은 신장 독성을 유발한다는 것은 이미 많이 보고되어 있으나 ciprofloxacin은 임상 사례 보고만이 보고되어 있다.
본 연구는 ciprofloxacin의 신장 독성을 알아보고 gentamicin과의 상승적인 신장독성을 유발하는지의 여부를 알아보기 위하여 먼저 ciprofloxacin을 치료 용량의 10배에서 최소 독성 용량까지 (50, 100, 250, 500mg/kg b.w.) 14일간 경구로 투여하였고, gentamicin과 ciprofloxacin의 상호작용을 알아보기 위하여 gentamicin (100mg/kg b.w.)을 10일간 근육주사후 ciprofloxacin을 14일간 투여하였으며 gentamicin과 ciprofloxacin을 같이 14일간 투여하여 랫트의 임상 증상 및 혈액 학적, 병리 조직학적 소견을 관찰하였다. Ciprofloxacin 단독 투여로 인한 독성 증상으로는 체중 증가율의 저하, 미약한 단백뇨, 혈중 요소치의 증가, 국소성 부종과 국소성 간질성 신염이 특히 500mg/kg b.w. 투여 군에서 관찰되었다. Gentamicin 투여후 ciprofloxacin투여로 인한 독성 증상으로는 체중 감소와 식욕 감퇴, 중등 도의 단백뇨, 혈중 요소치의 증가 (500mg/kg b.w.), 신장 세뇨관 상피 세포의 괴사와 재생, 국소성 간질성 신염과 그 염증으로 인한 세뇨관 상피의 위축이 관찰되었다 (250, 500mg/kg b.w.). Gentamicin과 ciprofloxacin 복합 투여로 인한 독성 중상으로는 체중 감소와 식욕 감퇴, 심한 단백뇨, 혈중요소치 및 크레아틴치의 증가, 심한 세뇨관 상피 세포의 괴사, 편평화, 상피 세포의 탈락과 중등도의 간질성 신염이 관찰되었다 (250, 500mg/kg b.w.). 부가적으로 백혈구 감소와 헤모글로빈치 저하도 관찰되었다 (500mg/kg b.w.).
이상의 결과로 볼 때 gentamicin과 ciprofloxacin 사이에 상승적인 신장 독성이 있는 것으로 사료된다.

다국어 초록 (Multilingual Abstract)

It has been reported that ciprofloxacin and gentamicin, one of broad spectrum antibiotics, were widespread acceptance to human patients and animals. The two drugs employed in this study have individually been demonstrated to be nephrotoxicity in experimental animals as well as in human patients. However most of ciprofloxacin-induced nephrotoxicity were observed from clinical cases.
To investigate synergistic nephrotoxicity of ciprofloxacin and gentamicin in rats, observation of clinical signs, hematological assays, and evaluation histopathological alterations in kidneys were performed. To find renal changes to ciprofloxacin, ciprofloxacin was administered orally to male Sprague-Dawley(SD) rats from ten times of the clinical recommended dosage to minimal toxic dosage for 14 days. To find synergistic effects on renal changes to gentamicin and ciprofloxacin, after gentamicin treatment (100mg/kg b.w.; IM) for 10 days, ciprofloxacin was administered orally to male SD rats from ten times of the clinical recommended dosage to minimal toxic dosage for 14 days. Combined treatment of ciprofloxacin (oral) and gentamicin (IM) was used for male SD rats at the same dosage for 2 weeks.
As a result of administration of ciprofloxacin alone daily weight gains decrease, mild proteinuria, and edema and focal interstitial nephritis with mild tubular epithelial cell degeneration were shown at 500 mg/kg/day. As a result of sequential administration of ciprofloxacin and gentamicin, decrease in body weight, moderate proteinuria, elevated BUN values, and edema and multifocal interstitial nephritis with atrophied tubular epithelial cell were shown at 250 and 500 mg/kg b.w. As a result of combined administration of ciprofloxacin and gentamicin, decrease in body weight, severe proteinuria, elevated BUN, CREA, and ALT values, edema and multifocal interstitial nephritis, and severe necrotic, flattened and desquamated tubular epithelial cell were observed at 250 and 500 mg/kg b.w. Additionally, this treatment shown leukopenia and decrease of hemoglobin(HGB) levels at 500mg/kg b.w. (p＜0.05).
A result of this study suggested that ciprofloxacin and gentamicin when given alone their sequential or combined treatment at 250 and 500mg/kg b.w. would induced mild synergistic nephrotoxicity.

목차 (Table of Contents)

• 목차 = ⅳ
• ABSTRACT = ⅰ
• 국문초록 = ⅲ
• LIST OF TABLES = ⅵ
• LIST OF FIGURES = ⅶ
• 1.0 INTRODUCTION = 1
• 2.0 LITERATURE REVIEW = 4
• 2.1 Fluoroquinolones = 4
• 2.1.1 History of Fluoroquinolones = 4
• 2.1.2 Chemical and Physical Property of Ciprofloxacin = 5
• 2.1.3 Pharmacological Characteristics of Ciprofloxacin = 6
• 2.1.4. Clinical Application of Ciprofloxacin = 7
• 2.1.5. Toxicities of Fluoroquinolones = 7
• 2.1.5.1. Nephrotoxicology of Ciprofloxacin = 9
• 2.2 Aminoglycosides = 11
• 2.2.1 History of Aminoglycosides = 11
• 2.2.2 Chemical and Physical Property of Gentamicin = 12
• 2.2.3 Pharmacological Characteristics of Gentamicin = 13
• 2.2.4 Clinical Application of Gentamicin = 14
• 2.2.5 Toxicities of Aminoglycosides = 15
• 2.2.5.1 Nephrotoxicology of Gentamicin = 16
• 3.0 PURPOSE AND OBJECTIVES = 18
• 4.0 MATERIALS AND METHODS = 19
• 4.1 Animals and Caire = 19
• 4.2 Chemicals and Administration = 19
• 4.3 Hematological Assay = 20
• 4.4 Urinalysis = 21
• 4.5 The Measurement of Body weight and Kidney weight = 21
• 4.6 Observations of Clinical Signs and Necropsy = 22
• 4.7 Statistical Analyses = 22
• 5.0 RESULT = 24
• 5.1 Clinical Observations = 24
• 5.2 Histopathological Alterations = 24
• 5.3 Histopathological Effects = 37
• 5.3.1 The Changes of Clinical Chemistry = 37
• 5.3.2 The Changes of Hematological Assay = 39
• 5.4 The Effects of Urinalysis = 41
• 5.5 The Effects on kidney weight relative to body weight (KBr) = 45
• 6.0 DlSCUSSION = 47
• 7.0 CONCLUSIONS = 56
• 8.0 LIST OF REFERENCES = 57